Y-Box-Binding Proteins Have a Dual Impact on Cellular Translation.

Y-box-binding proteins (YB proteins) are multifunctional DNA- and RNA-binding proteins that play an important role in the regulation of gene expression. The high homology of their cold shock domains and the similarity between their long, unstructured C-terminal domains suggest that Y-box-binding proteins may have similar functions in a cell. Here, we consider the functional interchangeability of the somatic YB proteins YB-1 and YB-3. RNA-seq and Ribo-seq are used to track changes in the mRNA abundance or mRNA translation in HEK293T cells solely expressing YB-1, YB-3, or neither of them. We show that YB proteins have a dual effect on translation. Although the expression of YB proteins stimulates global translation, YB-1 and YB-3 inhibit the translation of their direct CLIP-identified mRNA targets. The impact of YB-1 and YB-3 on the translation of their mRNA targets is similar, which suggests that they can substitute each other in inhibiting the translation of their mRNA targets in HEK293T cells.

Laparoscopic intracorporeal ileal ureter replacement: multi-institutional data from 102 patients.

OBJECTIVE: To present long-term results of our laparoscopic intracorporeal ileal ureter replacement (LIUR) cohort, including more complex cases of laparoscopic ileocalycostomy. MATERIAL AND METHODS: We collected records of patients undergoing LIUR. Follow-up included a chemical profile and urine cultures. Imaging consisted of renal ultrasonography, excretory urography, cystography, and computer tomographic or magnetic resonance urography. RESULTS: One hundred and two patients were included. Stricture location was left (46.1%), right (39.2%), or bilateral (14.7%). No open conversion was performed. Seventy-four patients (72.5%) underwent a total ureteral unit removal. The mean operative time was 289.4 (120 - 680) minutes. The estimated blood loss was 185.2 (10-400) mL. Three patients had intraoperative complications, and fifteen had early postoperative complications. The mean postoperative hospital stay was 12.2 (7-35) days. The mean follow-up duration period was 37.7 (12-162) months. Most patients' follow-up was uneventful (88%), and seven patients presented with Grade 2 late complications. CONCLUSIONS: Intracorporeal laparoscopic ileal ureteral replacement in cases of extensive ureteral lesions offers optimal long-term outcomes and a low complication rate. Ileocalycostomy constitutes a viable option in the small group of patients with long proximal ureteral strictures and intrarenal pelvis.

Regulation of autophagy of the heart in ischemia and reperfusion.

Ischemia/reperfusion (I/R) of the heart leads to increased autophagic flux. Preconditioning stimulates autophagic flux by AMPK and PI3-kinase activation and mTOR inhibition. The cardioprotective effect of postconditioning is associated with activation of autophagy and increased activity of NO-synthase and AMPK. Oxidative stress stimulates autophagy in the heart during I/R. Superoxide radicals generated by NADPH-oxidase acts as a trigger for autophagy, possibly due to AMPK activation. There is reason to believe that AMPK, GSK-3ß, PINK1, JNK, hexokinase II, MEK, PKCα, and ERK kinases stimulate autophagy, while mTOR, PKCδ, Akt, and PI3-kinase can inhibit autophagy in the heart during I/R. However, there is evidence that PI3-kinase could stimulate autophagy in ischemic preconditioning of the heart. It was found that transcription factors FoxO1, FoxO3, NF-κB, HIF-1α, TFEB, and Nrf-2 enhance autophagy in the heart in I/R. Transcriptional factors STAT1, STAT3, and p53 inhibit autophagy in I/R. MicroRNAs could stimulate and inhibit autophagy in the heart in I/R. Long noncoding RNAs regulate the viability and autophagy of cardiomyocytes in hypoxia/reoxygenation (H/R). Nitric oxide (NO) donors and endogenous NO could activate autophagy of cardiomyocytes. Activation of heme oxygenase-1 promotes cardiomyocyte tolerance to H/R and enhances autophagy. Hydrogen sulfide increases cardiac tolerance to I/R and inhibits apoptosis and autophagy via mTOR and PI3-kinase activation.

The value of cardiac sympathetic activity and mechanical dyssynchrony as cardiac resynchronization therapy response predictors: comparison between patients with ischemic and non-ischemic heart failure.

BACKGROUND: Impaired cardiac sympathetic activity and mechanical dyssynchrony (MD) are associated with poor prognosis in patients with heart failure (HF) after cardiac resynchronization therapy (CRT). The study aims to assess the significance of scintigraphic evaluation of cardiac sympathetic innervation and contractility in predicting response to CRT in patients with ischemic and non-ischemic chronic HF. METHODS AND RESULTS: The study includes 58 HF patients, who were referred for CRT. Prior to CRT all patients underwent 123I-metaiodobenzylguanidine (123I-MIBG) imaging and gated myocardial perfusion imaging (MPI) using a cadmium-zinc-telluride (CZT) SPECT/CT device. At a one-year follow-up post-CRT, the delayed heart-to-mediastinum 123I-MIBG uptake ratio was an independent predictor of CRT response in non-ischemic HF patients (OR 1.469; 95% CI 1.076-2.007, p = .003). In ischemic HF patients the MD index histogram bandwidth (HBW) obtained by CZT-gated MPI had a predictive value (OR 1.06, 95% CI 1.001-1.112, p = .005) to CRT response. CONCLUSION: CRT response can be predicted by cardiac 123I-MIBG scintigraphy, specifically by the heart-to-mediastinum ratio in non-ischemic HF and by the MD index HBW in ischemic HF. These results suggest the value of a potentially useful algorithm to improve outcomes in HF patients who are candidates for CRT.

Effect of Chitosan on Rheological, Mechanical, and Adhesive Properties of Pectin-Calcium Gel.

In the present study, chitosan was included in the pectin ionotropic gel to improve its mechanical and bioadhesive properties. Pectin-chitosan gels P-Ch0, P-Ch1, P-Ch2, and P-Ch3 of chitosan weight fractions of 0.00, 0.25, 0.50, and 0.75 were prepared and characterized by dynamic rheological tests, penetration tests, and serosal adhesion ex vivo assays. The storage modulus (G') and loss modulus (G″) values, gel hardness, and elasticity of P-Ch1 were significantly higher than those of P-Ch0 gel. However, a further increase in the content of chitosan in the gel significantly reduced these parameters. The inclusion of chitosan into the pectin gel led to a decrease in weight and an increase in hardness during incubation in Hanks' solution at pH 5.0, 7.4, and 8.0. The adhesion of P-Ch1 and P-Ch2 to rat intestinal serosa ex vivo was 1.3 and 1.7 times stronger, whereas that of P-Ch3 was similar to that of a P-Ch0 gel. Pre-incubation in Hanks' solution at pH 5.0 and 7.4 reduced the adhesivity of gels; however, the adhesivity of P-Ch1 and P-Ch2 exceeded that of P-Ch0 and P-Ch3. Thus, serosal adhesion combined with higher mechanical stability in a wide pH range appeared to be advantages of the inclusion of chitosan into pectin gel.

Serosal Adhesion Ex Vivo of Hydrogels Prepared from Apple Pectin Cross-Linked with Fe3+ Ions.

The study aims to investigate the adhesion of a hydrogel made of cross-linked low-methyl esterified pectin to rat intestinal serosa ex vivo. The adhesivity of the FeP hydrogel, which was cross-linked by Fe3+ cations, exceeded that of hydrogels cross-linked by Ca2+, Zn2+, and Al3+ cations. The concentration of the cross-linking cation failed to influence the adhesion of the pectin hydrogel to the serosa. The mechanical properties and surface microrelief of the pectin hydrogel were influenced by the type and concentration of the cross-linking cations. Fe3+ cations form a harder and more elastic gel than Ca2+ cations. Scanning electron microscopy analysis revealed the characteristic surface pattern of FeP hydrogel and its denser internal structure compared to Ca2+ cross-linked hydrogel. The effect of the salt composition of the adhesion medium was shown since the FeP hydrogel's adhesion to the serosa was lower in physiological solutions than in water, and adhesion in Hanks' solution was higher than in phosphate buffered saline. Serum proteins and peritoneal leukocytes did not interfere with the serosal adhesion of the FeP hydrogel. Pre-incubation in Hanks' solution for 24 h significantly reduced the adhesion of the FeP hydrogel to the serosa, regardless of the pH of the incubation. Thus, serosal adhesion combined with excellent stability and mechanical properties in physiological environments appeared to be advantages of the FeP hydrogel, demonstrating it to be a promising bioadhesive for tissue engineering.

The regulation of necroptosis and perspectives for the development of new drugs preventing ischemic/reperfusion of cardiac injury.

In the last 10 years, mortality from acute myocardial infarction (AMI) has not significantly decreased. This situation is associated with the absence in clinical practice of highly effective drugs capable of preventing the occurrence of reperfusion injury of the heart. Necroptosis inhibitors may become prototypes for the creation of highly effective drugs that increase cardiac tolerance to ischemic/reperfusion (I/R) and reduce the mortality rate in patients with AMI. Necroptosis is involved in I/R cardiac injury and inhibition of RIPK1 or RIPK3 contributes to an increase in cardiac tolerance to I/R. Necroptosis could also be involved in the development of adverse remodeling of the heart. It is unclear whether pre- and postconditioning could inhibit necroptosis of cardiomyocytes and endothelial cells. The role of necroptosis in coronary microvascular obstruction and the no-reflow phenomenon also needs to be studied. MicroRNAs and LncRNAs can regulate necroptotic cell death. Ca2+ overload and reactive oxygen species could be the triggers of necroptosis. Activation of kinases (p38, JNK1, Akt, and mTOR) could promote necroptotic cell death. The interaction of necroptosis, apoptosis, autophagy, ferroptosis, and pyroptosis is discussed. The water-soluble necroptosis inhibitors may be highly effective drugs for treatment of AMI or stroke. It is possible that microRNAs may become the basis for creating drugs for treatment of diseases triggered by I/R of organs.

Prediction of appropriate ICD therapy in patients with ischemic heart failure.

BACKGROUND: Previous studies show inconsistent results on the role of innervation imaging (with I-123-mIBG) and perfusion imaging in predicting appropriate ICD therapy (aICDth). These studies included patients with both dilated and ischemic cardiomyopathy. This study compared the ability of 123I-mIBG imaging along with perfusion imaging (using thallium-199) to predict aICDth in patients with ischemic heart failure (IHF) in relation to indication for ICD implantation (primary vs. secondary prevention of sudden cardiac death (SCD)). METHODS: mIBG/thallium SPECT imaging were performed before ICD implantation in 80 patients with IHF: 49 candidates for primary and 31 for secondary SCD prevention. RESULTS: During a mean follow-up of 18 months, the imaging results could not predict patients with appropriate ICD therapy among patients with ICD implants for primary SCD prevention. While in the secondary SCD prevention group, those who received a ICDth had significantly larger summed scores of regional perfusion and innervation impairment, but not higher heart-to-mediastinal mIBG ratio. The best results to predict aICDth were using mIBG summed score (cut-off point > 34%, sensitivity 72%, specificity 100%, AUC 0.909, P < 0.0001). CONCLUSION: The prognostic value of innervation and perfusion imaging in patients with IHF differ based on indication for ICD implantation (primary vs. secondary prevention of SCD).

Ventricular tachycardia incidence and erythrocyte membranes ß-adrenoreactivity in patients with implanted cardioverter-defibrillator.

BACKGROUND: In patients with high risk of ventricular tachycardia (VT) the proven beneficial therapy is the implantable cardioverter defibrillator (ICD). It has been shown that the coronary artery disease (CAD) and VT development are accompanied by a persistent change of the sympathoadrenal system activity. This leads to a decrease in the total density of the erythrocyte membrane ß-adrenergic receptors. The purpose of this study was to identify the relationship of the erythrocyte membranes ß-adrenoreactivity (EMA) with VT development in patients with CAD and ICD. METHOD: Sixty-three patients (male - 53, age - 66.6 ± 9.2 years) with CAD and ICD were included to the study. EMA was studied using a method for assessing erythrocyte osmoresistance increase as a result of ß-adrenergic receptors blockade by a selective ß-adrenergic blocker. VT and ventricular fibrillation (VF) events recorded by ICD were evaluated. RESULTS: The 1st group consist of 23 patients with VT/VF events recorded by ICD during 27.0 [14.0; 53.0] months follow-up period. EMA indicator in this group was 41.54% [27.15; 51.26]. The 2nd group consist of 40 patients without VT/VF events and the same indicator was significantly higher - 55.42% [35.67; 62.33] (p = .04). The ROC-analysis (AUC = 0.657; Sen = 78.26; Spe = 55.00; p = .031) and binary logistic regression (OR = 0.9679; 95% CI: 0.9384-0.9983; p = .038) showed that EMA indicator 51.26% or lower was the independent predictor of VT events. CONCLUSIONS: In patients with CAD and ICD erythrocyte membranes ß-adrenoreactivity indicator 51.26% or lower is the predictor of VT episodes.

A secret of salivary secretions: Multimodal effect of saliva in sensory perception of food.

Saliva plays multifunctional roles in oral cavity. Even though its importance for the maintenance of oral health has long been established, the role of saliva in food perception has attracted increasing attention in recent years. We encourage researchers to discover the peculiarity of this biological fluid and aim to combine the data concerning all aspects of the saliva influence on the sensory perception of food. This review presents saliva as a unique material, which modulates food perception due to constant presence of saliva in the mouth and thanks to its composition. Therefore, we highlight the salivary components that contribute to these effects. Moreover, this review is an attempt to structure the effects of saliva on perception of different food categories, where the mechanisms of salivary impact in perception of liquid, semi-solid, and solid foods are revealed. Finally, we emphasize that the large inter-individual variability in salivary composition and secretion appear to contribute to the fact that everyone experiences food in their own way. Therefore, the design of the sensory studies should consider the properties of volunteers' saliva and also carefully monitor the experimental conditions that affect salivary composition and flow rate.

Characterization and Biocompatibility Properties In Vitro of Gel Beads Based on the Pectin and κ-Carrageenan.

This study aimed to investigate the influence of kappa (κ)-carrageenan on the initial stages of the foreign body response against pectin gel. Pectin-carrageenan (P-Car) gel beads were prepared from the apple pectin and κ-carrageenan using gelling with calcium ions. The inclusion of 0.5% κ-carrageenan (Car0.5) in the 1.5 (P1.5) and 2% pectin (P2) gel formulations decreased the gel strength by 2.5 times. Car0.5 was found to increase the swelling of P2 gel beads in the cell culture medium. P2 gel beads adsorbed 30-42 mg/g of bovine serum albumin (BSA) depending on pH. P2-Car0.2, P2-Car0.5, and P1.5-Car0.5 beads reduced BSA adsorption by 3.1, 5.2, and 4.0 times compared to P2 beads, respectively, at pH 7. The P1.5-Car0.5 beads activated complement and induced the haemolysis less than gel beads of pure pectin. Moreover, P1.5-Car0.5 gel beads allowed less adhesion of mouse peritoneal macrophages, TNF-α production, and NF-κB activation than the pure pectin gel beads. There were no differences in TLR4 and ICAM-1 levels in macrophages treated with P and P-Car gel beads. P2-Car0.5 hydrogel demonstrated lower adhesion to serous membrane than P2 hydrogel. Thus, the data obtained indicate that the inclusion of κ-carrageenan in the apple pectin gel improves its biocompatibility.

Swelling, Protein Adsorption, and Biocompatibility In Vitro of Gel Beads Prepared from Pectin of Hogweed Heracleum sosnówskyi Manden in Comparison with Gel Beads from Apple Pectin.

The study aims to develop gel beads with improved functional properties and biocompatibility from hogweed (HS) pectin. HS4 and AP4 gel beads were prepared from the HS pectin and apple pectin (AP) using gelling with calcium ions. HS4 and AP4 gel beads swelled in PBS in dependence on pH. The swelling degree of HS4 and AP4 gel beads was 191 and 136%, respectively, in PBS at pH 7.4. The hardness of HS4 and AP4 gel beads reduced 8.2 and 60 times, respectively, compared with the initial value after 24 h incubation. Both pectin gel beads swelled less in Hanks' solution than in PBS and swelled less in Hanks' solution containing peritoneal macrophages than in cell-free Hanks' solution. Serum protein adsorption by HS4 and AP4 gel beads was 118 ± 44 and 196 ± 68 µg/cm2 after 24 h of incubation. Both pectin gel beads demonstrated low rates of hemolysis and complement activation. However, HS4 gel beads inhibited the LPS-stimulated secretion of TNF-α and the expression of TLR4 and NF-κB by macrophages, whereas AP4 gel beads stimulated the inflammatory response of macrophages. HS4 gel beads adsorbed 1.3 times more LPS and adhered to 1.6 times more macrophages than AP4 gel beads. Thus, HS pectin gel has advantages over AP gel concerning swelling behavior, protein adsorption, and biocompatibility.

Effect of Cross-Linking Cations on In Vitro Biocompatibility of Apple Pectin Gel Beads.

The study aimed to compare the in vitro biocompatibility of pectin gels formed by different cross-linking cations. Hydrogel beads named CaPG, ZnPG, FePG, and AlPG were prepared from 4% solutions of apple pectin using ionotropic gelling with CaCl2, ZnCl2, FeCl3, and AlCl3, respectively. Cations influenced the gel strength of the wet gel beads in the following order (least strong) Ca2+ < Zn2+ < Fe3+~Al3+ (most strong). The swelling degree of the CaPG beads after 24 h of incubation in the RPMI-1640 medium was 104%, whereas the ZnPG, FePG, and AlPG beads swelled by 76, 108, and 134%, respectively. The strength of the pectin gel decreased significantly after incubation in the RPMI-1640 medium for 24 h, regardless of the cross-linking cation, although the FePG beads remained the strongest. All the pectin beads adsorbed serum proteins to a low degree, however the serum protein adsorption by the ZnPG and FePG beads (1.46 ± 0.87 and 1.35 ± 0.19 µg/mm2) was more than the CaPG and AlPG beads (0.31 ± 0.36 and 0.44 ± 0.25 µg/mm2). All the pectin beads reduced the production of TNF-α and IL-10 by hPBMCs in response to LPS stimulation. The IL-1ß response of cells to LPS was significantly reduced by the CaPG, ZnPG, and FePG beads, whereas the AlPG beads enhanced it twofold. The CaPG, FePG, and AlPG beads had no cytotoxicity. The viability of hPBMCs and human fibroblasts incubated with ZnPG beads was 5.3 and 7.2%, respectively. Thus, the use of different cross-linking cations changed the properties of the pectin gel, which is important for biocompatibility.

Polysaccharides of Salsola passerina: Extraction, Structural Characterization and Antioxidant Activity.

The above-ground part of the Salsola passerine was found to contain ~13% (w/w) of polysaccharides extractable with water and aqueous solutions of ammonium oxalate and sodium carbonate. The fractions extracted with aqueous sodium carbonate solutions had the highest yield. The polysaccharides of majority fractions are characterized by similar monosaccharide composition; namely, galacturonic acid and arabinose residues are the principal components of their carbohydrate chains. The present study focused on the determination of antioxidant activity of the extracted polysaccharide fractions and elucidation of the structure of polysaccharides using nuclear magnetic resonance (NMR) spectroscopy. Homogalacturonan (HG), consisting of 1,4-linked residues of α-D-galactopyranosyluronic acid (GalpA), rhamnogalacturonan-I (RG-I), which contains a diglycosyl repeating unit with a strictly alternating sequence of 1,4-linked D-GalpA and 1,2-linked L-rhamnopyranose (Rhap) residues in the backbone, and arabinan, were identified as the structural units of the obtained polysaccharides. HMBC spectra showed that arabinan consisted of alternating regions formed by 3,5-substituted and 1,5-linked arabinofuranose residues, but there was no alternation of these residues in the arabinan structure. Polysaccharide fractions scavenged the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical at 0.2-1.8 mg/mL. The correlation analysis showed that the DPPH scavenging activity of polysaccharide fractions was associated with the content of phenolic compounds (PCs).

Association between food addiction and time perspective during COVID-19 isolation.

PURPOSE: The concept of time perspective (TP) implies that a mental focus on past, present, or future affect a person makes decisions and take action. Inability to plan their life for a sufficiently long time perspective due to the COVID-19 pandemic appeared to have a pronounced impact on a human's lifestyle influencing their thoughts, feelings, and behaviors, including eating behavior. This study tested two hypotheses: (a) that during COVID-19 isolation, the incidence rate of food addiction is increased, and (b) people with present TP are more likely exhibited signs of food addiction (FA). METHODS: The final study sample included 949 people, mean age 21.8 ± 7.8 years (range: 17-71 years, women: 78.3%). Each participant indicated their personal data and completed Yale Food Addiction Scale and the Zimbardo Time Perspective Inventory. RESULTS: There was an increased incidence rate of FA (OR = 1.678, 95% CI = 1.324, 2.148, p = 0.000) during COVID-19 isolation. Individuals with balanced, future, and past positive TP were less likely to exhibit symptoms of FA. Persons with past negative, and present hedonistic TP were more likely to exhibit signs of FA. CONCLUSION: There was an increased incidence rate of FA during COVID-19 isolation. Persons with shortened time horizon are more likely to exhibit symptoms of FA. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.

Laparoscopic totally intracorporeal ileal ureter replacement: a multi-institutional study.

OBJECTIVE: To prove the feasibility, as well as the reproducibility of laparoscopic totally intracorporeal ileal ureter replacement (LIUR), by presenting a multicenter patient cohort with a long follow-up. MATERIAL AND METHODS: Records of patients undergoing different types of ureteral replacements have been collected. Follow-up included a chemical profile and urine cultures. Imaging consisted of renal ultrasonography and excretory urography, as well as a cystography or an isotopic renography when indicated. RESULTS: Forty patients were included in the study. Twelve underwent a right, 20 a left, and eight a bilateral laparoscopic ureteral replacement. The mean procedure time was 335 (150-680) minutes and the mean estimated blood loss was 221 (50-400) mL. Only three patients presented intraoperative complications, which were managed immediately, and three patients presented a Clavien III postoperative complication. Abdominal drains and nephrostomy tubes were removed after 24-36 h and 7-10 days, respectively. The mean hospital stay was 13.5 (10-35) days. Follow-up was at least six months. CONCLUSIONS: LIUR constitutes a feasible and reproducible method for the restoration of long ureteral defects.

PECULIARITIES OF THYROID STATUS OF PRESCHOOL CHILDREN WITH ACUTE BRONCHITIS.

OBJECTIVE: The aim: The aim of this study was to determine the characteristics of thyroid status (thyroid hormone, total and free fractions of triiodothyronine and thyroxine, reversible triiodothyronine, antibodies to thyroperoxidase) of preschool children with acute bronchitis. PATIENTS AND METHODS: Materials and methods: We examined 135 preschool children (from 3 to 6 years old) with acute bronchitis (main group) and 28 apparently healthy subjects who were in the control group. It used clinical-anamnestic, laboratory and instrumental research methods. Evaluation of the course of acute bronchitis was carried out in the acute period of the disease. All results were statistically processed using the SPSS 26 package. RESULTS: Results: In 33 % of patients with acute bronchitis there are subclinical abnormalities of thyroid hormones, which manifest themselves in the form of euthyroid sick syndrome. Namely, we found an increased concentration of reversible triiodothyronine in the serum, as well as a decrease in total triiodothyronine and its free fraction. CONCLUSION: Conclusions: In patients with acute bronchitis in almost every third case there are functional shifts in hormonal status, which are manifested in the form of the first variant of the euthyroid sick syndrome.

Catheter ablation or medical therapy to delay progression of atrial fibrillation: the randomized controlled atrial fibrillation progression trial (ATTEST).

AIMS: Delay of progression from paroxysmal to persistent atrial fibrillation (AF) is an important measure of long-term success of AF treatment. However, published data on the impact of catheter ablation on AF progression are limited. This study evaluates whether radiofrequency (RF) catheter ablation delays the progression of AF compared with antiarrhythmic drug (AAD) treatment using current AF management guidelines. METHODS: This prospective, randomized, controlled, two-arm, open-label trial was conducted at 29 hospitals and medical centres across 13 countries. Patients were randomized 1 : 1 to RF ablation or AAD treatment. The primary endpoint was the rate of persistent AF/atrial tachycardia (AT) at 3 years. RESULTS: After early study termination following slow enrolment, 255 (79%) of the planned 322 patients were enrolled (RF ablation, n = 128, AAD, n = 127); 36% of patients in the RF ablation group and 41% in the AAD group completed 3 years of follow-up. For the primary endpoint, the Kaplan-Meier estimate of the rate of persistent AF/AT at 3 years was significantly lower with RF ablation [2.4% (95% confidence interval (CI), 0.6-9.4%)] than with AAD therapy [17.5% (95% CI, 10.7-27.9%); one-sided P = 0.0009]. Patients ≥65 years were ∼4 times more likely to progress to persistent AF/AT than patients <65 years, suggesting RF ablation can delay disease progression [hazard ratio: 3.87 (95% CI, 0.88-17.00); P = 0.0727]. Primary adverse events were reported for eight patients in the RF ablation group. CONCLUSIONS: Radiofrequency ablation is superior to guideline-directed AAD therapy in delaying the progression from paroxysmal to persistent AF.

Design and linkage optimization of ursane-thalidomide-based PROTACs and identification of their targeted-degradation properties to MDM2 protein.

Ursolic acid (UA) is an accessible triterpenoid, widely applied in the design and synthesis of antitumor compounds. However, the mechanism of its anti-tumor effect is still unclear. To verify the molecular mechanism of its biological activity, based on the bifunctional activity of ubiquitination and subsequent proteasomal degradation of the target protein of the proteolysis-targeting chimeras (PROTACs) strategy, here we report the design, synthesis and cellular activity of six UA PROTAC hydrochloride compounds 1A-1F, in which UA acts as the binding ligand of the PROTAC and is linked to thalidomide (E3 ligand) through a series of synthetic linkers. The results revealed that compound 1B, connected with a POE-3 (3-Polyoxyether) possessed remarkable in vitro antitumor activity (with the IC50 value of 0.23 ~ 0.39 µM against A549, Huh7, HepG2). WB results demonstrated that the administration of compound 1B induced significant degradation of MDM2 (only 25% to that of SM1), and promoted the expression of P21 and PUMA proteins, and thus inhibited the proliferation (77.67% of 1B vs 60.37% of CON in G1 phase) and promoted the apoptosis (26.74% of 1B vs 3.35% of CON) of A549 cells. This work demonstrated proof of designing the efficient target protein degradation by UA PROTACs with the POE linkers. In addition, we confirmed that UA possess the characteristic of targeted-binding the protein of murine double minute-2 protein (MDM2). This will lay a foundation for the comprehensive utilization of forest natural compound UA.

Food addiction and weight in students with high academic performance.

OBJECTIVE: The purpose of this study was to analyse the relationships between food addiction (FA), anthropometric characteristics and academic performance. DESIGN: The average age (sd) of the participants was 17·5 (sd 2·7) years (64·1 % female). Each study participant indicated their sex, height, weight and academic performance and completed the Yale Food Addiction Scale. SETTING: Syktyvkar, Kirov, Tyumen, Yekaterinburg, Russia; Aizawl, India. PARTICIPANTS: The study involved 3426 people. RESULTS: FA was found in 8·7 % of participants from Russia and 14·6 % from India. In schoolchildren but not in university students, high academic performance was associated with a higher incidence rate of FA detection (OR = 1·16, 95 % CI 1·07, 1·26) and a lower BMI (OR = 0·72, 95 % CI 0·56, 0·94). CONCLUSIONS: These data showed an increased incidence rate of FA detection in adolescents with high academic performance.