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Rupture of abdominal aortic aneurysms (AAAs) is one of the leading causes of sudden death in the elderly population. The osteogenic transcription factor runt-related gene (RUNX) encodes multifunctional mediators of intracellular signal transduction pathways in vascular remodeling and inflammation. We aimed to evaluate the roles of RUNX2 and its putative downstream target miR-424/322 in the modulation of several AAA progression-related key molecules, such as matrix metalloproteinases and vascular endothelial growth factor. In the GEO database, we found that male patients with AAAs had higher RUNX2 expression than did control patients. Several risk factors for aneurysm induced the overexpression of MMPs through RUNX2 transactivation, and this was dependent on Smad2/3 upregulation in human aortic smooth muscle cells. miR-424 was overexpressed through RUNX2 after angiotensin II (AngII) challenge. The administration of siRUNX2 and miR-424 mimics attenuated the activation of the Smad/RUNX2 axis and the overexpression of several AAA progression-related molecules in vitro. Compared to their littermates, miR-322 KO mice were susceptible to AngII-induced AAA, whereas the silencing of RUNX2 and the administration of exogenous miR-322 mimics ameliorated the AngII-induced AAA in ApoE KO mice. Overall, we established the roles of the Smad/RUNX2/miR-424/322 axis in AAA pathogenesis. We demonstrated the therapeutic potentials of miR-424/322 mimics and RUNX2 inhibitor for AAA progression., Graphical abstract, Microcalcification and degeneration of the elastic lamina are common pathological features of AAAs. The osteogenic transcription factor RUNX2 encodes multifunctional mediators in vascular remodeling and inflammation. Tsai et al. established the roles of Smad2/3/RUNX2/miR-424/322 axis in AAA and demonstrated the therapeutic potentials of miR-424/322 mimics and RUNX2 inhibitor for AAA progression.

Subclinical hypertrophic cardiomyopathy (HCM) is a phenotypic entity that has emerged from the increased use of cardiovascular magnetic resonance imaging in the evaluation and family screening of patients with HCM. We describe the case of a competitive athlete with a sarcomere gene mutation and family history of HCM who was found to exhibit the subclinical HCM phenotype on cardiovascular magnetic resonance imaging in the absence of left ventricular hypertrophy. We discuss the clinical uncertainties in her management. (Level of Difficulty: Advanced.), Central Illustration

Malonyl-CoA is an energy-rich molecule formed by the ATP-dependent carboxylation of acetyl coenzyme A catalyzed by acetyl-CoA carboxylase. This molecule is an important precursor for many biotechnologically interesting compounds such as flavonoids, polyketides, and fatty acids. The yeast Saccharomyces cerevisiae remains one of the preferred cell factories, but has a limited capacity to produce malonyl-CoA compared to oleaginous organisms. We developed a new S. cerevisiae strain with a conditional allele of ACC1, the essential acetyl-CoA carboxylase (ACC) gene, as a tool to test heterologous genes for complementation. Yarrowia lipolytica is an oleaginous yeast with a higher capacity for lipid production than S. cerevisiae, possibly due to a higher capacity to produce malonyl-CoA. Measuring relative intracellular malonyl-CoA levels with an in-vivo biosensor confirmed that expression of Y. lipolytica ACC in S. cerevisiae leads to a higher accumulation of malonyl-CoA compared with overexpression of the native gene from an otherwise identical vector. The higher accumulation was generally accompanied by a decreased growth rate. Concomitant expression of both the homologous and heterologous ACC1 genes eliminated the growth defect, with a marginal reduction of malonyl-CoA accumulation., This work was supported by the Fundação para a Ciência e Tecnologia Portugal (FCT) through Project FatVal POCI-01-0145-FEDER-032506; CBMA was supported by the strategic program UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569) and CEB by UIDB/04469/2020 funded by national funds through the FCTI.P. and by the ERDF through the COMPETE2020 - Programa Operacional Competitividade e Internacionalizacão (POCI). Humberto Pereira acknowledges FCT for the PhD scholarship, SFRH/BD/148722/2019. We thank Professors Jin Hou, Xiaoming Bao and colleagues for sending us the malonyl-CoA sensor, info:eu-repo/semantics/publishedVersion

In this paper, we prepared a self-crosslinking amino-functional graphene oxide/styrene acrylic hybrid emulsion (AGO/SA). The styrene acrylic emulsion (SA) was synthesized with acetoacetoxyethyl methacrylate (AAEM) by semicontinuous seeded emulsion polymerization. Then, amino-functionalized graphene oxide (AGO) was prepared via the modification of graphene oxide (GO) with 3-aminopropyltriethoxysilane (APTES) and reacted with the SA emulsion as a crosslinking agent by in situ polymerization. Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), X-ray diffraction (XRD), thermal gravity analysis (TGA), and transmission electron microscopy (TEM) were applied to explore the chemical structures and morphologies of the samples. The anti-corrosion performance of the AGO/SA coatings was evaluated by Tafel polarization and electrochemical impedance spectroscopy (EIS). Along with the crosslink between AGO and SA, the micropores in the matrix were reduced, the coating expressed improved corrosion resistance due to the graphene barrier, and the hybrid emulsion with 0.7 wt.% AGO exhibited the best anti-corrosion properties. These results indicate that AGO can act as both a crosslinking agent and an anti-corrosion agent in self-crosslinking hybrid emulsions, which have great potential in the field of environmentally friendly emulsions.

Filopodia, a finger-like structure and actin-rich plasma-membrane protrusion at the leading edge of the cell, has important roles in cell motility. However, the mechanisms of filopodia generation are not well-understood via the actin-related protein 2/3 (ARP2/3) complex in Non-Small Cell Lung Cancer (NSCLC) cells. We previously have demonstrated that PRR11 associates with the ARP2/3 complex to regulate cytoskeleton-nucleoskeleton assembly and chromatin remodeling. In this study, we further demonstrate that PRR11 involves in filopodia formation, focal adhesion turnover and cell motility through ARP2/3 complex. Cell phenotype assays revealed that the silencing of PRR11 increased cellular size and inhibited cell motility in NSCLC cells. Mechanistically, PRR11 recruited and co-localized with Arp2 at the membrane protrusion to promote filopodia formation but not lamellipodia formation. Notably, PRR11 mutant deletion of the proline-rich region 2 (amino acid residues 185–200) abrogated the effect of filopodia formation. In addition, PRR11-depletion inhibited filopodial actin filaments assembly and increased the level of active integrin β1 in the cell surface, whereas reduced the phosphorylation level of focal adhesion kinase (FAKY397) to repress focal adhesion turnover and cell motility in NSCLC cells. Taken together, our findings indicate that PRR11 has critical roles in controlling filopodia formation, focal adhesion turnover and cell motility by recruiting ARP2/3 complex, thus dysregualted expression of PRR11 potentially facilitates tumor metastasis in NSCLC cells.

Studying bacterial cell envelope architecture with electron microscopy is challenging due to the poor preservation of microbial ultrastructure with traditional methods. Here, we established and validated a super-resolution cryo-correlative light and electron microscopy (cryo-CLEM) method, and combined it with cryo-focused ion beam (cryo-FIB) milling and scanning electron microscopy (SEM) volume imaging to structurally characterize the bacterium Deinococcus radiodurans. Subsequent cryo-electron tomography (cryo-ET) revealed an unusual diderm cell envelope architecture with a thick layer of peptidoglycan (PG) between the inner and outer membranes, an additional periplasmic layer, and a proteinaceous surface S-layer. Cells grew in tetrads, and division septa were formed by invagination of the inner membrane (IM), followed by a thick layer of PG. Cytoskeletal filaments, FtsA and FtsZ, were observed at the leading edges of constricting septa. Numerous macromolecular complexes were found associated with the cytoplasmic side of the IM. Altogether, our study revealed several unique ultrastructural features of D. radiodurans cells, opening new lines of investigation into the physiology and evolution of the bacterium.

Objectives The purpose of this study was (i) to investigate whether nanocomposite poly(methyl-methacrylate)-zinc oxide nanowires (PMMA-ZnO-NWs) have C. albicans antibiofilm activity; (ii) to evaluate the interaction between components of the nanocomposites based on PMMA-ZnO-NWs by Raman spectroscopy; and (iii) to assess ultrastructural alterations. Design Sixty-eight rectangles (17 PMMA (control) and 51 PMMA–ZnO-NWs (250, 500, 1000 ppm ZnO nanowires) were fabricated. C. albicans ATCC 10231 and a C. albicans clinical strain were tested. Adherence, biofilm formation and ultrastructural alterations were assessed by transmission electron microscopy. Raman mapping images and spectra were analyzed using main component analysis. Results Nanocomposite PMMA-ZnO-NWs inhibited the formation of C. albicans biofilms 94% at 1000 ppm and 80% at 500 ppm against both C. albicans strains. PMMA-ZnO-NWs induced ultrastructural alterations, including cell wall damage and disorganization of the cytoplasmic membrane, resulting in cell lysis. Raman spectroscopy showed new vibrational modes (300–365–485–600 cm−1) for PMMA and ZnO-NW interactions. Conclusions PMMA-ZnO-NWs inhibited C. albicans dose-dependent biofilm formation and led to changes in the structures and cell membrane. Raman spectroscopy showed chemical interactions between ZnO-NWs and PMMA, as suggested by the appearance of new bands at 301 and 485 cm−1.

A man affected by hereditary hemorrhagic telangiectasia who had chronic severe hypoxemia is presented. This hypoxemia was synergistically caused by high-output heart failure due to severe hepatic shunts and multiple pulmonary arteriovenous shunts. The symptomatic combination is rare, and genetic testing showed a novel endoglin mutation. (Level of Difficulty: Advanced.), Central Illustration

Background Barbed suture has become popular for closure of the arthrotomy and overlying tissues in total knee arthroplasty. STRATAFIX Symmetric PDS Knotless Tissue Control Device, a unique and novel barbed suture, with barbs formed integral to the suture core provides greater suture strength than the more common cut barbed suture designs. It is the only barbed suture commercially available with an indication in high tension areas, such as fascia. The purpose of this study was to evaluate the use of this novel barbed suture in the formation of a water-tight arthrotomy closure, using a continuous suture pattern, compared to conventional Coated VICRYL (polyglactin 910) Suture, using an interrupted suture pattern, in a cadaveric knee arthrotomy. Methods Twenty fresh-frozen cadaver knees underwent randomization to provide donor-paired matching of the knee arthrotomy closures using barbed suture in a continuous pattern or conventional suture in an interrupted pattern. Each specimen underwent 5 phases of testing that included 1) predynamic static leak testing; 2) dynamic motion leak testing; 3) postdynamic static leak testing; 4) suture release static leak testing; and 5) postsuture release dynamic motion leak testing, to assess the fluid leak rate. Results Under the initial static conditions, watertightness was similar for the 2 types of sutures. However, in all subsequent phases of testing, continuous barbed suture created a better watertight closure than interrupted conventional suture. Conclusions In this study, it was observed that closure of a knee arthrotomy using the novel barbed suture provided improved watertightness compared to conventional interrupted closure under dynamic conditions and suture release.

Pressure-sensitive adhesives (PSAs) are used in various industries, and have been widely applied in smart devices. In this study, the adhesion properties, viscoelastic properties, and gel fraction of PSAs were investigated after primary and secondary curing to understand their UV-curing behavior. In addition, the impact of concentration of crosslinking agent on the crosslinking density and the degree of crosslinking was investigated. In general, as more crosslinking agent was added, the hardness increased, but this result can be explained by the difference between “crosslinking density” and “degree of crosslinking” at the highest concentration of crosslinking agent actually led to a decrease in “degree of crosslinking”.

Background The aim of the present study was to fabricate double layered scaffolds of electrospun polycaprolactone (PCL) and poly(ethylene oxide) (PEO). The electrospun PCL fibers were functionalized with wintergreen oil (WO) as a novel approach to prevent vascular grafts failure due to thrombosis by adjusting biomaterial–blood interactions. Methods PCL tubular scaffolds were prepared by electrospinning approach and coated with PEO as a hydrophilic polymer. The single and double layered scaffolds were characterized in terms of their morphological, chemical properties -as well as-hemocompatibility assays (i.e. prothrombin time, hemolysis percentage and platelets adhesion). Moreover, the antioxidant potential of WO-PCL samples were measured by 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) free radical assay. Results The results demonstrated that incorporation of WO during the electrospinning process decreased the PCL fiber diameter. In addition, the prothrombine time assay shows that WO could be used to lower the electrospun PCL fiber tendency to induce blood clotting. Moreover, SEM observations of platelets adhesion of both single and double layered PCL/PEO scaffolds fiber shows an increase of platelets number, compared with the scaffolds containing WO. Conclusions The antioxidant potential and blood compatibility measurements of WO-PCL/PEO samples highlight the approach made so far as an ideal synthetic small size vascular grafts to overcome autogenous grafts shortages and drawbacks.

This study aimed to investigate the effects of volume ratio in the continuous phase and the dispersed phase (CP/DP) and stirring speed on yield, water absorption, particle size, morphology surface, and cumulative release of nitrogen from the chitosan microsphere. The chitosan microsphere preparation method was emulsion cross-linking with glutaraldehyde saturated toluene (GST) as the cross-linking agent. Urea was mixed with chitosan solution and put into the oil. It was then stirred to form an emulsion. Glutaraldehyde saturated toluene (GST) was added slowly, followed by 2 ml glutaraldehyde, stirred continuously for 2 h. The formed chitosan microsphere was eventually washed and dried to be analyzed. The yield obtained was about 87.01%-96.71%, the water absorption was 79.77%–89.25%, and the diameter size of chitosan microspheres was from 153.66 ± 26.35 μm to 179.39 ± 34.95 μm. The chitosan microspheres morphology were good sphericity even though there were irregular size. Cumulative release analysis was obtained from 32.38%–37.69% by release mechanism such as anomalous behavior (non-Fickian kinetics)

Preprocedural planning and postprocedural evaluation after transcatheter treatment of severe tricuspid regurgitation remain challenging and require further research and standardization. We illustrate the use of multimodality imaging techniques in 3 patients undergoing implantation of a novel custom-made bicaval valved stent for symptomatic treatment of severe tricuspid regurgitation. (Level of Difficulty: Advanced.), Central Illustration

Background New treatments for transthyretin amyloidosis improve survival, but diagnosis remains challenging. Pathogenic or likely pathogenic (P/LP) variants in the transthyretin (TTR) gene are one cause of transthyretin amyloidosis, and genomic screening has been proposed to identify at-risk individuals. However, data on disease features and penetrance are lacking to inform the utility of such population-based genomic screening for TTR. Objectives This study characterized the prevalence of P/LP variants in TTR identified through exome sequencing and the burden of associated disease from electronic health records for individuals with these variants from a large (N = 134,753), primarily European-ancestry cohort. Methods We compared frequencies of common disease features and cardiac imaging findings between individuals with and without P/LP TTR variants. Results We identified 157 of 134,753 (0.12%) individuals with P/LP TTR variants (43% male, median age 52 [Q1-Q3: 37–61] years). Seven P/LP variants accounted for all observations, the majority being V122I (p.V142I; 113, 0.08%). Approximately 60% (n = 91) of individuals with P/LP TTR variants (all V122I) had African ancestry. Diagnoses of amyloidosis were limited (2 of 157 patients), although related heart disease diagnoses, including cardiomyopathy and heart failure, were significantly increased in individuals with P/LP TTR variants who were aged >60 years. Fourteen percent (7 of 49) of individuals aged ≥60 or older with a P/LP TTR variant had heart disease and ventricular septal thickness >1.2 cm, only one of whom was diagnosed with amyloidosis. Conclusions Individuals with P/LP TTR variants identified by genomic screening have increased odds of heart disease after age 60 years, although amyloidosis is likely underdiagnosed without knowledge of the genetic variant., Central Illustration

The selection of pretreatment conditions has important meaning for the high-value utilization of lignocellulose. This study explored the influence of different acid-deep eutectic solvent (DES) systems on the extraction of lignin. It was found that the lignin samples extracted with ChCl (Choline chloride)-formic acid (FDES) had a greater degree of damage, and they had a lower molecular weight (Mw 10%) and the structure was less damaged, but with increasing reaction time, the polymerization effect of lignin became more obvious. This research is meaningful for exploring the process of acid DES separation of lignin and the green transformation of biomass.

Hypertrophic cardiomyopathy (HCM) is the primary cause of sudden cardiac death in children and adolescents. Patients with HCM frequently have ventricular tachycardia and ventricular fibrillation, although complete atrioventricular block (CAVB) is very rare. We report a case of HCM with CAVB in an 8-year-old girl who underwent transvenous implantable cardioverter-defibrillator placement after resuscitation. In this patient, we identified a de novo heterozygous missense variant, Arg406Trp (c.1216C > T), in the desmin (DES) gene. Pathogenic variants in the DES gene result in cardiomyopathy, conduction disorders, and skeletal muscle weakness. This recently identified variant may cause HCM with CAVB. Résumé: La cardiomyopathie hypertrophique (CMH) est la première cause de mort subite d'origine cardiaque chez les enfants et les adolescents. Les patients atteints de CMH présentent fréquemment une tachycardie ventriculaire et une fibrillation ventriculaire, bien que le bloc auriculo-ventriculaire complet (BAVC) soit très rare. Nous rapportons un cas de CMH avec BAVC chez une fillette de 8 ans qui a reçu un défibrillateur cardioverteur implantable par voie transveineuse après réanimation. Chez cette patiente, nous avons isolé un variant faux sens hétérozygote de novo, Arg406Trp (c.1216C > T), dans le gène de la desmine (DES). Les variants pathogènes du gène DES entraînent une cardiomyopathie, des troubles de la conduction et une faiblesse des muscles squelettiques. Ce variant récemment identifié peut causer une CMH avec BAVC.

High-performance conductive hydrogels are desired for the development of flexible wearable sensors. However, it remains a challenge to simultaneously realize high stretchable, freezing tolerance, and attractive conductivity through a simple approach. In this work, we present stretchable, water retention, anti-freezing, and conductive hemicellulose/polypyrrole (H/PPY) composite hydrogels for application in epidermal strain sensors via freezing-thawing method. The composite hydrogels were obtained using hemicellulose as a hydrophilic carrier and polypyrrole as a conductive matrix. The freezing and thawing temperatures of the hydrogels decreased and the conductivity increased benefiting from the introduction of glycerol and NaCl. The hydrogels had good mechanical properties, remodeling ability and water retention after storage for 7 days. In addition, the strain sensors assembled by hydrogels accurately monitored the signals of human motions with good strain sensing durability. It is expected that the as-prepared hydrogels have the potential to be applied in the fields of wearable devices.

This study focused on improving plasma-electrolytic oxidation (PEO) technology of aluminum alloys with the aim to increase their abrasive wear resistance. Using thermodynamic calculations of the reactions between hydrogen and aluminum oxides in solid, liquid and gaseous states, it is established that hydrogen (while in the channels of microplasma discharges) can promote recovery of aluminum oxides, especially non-stoichiometric composition. Consequently, this reduces an interaction between oxygen and aluminum and slows down the synthesis of PEO coatings. The synthesis of PEO layers was carried out in a weakly alkaline electrolyte with the addition of hydrogen peroxide or by blowing it with ozone. To obtain layers with better properties, we optimized the ratio between the cathodic and anodic currents densities. Our tests demonstrated that both the thickness and the abrasive wear resistance of the oxide layers increase at higher rates when hydrogen peroxide is added to the electrolyte, as compared with the use of ozone blowing. The proposed ways to improve the PEO technology made it possible to increase the synthesis rate of PEO layers by factor of 1.8 … 2, provide the optimal phase composition of PEO layers and increase their abrasive wear resistance by factor of 6.

This study investigates the feasibility and effect of poly(lactic) acid (PLA) on bitumen modification. The chemical and physical properties were evaluated for the modified bitumen produced with varying percentages of PLA ranging from 3 to 9%. Several testings such as the nuclear magnetic resonance (NMR), Fourier Transform Infrared Spectroscopy (FTIR), Gel permeation chromatography (GPC), penetration, softening and ductility, and thermal storage stability were evaluated. The results show that chemical interaction exists between PLA and bitumen. The GPC analysis indicates high compatibility of the bitumen with the PLA modifier. Moreover, the results indicated that the addition of PLA increased the consistency of modified bitumen. The storage stability and segregation of phases were positively affected in the PLA modified bitumen. The PLA and base bitumen interact at physical and chemical levels which results in enhancement of performance of modified bitumen to produce a high-quality binding material for pavement construction.

The surgical intervention to treat isolated severe tricuspid regurgitation (TR) is challenging due to the severe TR patients’ high-risk profile, hence associated with a high complication rate. Herein, we describe a first-in-human percutaneous deployment of a novel transcatheter prosthetic xenograft valve to treat severe TR. (Level of Difficulty: Advanced.), Central Illustration

Highlights • Chronic severe AR progresses slowly with a long asymptomatic compensated phase. • Stress echocardiography (SE) has the ability to uncover subclinical LV dysfunction. • SE can identify patients with severe AR who may benefit from earlier intervention., Graphical abstract

Double-bundle posterior cruciate ligament (PCL) reconstruction has long been attempted to obtain better clinical results than single-bundle PCL reconstruction. In most previous reports regarding double-bundle PCL reconstruction, one tibial tunnel and various kinds of grafts were used. We introduce a two-tibial tunnel, double-bundle PCL reconstruction technique with ultra-strong grafts. The critical points of this technique are proper creation of the tibial tunnels and the protection of the posterior neurovascular structures. Our clinical experience indicates this technique can lead to satisfactory stable outcomes. We believe that this technique will provide a reasonable choice for PCL reconstruction without remnant preservation., Technique Video Video 1 Four-tunnel, double-bundle anatomical posterior cruciate ligament reconstruction without remnant preservation is performed in the following steps: 1. This procedure is performed in the left knee. The arthroscope is inserted through the anterolateral (AL) portal to the posteromedial (PM) compartment, and the PM portal is created. 2. The arthroscope is inserted into the PM compartment through the PM portal and then passed through the posterior septum to the posterolateral (PL) compartment. The PL portal is created. A shaver is inserted into the posterior septum through the PL portal. Part of the posterior septum is removed to connect the posterior compartments. The PCL remnant at the tibial insertion is removed to leave a 2-3-mm stump. 3. The arthroscope is inserted through the AL portal, and a PCL tibial tunnel locator is inserted through the anteromedial (AM) portal to the posterior compartments. The arthroscope is inserted into the PM compartment through the PM portal. The PCL tibial tunnel locator is set at the AL part of the PCL tibial attachment site. A K wire is drilled in from the medial edge of the tibial tubercle. The tibial tunnel locator is set at the PM part of the PCL tibial insertion site. Another K wire is drilled in paralleling the former K wire. 4. The arthroscope is inserted through the AL portal; the locations of the femoral tunnels are marked with a radiofrequency probe. The arthroscope is inserted through the AM portal, and the femoral tunnels are created. 5. The arthroscope is inserted through the PM portal. A switching stick is inserted through the PL portal to elevate the posterior capsule from the PCL tibial insertion to increase the buffer space for the drilling. The tibial tunnels are created with corresponding cannulated drills over the K wires. One guide suture loop is passed through each tibial tunnel into the posterior compartments and pulled to the anterior compartment. 6. An incision is made over the medial femoral epicondyle. The arthroscope is inserted through the AM portal, the proximal ends of the guide suture loops are passed through the corresponding femoral tunnels, with a suture loop tailing a guide pin, out of the medial incision. 7. With the guide suture loop, the fixing sutures on the proximal end of the PM-bundle graft are pulled through the tibial tunnel into the joint and through the femoral tunnel out. A switching stick is inserted through the PM portal to the anterior inferior side of the fixing sutures at the inner orifice of the tibial tunnel. With constant pulling of the fixing sutures, the graft is moved into the posterior compartments and pulled to the femoral tunnel with repeated maneuvers. 8. The arthroscope is inserted through the AL portal. The PM-bundle graft is pulled into the femoral tunnel. The proximal fixing sutures are attached to a cortical fixation button. 9. The arthroscope is inserted through the PM portal. A switching stick is inserted through the PL portal to the anterior inferior side of the guide suture loop for the AL-bundle graft at the inner orifice of the tibial tunnel. With the guide suture loop, the fixing sutures on the proximal end of the AL-bundle graft are pulled through the tibial tunnel into the joint and through the femoral tunnel out. 10. The AL-bundle graft is pulled through the tibial tunnel into the femoral tunnel and affixed to a cortical fixation button.

Left ventricular assist devices (LVADs) are surgically implanted mechanical devices indicated for patients with advanced heart failure and are known to come with several complications. Here we present a case series, and review 1 documented report, of LVAD vasculitis, a presumed new LVAD immune/humoral related phenomenon. (Level of Difficulty: Advanced.), Central Illustration

The dislocation density in strain-hardened Alloy 690 was analyzed using scanning transmission electron microscopy (STEM) to study the relationship between the local plastic strain and susceptibility to primary water stress corrosion cracking (PWSCC) in nuclear power plants. The test material was cold-rolled at various thickness reduction ratios from 10% to 40% to simulate the strain-hardening condition of plant components. The dislocation densities were measured at grain boundaries (GB) and in grain interiors of strain-hardened specimens from STEM images. The dislocation density in the grain interior monotonically increased as the strain-hardening proceeded, while the dislocation density at the GB increased with strain-hardening up to 20% but slightly decreases upon further deformation to 40%. The decreased dislocation density at the GB was attributed to the formation of deformation twins. After the PWSCC growth test of strain-hardened Alloy 690, the fraction of intergranular (IG) fracture was obtained from fractography. In contrast to the change in the dislocation density with strain-hardening, the fraction of IG fracture increased remarkably when strain-hardened over 20%. From the results, it was suggested that the PWSCC growth behavior of strain-hardened Alloy 690 not only depends on the dislocation density, but also on the microstructural defects at the GB.

Cardiac Troponin I (cTnI) is a subunit of the thin filament involved in regulation of heart contraction. Mutated cTnI accounts for most genetic mutations associated with restrictive cardiomyopathy (RCM). We previously found phosphodiesterase 4D (PDE4D) decreased in RCM mice with cTnIR193H mutation and the mutant cTnI might be involved in PDE4D reduction. This study aims to elucidate a novel role of cTnIR193H mutant as a gene regulator. Overexpression of cTnIR193H mutant in cardiomyocytes showed decrease in PDED4D protein expression, while the enrichment of histone deacetylase 1 (HDAC1) was increased along with decreases in acetylated lysine 4 (acH3K4) and 9 (acH3K9) levels in the PDE4D promoter. HDAC1 overexpression could also downregulate PDE4D via reducing acH3K4 and acH3K9 levels. Co-IP assays showed that cTnIR193H mutant owed increased binding ability to HDAC1 compared with wild type cTnI. EGCG as a HDAC1 inhibitor could diminish the strength of cTnIR193H-HDAC1 interactions and alleviate the reduction in PDE4D expression. Together, our data indicated that cTnIR193H mutant could repress PDE4D expression in cardiomyocytes through HDAC1 associated histone deacetylation modification. Unlike the typical function of cTnI in cytoplasm, our study suggested a novel role of cTnI mutants in nuclei in regulating gene expression.

An increasing proportion of patients with atrial fibrillation are undergoing implantation with hypoglossal nerve stimulators for the treatment of obstructive sleep apnea. We present a case of hypoglossal nerve stimulator–associated neurapraxia following electrical cardioversion of atrial fibrillation. (Level of Difficulty: Advanced.), Central Illustration

Chondroitin sulfate-mediated albumin corona nanoparticles were readily prepared without any chemical reaction, and their active tumor targeting and therapeutic effects were examined. Negatively charged chondroitin sulfate (CS) and positively charged doxorubicin (DOX) self-assembled into nanoparticles (CS-DOX-NPs) via electrostatic interactions. Bovine serum albumin (BSA) was then adsorbed on the surface of CS-DOX-NPs to form albumin corona nanoparticles (BC-DOX-NPs) protected from endogenous proteins. Due to the dual effect of BSA and CS, BC-DOX-NPs interacted with the gp60, SPARC and CD44 receptors on tumor cells, facilitating their rapid and efficient transcytosis and improving their accumulation and uptake within tumor tissues. The simultaneous presence of BSA and CS also allowed BC-DOX-NPs to target CD44 efficiently, leading to greater cellular uptake and cytotoxicity against 4T1 cells than CS-DOX-NPs or free DOX. Intravenous injection of BC-DOX-NPs into orthotopic 4T1 tumor-bearing mice led to greater drug accumulation at the tumor site than with CS-DOX-NPs or free DOX, resulting in significant inhibition of tumor growth and lower exposure of major organs to the drug., Graphical abstract Albumin corona can enhance the anti-tumor effect of chondroitin sulfate-mediated nanoparticles through BSA-gp60-SPARC pathway, which helps nanoparticles pass through the vascular endothelial barrier faster and accumulate more in tumor tissues.Image, graphical abstract

Background Previous reports have shown that pathogen-associated patterns (PAMPs) induce the production of interleukin (IL)-1β in macrophages. Moreover, studies using mouse models also suggest that chitin, which acts as a PAMP, induces adjuvant effects and eosinophilic infiltration in the lung. Thus, we investigated the effects of inhaled chitin in mouse models. Methods We developed mouse models of inhaled chitin particle-induced airway inflammation and steroid-resistant ovalbumin (OVA)-induced airway inflammation. Some experimental groups of mice were treated additionally with dexamethasone (DEX). Murine alveolar macrophages (AMs), which were purified from bronchoalveolar lavage (BAL) fluids, were incubated with chitin, and treated with or without DEX. Results The numbers of total cells, AMs, lymphocytes, eosinophils, and neutrophils among BAL-derived cells, as well as the IL-1β levels in BAL fluids and the numbers of IL-1β-positive cells in lung, were significantly increased by chitin stimulation. Airway hyperresponsiveness (AHR) was aggravated in mice of the chitin inflammation model compared to control animals. The production of IL-1β was significantly increased in murine AMs by chitin treatment, but DEX administration did not inhibit this chitin-induced IL-1β production. Furthermore, in mouse models, DEX treatment inhibited the OVA-induced airway inflammation and AHR but not the airway inflammation and AHR induced by chitin or the combination of OVA and chitin. Conclusions These results suggest that inhaled chitin induces airway inflammation, AHR, and the production of IL-1β. Furthermore, our findings demonstrate for the first time that inhaled chitin induces steroid-resistant airway inflammation and AHR. Inhaled chitin may contribute to features of steroid-resistant asthma.

Prolonged B-cell depletion due to anti-CD20 monoclonal antibody (mAbs) therapy impairs the adaptive immune response, causing severe manifestations during COronaVIrus Disease-2019 (COVID-19). The cases of two patients under anti-CD20 therapy who experienced prolonged and severe COVID-19 successfully treated with mAbs against Severe Acute Respiratory Syndrome-CoV-2 spike proteins are reported.

Carotenoids play important roles in living organisms. However, animals cannot synthesize carotenoids by themselves, and they must absorb and accumulate carotenoids from their diets in which some key genes are involved. In present study, a gene named StAR-like-3 was characterized in the noble scallop Chlamys nobilis, and its function was identified using golden scallops with higher carotenoids content and brown scallops with less carotenoids content by immunohistochemistry, carotenoid binding assay and RNAi. Results showed that the StAR-like-3 encodes a 54.7 kDa transmembrane protein (named as StAR3) of 481 amino acids containing a MENTAL domain and a START (Steroidogenic acute regulatory protein-related lipid transfer) domain, and its expression level in hemocytes and intestine of golden scallops were significantly higher than those of brown ones. Subsequently, the StAR3 protein was detected in the intestinal epithelial cells of golden scallops, and recombinant StAR3 could bind lutein conjugated to protein G and antibody to form a yellow complex, suggesting it is a carotenoid binding protein involving in carotenoids accumulation in golden scallops. Furthermore, total carotenoids content of hemolymph in golden scallops was significantly decreased when the expression of StAR-like-3 suppressed, suggesting this gene plays an important role in transport of carotenoids. Conclusion, the present results indicated that the StAR-like-3 is a key gene responsible for the carotenoids accumulation in the scallop.

The ubiquitin ligase Nedd4-1 plays key roles in organ development, tissue homeostasis and cancer, but its functions in the skin are largely unknown. Here we show perturbations in keratinocyte proliferation and terminal differentiation, epidermal barrier function, and hair follicle cycling as well as increased UV-induced apoptosis in mice lacking Nedd4-1 in keratinocytes. In particular, re-epithelialization of full-thickness excisional wounds was delayed in the mutant mice. This was caused by severely impaired migration and proliferation of Nedd4-1-deficient keratinocytes. Therefore, a few keratinocytes, which had escaped recombination and expressed Nedd4-1, obtained a growth advantage and contributed to re-epithelialization. Mechanistically, Nedd4-1-deficient keratinocytes failed to efficiently activate the Erk1/2 mitogen-activated kinases and the YAP transcriptional co-activator. These results identify Nedd4-1 as an essential player in wound repair through its effect on mitogenic and motogenic signaling pathways in keratinocytes. ISSN:0022-202X ISSN:1523-1747

Giant abdominal aortic aneurysms (AAAs) are defined as AAAs >10 to 13 cm in the maximum transverse diameter. We have described a case of a patient who had presented for open repair of an 18-cm AAA and a review of reported cases of giant AAAs >10 cm in the maximum transverse diameter. Forty cases were compiled. The average maximum AAA diameter was 14.5 ± 4.1 cm. The AAA was ruptured on presentation in 12 patients (30%). Of the 40 cases, 34 (85%) were repaired with open surgery. The reported mortality was 15%. Despite the case complexity, five endovascular repairs were attempted.

In the current study, gefitinib loaded PLGA nanoparticles (GFT-PLGA-NPs) and chitosan coated PLGA nanoparticles (GFT-CS-PLGA-NPs) were synthesized to investigate the role of surface charge of NPs for developing drug delivery system for non-small-cell lung cancer (NSCLC). The developed NPs were evaluated for their size, PDI, zeta potential (ZP), drug entrapment, drug loading, DSC, FTIR, XRD, in vitro release profile, and morphology. The anti-cancer activity of GFT loaded PLGA NPs and GFT loaded CS-PLGA-NPs were examined in human A549 lung cancer cell lines. In vitro release studies of GFT-CS-PLGA-NPs showed more sustained release in comparison to GFT-PLGA-NPs due surface charge attraction of chitosan. In addition, viability of A549 cells decreases significantly with the increasing concentration of GFT-PLGA NPs and GFT-CS-PLGA-NPs when compared to that of pure GFT and blank PLGA NPs. In addition, the microscopic analysis and counting of viable cells also validate the cytotoxicity of the developed NPs. This investigation proved that the developed NPs would be efficient carriers to deliver GFT with improved efficacy against NSCLC.

Host–guest molecular recognition at the liquid–liquid interface endows the interface with unique properties, including stimuli-responsiveness and self-regulation, due to the dynamic and reversible nature of non-covalent interactions. Increasing research efforts have been put into the preparation of supramolecular interfacial systems such as films and microcapsules by integrating functional components (e.g., colloidal particles, polymers) at the interface, providing tremendous opportunities in the areas of encapsulation, delivery vehicles, and biphasic reaction systems. In this review, we summarize recent progress in supramolecular interfacial systems assembled by host–guest chemistry, and provide an overview of the fabrication process, functions, and promising applications of the resultant constructs.

Monomethoxy poly(ethylene glycol)-block-poly( d , l -lactic acid) (PEG-PLA) is a typical amphiphilic di-block copolymer widely used as a nanoparticle carrier (nanocarrier) in drug delivery. Understanding the in vivo fate of PEG-PLA is required to evaluate its overall safety and promote the development of PEG-PLA-based nanocarrier drug delivery systems. However, acquiring such understanding is limited by the lack of a suitable analytical method for the bioassay of PEG-PLA. In this study, the pharmacokinetics, biodistribution, metabolism and excretion of PEG-PLA were investigated in rat after intravenous administration. The results show that unchanged PEG-PLA is mainly distributed to spleen, liver, and kidney before being eliminated in urine over 48 h mainly (>80%) in the form of its PEG metabolite. Our study provides a clear and comprehensive picture of the in vivo fate of PEG-PLA which we anticipate will facilitate the scientific design and safety evaluation of PEG-PLA-based nanocarrier drug delivery systems and thereby enhance their clinical development.

Aim of the work: To investigate the value of neutrophil- lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR), red blood cell distribution width (RDW), mean platelet volume (MPV) as biomarkers of disease severity and clinical manifestations in systemic sclerosis (SSc). Patients and methods: This study included 35 SSc patients, together with 45 controls. Disease severity was assessed by Medsger severity score (MSS). NLR, PLR, MPV, RDW were measured by COULTER LH 750 assay analyzer. Results: The mean age of SSc patients and controls was 42.8 ± 12.6 and 40.8 ± 9.7 years respectively. MPV, RDW, NLR, PLR were significantly higher in patients compared to controls (p = 0.03, < 0.001

Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents. Administration of these drugs with siRNA is an efficacious strategy in this battle. Here, the present study tried to incorporate siRNA and paclitaxel (PTX) simultaneously into a novel nanocarrier. The selectivity of carrier to target cancer tissues was optimized through conjugation of folic acid (FA) and glucose (Glu) onto its surface. The structure of nanocarrier was formed from ternary magnetic copolymers based on FeCo-polyethyleneimine (FeCo-PEI) nanoparticles and polylactic acid-polyethylene glycol (PLA-PEG) gene delivery system. Biocompatibility of FeCo-PEI-PLA-PEG-FA(NPsA), FeCo-PEI-PLA-PEG-Glu (NPsB) and FeCo-PEI-PLA-PEG-FA/Glu (NPsAB) nanoparticles and also influence of PTX-loaded nanoparticles on in vitro cytotoxicity were examined using MTT assay. Besides, siRNA-FAM internalization was investigated by fluorescence microscopy. The results showed the blank nanoparticles were significantly less cytotoxic at various concentrations. Meanwhile, siRNA-FAM/PTX encapsulated nanoparticles exhibited significant anticancer activity against MCF-7 and BT-474 cell lines. NPsAB/siRNA/PTX nanoparticles showed greater effects on MCF-7 and BT-474 cells viability than NPsA/siRNA/PTX and NPsB/siRNA/PTX. Also, they induced significantly higher anticancer effects on cancer cells compared with NPsA/siRNA/PTX and NPsB/siRNA/PTX due to their multi-targeted properties using FA and Glu. We concluded that NPsAB nanoparticles have a great potential for co-delivery of both drugs and genes for use in gene therapy and chemotherapy., Graphical abstract Image 1, Highlights • A series of novel nanoparticles which composed of either glucose and/or folic acid conjugated FeCo@SiO2-SS-PEI-PLA-PEG copolymers were successfully synthesized and loaded with siRNA and PTX simultaneously. • The prepared nanoparticles had diameter in range of 100–150 nm, and released the drugs in sustainable manner. • The simultaneous PTX and siRNA loaded nanocarrier showed significant toxicity on MCF-7 cells and also their significant transfection efficiency in these cells was demonstrated through increased uptake of siRNA-FAM via fluorescence microscopy imaging.

Cyanoacrylate-based adhesives react aggressively with cotton in a highly exothermic manner. These adhesives are widely available, but the dangers of such glues in producing severe burns are still poorly understood, especially in pediatric populations. There are few case reports examining full-thickness burns resulting from nail glues (a cyanoacrylate-based adhesive), which are often stored in bottles lacking robust safety mechanisms. As a result, there is a lack of understanding by both the general populace and medical community of the severe consequences of such glues contacting cotton-based clothing in both adults and children. Here we present a case of full-thickness burns on the dorsal aspect of the foot of a two-year-old male who spilled nail glue on his sock. The resultant reaction rapidly produced three adjacent burns. The wound required consistent management and healed almost completely after 9 weeks. We aim to raise awareness of full-thickness burns resulting from nail glue spills, as well as to draw attention to the need for better warnings and safety features on glue bottles. We also hope to highlight best practices for the treatment of such burns.

We present the case of an 18-year-old man, with a history of subarachnoid hemorrhage, who is found to have the spiked helmet sign on electrocardiogram during a hospital admission for severe respiratory infection. The spiked helmet sign is a poorly understood electrocardiographic finding that mimics other electrocardiographic pathologies, and is associated with critical illness and high mortality. (Level of Difficulty: Beginner.), Central Illustration

We present a case of transcatheter heart valve thrombosis in a 76-year-old man with paroxysmal atrial fibrillation on therapeutic anticoagulation with apixaban and polycythemia vera. The incidence of transcatheter heart valve thrombosis in patients with atrial fibrillation and on adequate anticoagulation is not well reported. (Level of Difficulty: Intermediate.), Graphical abstract

Chronic patellar dislocation in the setting of severe knee osteoarthritis is a rare clinical problem. Surgical management often consists of total knee arthroplasty combined with realignment of the extensor mechanism. Several techniques have been described to anatomically restore the extensor apparatus, and literature regarding this topic consists mainly of case reports. We describe a technique using combined medial patellofemoral ligament reconstruction using allograft tissue and total knee arthroplasty with patellar resurfacing for the treatment of chronic patellar dislocation and severe osteoarthritis.

Highlights What is known•Adults with comorbidities are more likely to suffer from severe manifestations of COVID-19•Children with COVID-19 have less severe disease manifestations than adults•Children may experience multisystem inflammatory syndrome due to COVID-19 What is new•Children with comorbidities may be at an increased risk for PICU admission and/or severe COVID-19•Children with comorbidities may be at an increased risk of mortality during COVID-19 infection•Childhood obesity likely contributes to more serious manifestations of COVID-19, Objective There is limited information on the severity of COVID-19 infection in children with comorbidities. We investigated the effects of pediatric comorbidities on COVID-19 severity by means of a systematic review and meta-analysis of published literature. Methods PubMed, Embase, and Medline databases were searched for publications on pediatric COVID-19 infections published January 1st to October 5th, 2020. Articles describing at least one child with and without comorbidities, COVID-19 infection, and reported outcomes, were included. Results 42 studies containing 275,661 children without comorbidities and 9,353 children with comorbidities were included. Severe COVID-19 was present in 5.1% of children with comorbidities, and in 0.2% without comorbidities. Random-effects analysis revealed a higher risk of severe COVID-19 among children with comorbidities than for healthy children; relative risk ratio 1.79 (95% CI 1.27 – 2.51;I2 = 94%). Children with underlying conditions also had a higher risk of COVID-19-associated mortality; relative risk ratio 2.81 (95% CI 1.31 – 6.02; I2 = 82%). Children with obesity had a relative risk ratio of 2.87 (95% CI 1.16 – 7.07 I2 = 36%). Conclusions Children with comorbidities have a higher risk of severe COVID-19 and associated mortality than children without underlying disease. Additional studies are required to further evaluate this relationship.