Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors ...is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure‐based design of PPI inhibitors through stabilizing or mimicking turns, β‐sheets, and helices.
A matter of class: Inhibitors of protein–protein interactions can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to yield molecules that are generally referred to as peptidomimetics. This Review highlights these approaches and introduces a new classification for peptidomimetics that enables a clear assignment of available approaches.
The automated comparison of protein-ligand binding sites provides useful insights into yet unexplored site similarities. Various stages of computational and chemical biology research can benefit from ...this knowledge. The search for putative off-targets and the establishment of polypharmacological effects by comparing binding sites led to promising results for numerous projects. Although many cavity comparison methods are available, a comprehensive analysis to guide the choice of a tool for a specific application is wanting. Moreover, the broad variety of binding site modeling approaches, comparison algorithms, and scoring metrics impedes this choice. Herein, we aim to elucidate strengths and weaknesses of binding site comparison methodologies. A detailed benchmark study is the only possibility to rationalize the selection of appropriate tools for different scenarios. Specific evaluation data sets were developed to shed light on multiple aspects of binding site comparison. An assembly of all applied benchmark sets (ProSPECCTs-Protein Site Pairs for the Evaluation of Cavity Comparison Tools) is made available for the evaluation and optimization of further and still emerging methods. The results indicate the importance of such analyses to facilitate the choice of a methodology that complies with the requirements of a specific scientific challenge.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Climate change is likely to alter the geographic distribution of ticks and their host species, and the human populations at risk 3. Blood-borne virus screening was negative, as was serology for EBV, ...CMV, hepatitis A and hepatitis E. Toxoplasma IgG testing was positive, but IgM negative. Admission Bloods Haemoglobin 140 g/L Platelet count 85 × 109/L White cell count 6.7 × 109/L Lymphocyte count 0.37 × 109/L Eosinophil count 0.00 × 109/L Creatinine 121 μmol/L Urea 9.1 mmol/L Sodium 133 mmol/L Potassium 3.9 mmol/L eGFR 51 ml/min Bilirubin 10 μmol/L ALT 108 U/L ALP 227 U/L Albumin 30 g/L Glucose 7.4 mmol/L CRP 93 mg/L Table 1 Selected blood results from tests performed on presentation to hospital in Scotland.
Objectives
The aim of this study was to compare the diagnostic accuracy of salivary pepsin with oropharyngeal pH monitoring using the Restech measurement system (Dx‐pH) for the diagnosis of ...laryngopharyngeal reflux (LPR).
Study Design
Prospective cohort study.
Methods
Seventy patients with primary symptoms related to LPR underwent gastroscopy, high‐resolution manometry, pH throughout 24‐hour monitoring (MII‐pH), and barium esophagography between October 2015 and May 2018. In addition, an ear, nose, and throat examination was performed, including assessment of Belafsky Reflux Finding Score (RFS). Clinical symptoms were evaluated with the Belafsky Reflux Symptom Index (RSI) and the Gastrointestinal Quality of Life Index (GIQLI). Simultaneous to MII‐pH, pepsin determination and Dx‐pH were performed.
Results
Of 70 patients, 41 (58.6%) subjects with a pathological DeMeester score showed higher mean values of pepsin (mean value: 216 ng/mL, 95% confidence interval CI: 172 to 260), compared to patients with a normal DeMeester score (mean value: 161 ng/mL, 95% CI: 115 to 207). Salivary pepsin showed a specificity of 86.2% and sensitivity of 41.5% for diagnosing LPR using the optimal cutoff value of 216 ng/mL. Furthermore, a significant correlation between the values of salivary pepsin and the RSI score was seen in patients with pathological results in MII‐pH (r = 0.344; P = 0.046).
However, elevated Dx‐pH measurements showed no significant correlation with either MII‐pH, RSI score, RFS score, or GIQLI score, or with the results of pepsin measurement.
Conclusion
Pepsin measurement in saliva could be an alternative tool to assist office‐based diagnosis of LPR, whereas Dx‐pH does not seem to be an adequate test.
Level of Evidence
2B Laryngoscope, 130:1780–1786, 2020
Investigations focusing on the temperature sensitivity of microbial activity and nutrient turnover in soils improve our understanding of potential effects of global warming. This study investigates ...the temperature sensitivity of C mineralization, N mineralization, and potential enzyme activities involved in the C and N cycle (tyrosine amino‐peptidase, leucine amino‐peptidase, ß‐glucosidase, ß‐xylosidase, N‐acetyl‐ß‐glucosaminidase). Four different study sites in the Austrian alpine zone were selected, and soils were sampled in three seasons (summer, autumn, and winter). A simple first‐order exponential equation was used to calculate constant Q10 values for the C and N mineralization over the investigated temperature range (0–30°C). The Q10 values of the C mineralization (average 2.0) for all study sites were significantly higher than for the N mineralization (average 1.7). The Q10 values of both activities were significantly negatively related to a soil organic matter quality index calculated by the ratios of respiration to the organic soil carbon and mineralized N to the total soil nitrogen. The chemical soil properties or microbial biomass did not affect the Q10 values of C and N mineralization. Moreover, the Q10 values showed no distinct pattern according to sampling date, indicating that the substrate quality and other factors are more important. Using a flexible model function, the analysis of relative temperature sensitivity (RTS) showed that the temperature sensitivity of activities increased with decreasing temperature. The C and N mineralization and potential amino‐peptidase activities (tyrosine and leucine) showed an almost constant temperature dependence over 0–30°C. In contrast, ß‐glucosidase, ß‐xylosidase, and N‐acetyl‐ß‐glucosaminidase showed a distinctive increase in temperature sensitivity with decreasing temperature. Low temperature at the winter sampling date caused a greater increase in the RTS of all microbial activities than for the autumn and summer sampling dates. Our results indicate (1) a disproportion of the RTS for potential enzyme activities of the C and N cycle and (2) a disproportion of the RTS for easily degradable C compounds (ß‐glucose, ß‐xylose) compared with the C mineralization of soil organic matter. Thus temperature may play an important role in regulating the decay of different soil organic matter fractions due to differences in the relative temperature sensitivities of enzyme activities.
Although ion channels are crucial in many physiological processes and constitute an important class of drug targets, much is still unclear about their function and possible malfunctions that lead to ...diseases. In recent years, computational methods have evolved into important and invaluable approaches for studying ion channels and their functions. This is mainly due to their demanding mechanism of action where a static picture of an ion channel structure is often insufficient to fully understand the underlying mechanism. Therefore, the use of computational methods is as important as chemical-biological based experimental methods for a better understanding of ion channels. This review provides an overview on a variety of computational methods and software specific to the field of ion-channels. Artificial intelligence (or more precisely machine learning) approaches are applied for the sequence-based prediction of ion channel family, or topology of the transmembrane region. In case sufficient data on ion channel modulators is available, these methods can also be applied for quantitative structureactivity relationship (QSAR) analysis. Molecular dynamics (MD) simulations combined with computational molecular design methods such as docking can be used for analysing the function of ion channels including ion conductance, different conformational states, binding sites and ligand interactions, and the influence of mutations on their function. In the absence of a three-dimensional protein structure, homology modelling can be applied to create a model of your ion channel structure of interest. Besides highlighting a wide range of successful applications, we will also provide a basic introduction to the most important computational methods and discuss best practices to get a rough idea of possible applications and risks.
AIM:To investigate the comparative effect of laparoscopic and open cholecystectomy in elderly patients.METHODS:Laparoscopic cholecystectomy has induced a revolution in the treatment of gallbladder ...disease.Nevertheless,surgeons have been reluctant to implement the concepts of minimally invasive surgery in older patients.A systematic review of Medline was embarked on,up to June 2013.Studies which provided outcome data on patients aged 65 years or older,subjected to laparoscopic or open cholecystectomy were considered.Mortality,morbidity,cardiac and pulmonary complications were the outcome measures of treatment effect.The methodological quality of selected studies was appraised using valid assessment tools.Τhe random-effects model was applied to synthesize outcome data.RESULTS:Out of a total of 337 records,thirteen articles(2 randomized and 11 observational studies)reporting on the outcome of 101559 patients(48195in the laparoscopic and 53364 in the open treatment group,respectively)were identified.Odds ratios(OR)were constantly in favor of laparoscopic surgery,in terms of mortality(1.0%vs 4.4%,OR=0.24,95%CI:0.17-0.35,P<0.00001),morbidity(11.5%vs 21.3%,OR=0.44,95%CI:0.33-0.59,P<0.00001),cardiac(0.6%vs 1.2%,OR=0.55,95%CI:0.38-0.80,P=0.002)and respiratory complications(2.8%vs 5.0%,OR=0.55,95%CI:0.51-0.60,P<0.00001).Critical analysis of solid study data,demonstrated a trend towards improved outcomes for the laparoscopic concept,when adjusted for age and co-morbid diseases.CONCLUSION:Further high-quality evidence is necessary to draw definite conclusions,although bestavailable evidence supports the selective use of laparoscopy in this patient population.
Abstract Background Single-incision laparoscopic appendectomy has emerged as a less invasive alternative to conventional laparoscopic surgery. High-quality relevant evidence is limited. Methods A ...systematic review of electronic information sources was undertaken, with the objective of identifying randomized trials that compared single-incision with conventional laparoscopic appendectomy. Outcome measures included 30-day morbidity, abdominal abscess, wound infection, open conversion, reoperation, operative time, length of hospital stay, and postoperative pain. Fixed-effects and random-effects models were used to calculate combined overall effect sizes of pooled data. Data are presented as odds ratios or weighted mean differences with 95% confidence intervals (CIs). Results Five randomized trials were identified, with a total of 746 patients. Thirty-day morbidity (9.6% vs 8.6%; odds ratio, 1.14; 95% CI, .69 to 1.89) and wound infection rates were similar between single-incision and conventional laparoscopy (4.0% vs 4.8%; odds ratio, .83; 95% CI, .41 to 1.68), whereas the duration of surgery was longer in the single-incision group (46.3 vs 40.7 minutes; weighted mean difference, 6.01; 95% CI, 2.26 to 9.76). Available data were not adequately robust to reach conclusions regarding the remaining outcome measures. Conclusions Similar postoperative morbidity and wound infection rates for single-incision and conventional laparoscopic appendectomy are supported by the current literature, but single-incision surgery requires longer operative time.
Background
Previous studies suggest clinical effectiveness of endoscopic full-thickness plication in selected patients with gastroesophageal reflux disease (GERD). The aim of this study was to assess ...the clinical safety and efficiency of the GERDx™ device by evaluating clinical parameters, reflux symptom scores, and quality of life (QoL).
Methods
Prospective one-arm trial evaluating the outcome of forty patients with GERD subjected to endoscopic plication with the GERDx™ device. We included patients with at least one typical reflux symptom despite treatment with a PPI for > 6 months, pathologic esophageal acid exposure, hiatal hernia of size < 2 cm, and endoscopic Hill grade II–III. Evaluation of Gastrointestinal Quality of Life Index (GIQLI), symptom scores, esophageal manometry, and impedance-pH-monitoring were performed at baseline and at 3 months after surgery. (Trial Registration: ClinicalTrials.gov NCT 01798212.)
Results
There were no intraoperative complications. Four out of forty patients experienced postoperative complications requiring intervention. Seven of forty patients were subjected to laparoscopic fundoplication 3 months after endoscopic plication due to persistent symptoms and were lost to further follow-up. Thirty out of forty patients were available at 3-month follow-up. There was an improvement of the GIQLI score, from a mean of 92.45 ± 18.47 to 112.03 ± 13.11 (
p
< 0.001). The general reflux-specific score increased from a mean of 49.84 ± 24.83 to 23.93 ± 15.63 (
p
< 0.001), and the DeMeester score from a mean of 46.48 ± 30.83 to 20.03 ± 23.62 (
p
< 0.001). There was no significant change in manometric data after intervention. Three of thirty patients continued daily antireflux medication.
Conclusions
Endoscopic plication with the GERDx™ device reduced distal acid exposure of the esophagus, reflux-related symptoms, and improved GIQLI scores with minimal side effects in a selected cohort of patients and may be a safe alternative in the treatment of GERD.
Transcription-activator-like effector (TALE) proteins consist of concatenated repeats that recognize consecutive canonical nucleobases of DNA via the major groove in a programmable fashion. Since ...this groove displays unique chemical information for the four human epigenetic cytosine nucleobases, TALE repeats with epigenetic selectivity can be engineered, with potential to establish receptors for the programmable decoding of all human nucleobases. TALE repeats recognize nucleobases via key amino acids in a structurally conserved loop whose backbone is positioned very close to the cytosine 5-carbon. This complicates the engineering of selectivities for large 5-substituents. To interrogate a more promising structural space, we engineered size-reduced repeat loops, performed saturation mutagenesis of key positions, and screened a total of 200 repeat-nucleobase interactions for new selectivities. This provided insight into the structural requirements of TALE repeats for affinity and selectivity, revealed repeats with improved or relaxed selectivity, and resulted in the first selective sensor of 5-carboxylcytosine.
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