Genome-wide analysis of RNA-binding proteins co-expression with alternative splicing events in mitral valve prolapse.

Objectives: We investigated the role and molecular mechanisms of RNA-binding proteins (RBPs) and their regulated alternative splicing events (RASEs) in the pathogenesis of mitral valve prolapse (MVP). Methods: For RNA extraction, we obtained peripheral blood mononuclear cells (PBMCs) from five patients with MVP, with or without chordae tendineae rupture, and five healthy individuals. High-throughput sequencing was used for RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) analysis, alternative splicing (AS) analysis, functional enrichment analysis, co-expression of RBPs, and alternative splicing events (ASEs) analysis were conducted. Results: The MVP patients exhibited 306 up-regulated genes and 198 down-regulated genes. All down- and up-regulated genes were enriched in both Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Furthermore, MVP was closely associated with the top 10 enriched terms and pathways. In MVP patients, 2,288 RASEs were found to be significantly different, and four suitable RASEs (CARD11 A3ss, RBM5 ES, NCF1 A5SS, and DAXX A3ss) were tested. We identified 13 RNA-binding proteins (RBPs) from the DEGs and screened out four RBPs (ZFP36, HSPA1A, TRIM21, and P2RX7). We selected four RASEs based on the co-expression analyses of RBPs and RASEs, including exon skipping (ES) of DEDD2, alternative 3' splice site (A3SS) of ETV6, mutually exclusive 3'UTRs (3pMXE) of TNFAIP8L2, and A3SS of HLA-B. Furthermore, the selected four RBPs and four RASEs were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and showed high consistency with RNA sequencing (RNA-seq). Conclusion: Dysregulated RBPs and their associated RASEs may play regulatory roles in MVP development and may therefore be used as therapeutic targets in the future.

The association between preoperative blood calcium and postoperative blood loss in patients undergoing heart valve replacement surgery.

INTRODUCTION: Bleeding after heart valve surgery is a serious clinical challenge. Hypocalcemia has been associated with the extent of bleeding in patients with spontaneous intracerebral hemorrhage. However, the association between blood calcium levels and bleeding extent in heart valve replacement patients has not been clearly established. This study aimed at determining the association between blood calcium levels and perioperative hemorrhage after heart valve replacement therapy. METHODS: Based on preoperative blood calcium levels, patients were grouped into the hypocalcemia group and normocalcemia group. Postoperative bleeding, blood product use, and complications were monitored during hospitalization. The association between blood calcium levels and major bleeding was determined by multivariable logistic regression models. RESULTS: In the first 12 h after surgery, bleeding in hypocalcemia group was significantly larger than that of the normocalcemia group (338 ± 234 mL vs 232 ± 96 mL; p = .024). The outcome was the same when the overall chest tube output was considered (950 ± 447 mL vs 738 ± 220 mL; p = .038). The incidence of major bleeding was 65.91% in the hypocalcemia group and 18.97% in the normocalcemia group (p = .001). Postoperative complications in the two groups were similar. After adjusting for multiple covariates, the adjusted odds ratios (OR) for participants in hypocalcemia group was 10.01 (95% CI 3.35-34.82), compared with that in normocalcemia group (p < .001). CONCLUSION: In patients undergoing heart valve surgery, preoperative blood concentrations of calcium are associated with postoperative blood loss. Hypocalcemia before operation may increase the risk of postoperative bleeding. When patients with valvular heart disease present with hypocalcemia before surgery, prompt intervention may lead to better control of postoperative bleeding.

Aortic valve repair for the treatment of rheumatic aortic valve disease: a systematic review and meta-analysis.

Valvuloplasty for rheumatic aortic valve disease remains controversial. We conducted this study to explore whether aortic valvuloplasty is appropriate for the rheumatic population. A comprehensive search was conducted, and 7 eligible retrospective studies were identified from PubMed, Embase, Medline and Cochrane (up to April 7, 2020) according to the inclusion and exclusion criteria. The data for hospital mortality, 5-year survival, 5-year reoperation, aortic insufficiency grade (AIG) and aortic valve gradient (AVG) were extracted by 2 independent reviewers and were analysed to evaluate the safety and availability of aortic valvuloplasty for rheumatic patients. The heterogeneity of the results was estimated using the Q test and I2 statistics. The fixed pooling model was used when I2 ≤ 50%; otherwise, the random pooling model was selected. 7 articles with 418 patients were included. The pooled hospital mortality, 5-year survival and 5-year reoperation rates were 3.2%, 94.5% and 9.9%, respectively. The heterogeneities of the weighted mean differences (WMD) values of the AIG and AVG between preoperation and postoperation were extremely high (I2 = 81.5%, p < 0.001 in AIG, I2 = 97.6%, p = 0.003 in AVG). Subgroup analysis suggested that the AIG and AVG were improved by 3.03 grades (I2 = 0%, p < 0.001) and 3.16 mmHg (I2 = 0%, p < 0.001) in the European group, respectively. In the Asian group, the AIG and AVG were improved by 2.57 grades (I2 = 0%, p < 0.001) and 34.39 mmHg (I2 = 0%, p < 0.001), respectively. Compared with the values at discharge, the AIG was increased by 0.15 grades (I2 = 0%, p = 0.031) and the AVG was still decreased by 2.07 mmHg (I2 = 0%, p = 0.031) at the time of follow up. Valvuloplasty is safe and effective to treat rheumatic aortic insufficiency and stenosis, and the duration of maintenance required to improve stenosis was longer than that of insufficiency.

Tocilizumab for treating COVID-19: a systemic review and meta-analysis of retrospective studies.

OBJECTIVES: COVID-19 has become a global epidemic, and effective therapies have not been discovered up to now. We conducted this study to explore the effectiveness and safety of tocilizumab recently used for treating COVID-19. METHOD: A comprehensive search was conducted (up to September 27, 2020), and 19 eligible records were identified according to the inclusion and exclusion criteria. The data of the studies were extracted by 2 independent reviewers and were analyzed to evaluate the safety and availability of tocilizumab for treating COVID-19. RESULTS: Thirteen retrospective case-control studies (n = 2285 patients) and 6 retrospective single-armed studies (n = 208) were retrieved in this study. In the comparison of tocilizumab treatment group (TCZ) and standard treatment group (ST), significant associations with a lower risk of admission to ICU, use of ventilation, and mortality (OR, 95% CI: 0.53, 0.26~1.09; 0.66, 0.46~0.94; 0.44, 0.36~0.55) were found in the tocilizumab treatment group. What is more, patients treated with tocilizumab had better clinical improvement compared with the patients treated with ST (OR, 1.24; 95% CI, 0.96~1.62). After taking tocilizumab, the patients had lower C-reactive protein (CRP), white blood cell count (WBC), aspartate aminotransferase (AST) (WMD, 95% CI: - 99.66, - 156.24~- 43.09; - 0.95, - 1.8~- 0.11; - 12.58, - 18.88~-6.29) but higher troponin (WMD, 7.61; 95% CI, 3.06~12.15) than before. In addition, tocilizumab did not have significant influence on patients' neutrophil count (Neut), lymphocyte count (Lymp), platelet count (Plt), alanine aminotransferase (ALT), and creatine (WMD, 95% CI: - 0.29, - 2.91~2.33; 0.42, - 0.23~1.07; 5.2, - 2.85~13.25; 22.49, - 2.73~47.7; - 44.78, - 93.37~3.81). CONCLUSION: Tocilizumab may have potential effectiveness to treat COVID-19 according to the results of this study. However, more large-scale studies are needed for more accurate conclusions.

Multifarious Interfaces, Band Alignments, and Formation Asymmetry of WSe2-MoSe2 Heterojunction Grown by Molecular-Beam Epitaxy.

Monolayer (ML) transition-metal dichalcogenides (TMDs) continue to attract research attention, and the heterojunctions formed by vertically stacking or laterally stitching two different TMDs, e.g., MoSe2 and WSe2, may have many interesting electronic and optical properties and thus are at the center stage of current research. Experimentally realizing such heterojunctions with desired interface morphologies and electronic properties is of great demand. In this work, we report a diverse interface structure in molecular-beam epitaxial WSe2-MoSe2 heterojunction. The corresponding electronic bands show type-II band alignment for both monolayer ML-ML and ML-bilayer lateral junctions irrespective of the presence or absence of step states. Interestingly, a strong anisotropy in lateral heterojunction formation is observed, where sharp interfaces are obtained only when WSe2 deposition precedes MoSe2. Reversing the deposition order leads to alloying of the two materials without a notable boundary. This is explained by a step segregation process as suggested by the first-principles total energy calculations.

Room-temperature ferroelectricity in MoTe2 down to the atomic monolayer limit.

Ferroelectrics allow for a wide range of intriguing applications. However, maintaining ferroelectricity has been hampered by intrinsic depolarization effects. Here, by combining first-principles calculations and experimental studies, we report on the discovery of robust room-temperature out-of-plane ferroelectricity which is realized in the thinnest monolayer MoTe2 with unexploited distorted 1T (d1T) phase. The origin of the ferroelectricity in d1T-MoTe2 results from the spontaneous symmetry breaking due to the relative atomic displacements of Mo atoms and Te atoms. Furthermore, a large ON/OFF resistance ratio is achieved in ferroelectric devices composed of MoTe2-based van der Waals heterostructure. Our work demonstrates that ferroelectricity can exist in two-dimensional layered material down to the atomic monolayer limit, which can result in new functionalities and achieve unexpected applications in atomic-scale electronic devices.

MiR-889 promotes cell growth in human non-small cell lung cancer by regulating KLF9.

Currently, non-small cell lung cancer (NSCLC) is still the most common malignancy worldwide. Although miR-889 has been reported to play an important role in various malignancies, the physiological function of miR-889 in NSCLC remains unknown. This paper places emphasis on the influence of miR-889 on the development and progression of non-small cell lung cancer. To detect the expression level of miR-889 in NSCLC tissues and cell lines, quantitative real-time polymerase chain reaction (qRT-PCR) assay and In Situ Hybridization (ISH) were adopted in this study. Cell proliferation and colony forming ability were examined by Cell Counting Kit-8 (CCK-8) and colony formation assays. Furthermore, transwell experiments were conducted to determine the influence of miR-889 on migration. KLF9 expression was evaluated by qRT-PCR and Western blotting. First, miR-889 expression was increased in the cancer tissues of non-small cell lung cancer patients (n = 40) compared with adjacent tissues. Subsequently, knockdown of miR-889 significantly inhibited cell proliferation and migration, while overexpression of miR-889 had the opposite effect. KLF9 may be a potential target of miR-889. In addition, upregulation of miR-889 promotes tumorigenesis in vitro, and KLF9 protein levels are also reduced. The current study suggests that miR-889 may play a potential therapeutic role for NSCLC by targeting KLF9 to control NSCLC proliferation and migration.

Quantifying Intramolecular Protein Conformational Dynamics Under Lipid Interaction Using smFRET and FCCS.

FÓ§rster-type resonance energy transfer (FRET) with fluorescence cross-correlation spectroscopy (FCCS) is a powerful combination for observing intramolecular conformational dynamics on the micro- to millisecond timescale. Owing to its sensitivity to various physical parameters, FRET-FCCS has also been used to detect the reagent effects on proteins dynamics. However, FRET-FCCS alone cannot acquire the exact measurements of rate constants. Moreover, this technique is highly model dependent and can be unreliable when determining too many parameters at once. On the contrary, single-molecular FRET (smFRET) can measure the conformational states and their populations directly, although it is extremely challenging for probing fast dynamics under 1 ms. In this chapter, we describe how to realize sub-millisecond conformational dynamics measurements of a SNARE protein Ykt6 under lipid environments by smFRET and FRET-FCCS. This protocol includes sample preparation, microscope designs, data acquisition, and analysis methodology.

Ultra-low power Hf0.5Zr0.5O2 based ferroelectric tunnel junction synapses for hardware neural network applications.

Brain-inspired neuromorphic computing has shown great promise beyond the conventional Boolean logic. Nanoscale electronic synapses, which have stringent demands for integration density, dynamic range, energy consumption, etc., are key computational elements of the brain-inspired neuromorphic system. Ferroelectric tunneling junctions have been shown to be ideal candidates to realize the functions of electronic synapses due to their ultra-low energy consumption and the nature of ferroelectric tunneling. Here, we report a new electronic synapse based on a three-dimensional vertical Hf0.5Zr0.5O2-based ferroelectric tunneling junction that meets the full functions of biological synapses. The fabricated three-dimensional vertical ferroelectric tunneling junction synapse (FTJS) exhibits high integration density and excellent performances, such as analog-like conductance transition under a training scheme, low energy consumption of synaptic weight update (1.8 pJ per spike) and good repeatability (>103 cycles). In addition, the implementation of pattern training in hardware with strong tolerance to input faults and variations is also illustrated in the 3D vertical FTJS array. Furthermore, pattern classification and recognition are achieved, and these results demonstrate that the Hf0.5Zr0.5O2-based FTJS has high potential to be an ideal electronic component for neuromorphic system applications.

Total endoscopic repair of atrial septal defect under on-pump beating heart.

BACKGROUND: We previously reported the techniques for total endoscopic atrial septal defect (ASD) repair on hearts arrested with cardioplegia through three small incisions in the chest wall without aid of a surgical robotic system. The optimal results motivated us to use total thoracoscopic technology for ASD on perfused beating hearts. METHODS: From 2010 to 2017, 161 patients with a mean age of 28.31±12.34 years who underwent non-robotically assisted total thoracoscopic closure for ASD were included in this study, and those patients were also divided into two groups, including group A and group B. In group A, 115 patients underwent the procedure on beating hearts without aorta cross-clamped; in group B, 46 patients underwent the procedure on hearts arrested with cardioplegia with aorta cross-clamped. Cardiopulmonary bypass (CPB) was peripherally achieved as well. RESULTS: Total thoracoscopic ASD closures were successfully performed without in-hospital mortality or other serious complications in all patients of both groups. Dacron or bovine patches were used in 81 and 32 patients in the two groups, respectively. Duration of operation, duration of CPB, aorta cross-clamped time, duration of mechanical ventilation, the length of intensive care unit (ICU) and post-operative hospital stay in group A, were all shorter than those in group B (P<0.05). There was no statistically significant difference in blood transfusion during operation or post-operation thoracic drainage. During follow-up, echocardiograms at 3, 30, 90 and 365, showed no residual shunt or tricuspid regurgitation. CONCLUSIONS: Total thoracoscopic closure of ASD without assistance of a surgical robotic system on beating heart is safe and feasible and can be used as a therapeutic option for ASD, and by using the mentioned technique, less injuries are applied to patients.

Ultrathin ß-tellurium layers grown on highly oriented pyrolytic graphite by molecular-beam epitaxy.

Monolayer tellurium (Te) or tellurene has been suggested by a recent theory as a new two-dimensional (2D) system with great electronic and optoelectronic promises. Here we present an experimental study of epitaxial Te deposited on highly oriented pyrolytic graphite (HOPG) by molecular-beam epitaxy. Scanning tunneling microscopy of ultrathin layers of Te reveals rectangular surface cells with the cell size consistent with the theoretically predicted ß-tellurene, whereas for thicker films, the cell size is more consistent with that of the [101[combining macron]0] surface of the bulk Te crystal. Scanning tunneling spectroscopy measurements show that the films are semiconductors with the energy band gaps decreasing with increasing film thickness, and the gap narrowing occurs predominantly at the valence-band maximum (VBM). The latter is understood by strong coupling of states at the VBM but a weak coupling at conduction band minimum (CBM) as revealed by density functional theory calculations.

Multivalency-Driven Formation of Te-Based Monolayer Materials: A Combined First-Principles and Experimental study.

Contemporary science is witnessing a rapid expansion of the two-dimensional (2D) materials family, each member possessing intriguing emergent properties of fundamental and practical importance. Using the particle-swarm optimization method in combination with first-principles density functional theory calculations, here we predict a new category of 2D monolayers named tellurene, composed of the metalloid element Te, with stable 1T-MoS_{2}-like (α-Te), and metastable tetragonal (ß-Te) and 2H-MoS_{2}-like (γ-Te) structures. The underlying formation mechanism is inherently rooted in the multivalent nature of Te, with the central-layer Te behaving more metal-like (e.g., Mo), and the two outer layers more semiconductorlike (e.g., S). We also show that the α-Te phase can be spontaneously obtained from the magic thicknesses divisible by three layers truncated along the [001] direction of the trigonal structure of bulk Te, and both the α- and ß-Te phases possess electron and hole mobilities much higher than MoS_{2}. Furthermore, we present preliminary but convincing experimental evidence for the layering behavior of Te on HOPG substrates, and predict the importance of multivalency in the layering behavior of Se. These findings effectively extend the realm of 2D materials to group-VI elements.

A two-dimensional semiconductor transistor with boosted gate control and sensing ability.

Transistors with exfoliated two-dimensional (2D) materials on a SiO2/Si substrate have been applied and have been proven effective in a wide range of applications, such as circuits, memory, photodetectors, gas sensors, optical modulators, valleytronics, and spintronics. However, these devices usually suffer from limited gate control because of the thick SiO2 gate dielectric and the lack of reliable transfer method. We introduce a new back-gate transistor scheme fabricated on a novel Al2O3/ITO (indium tin oxide)/SiO2/Si "stack" substrate, which was engineered with distinguishable optical identification of exfoliated 2D materials. High-quality exfoliated 2D materials could be easily obtained and recognized on this stack. Two typical 2D materials, MoS2 and ReS2, were implemented to demonstrate the enhancement of gate controllability. Both transistors show excellent electrical characteristics, including steep subthreshold swing (62 mV dec-1 for MoS2 and 83 mV dec-1 for ReS2), high mobility (61.79 cm2 V-1 s-1 for MoS2 and 7.32 cm2 V-1 s-1 for ReS2), large on/off ratio (~107), and reasonable working gate bias (below 3 V). Moreover, MoS2 and ReS2 photodetectors fabricated on the basis of the scheme have impressively leading photoresponsivities of 4000 and 760 A W-1 in the depletion area, respectively, and both have exceeded 106 A W-1 in the accumulation area, which is the best ever obtained. This opens up a suite of applications of this novel platform in 2D materials research with increasing needs of enhanced gate control.

Realizing Stable p-Type Transporting in Two-Dimensional WS2 Films.

Two-dimensional (2D) semiconductors have become promising candidates for nanoelectronics applications due to their unique layered structure and rich physical properties. However, the significant lack of reproducible p-type doping methods that can avoid the instability induced by the widely used charge transfer doping method greatly limits the applications of these semiconductors in complementary metal-oxide-semiconductor (CMOS) integrated digital circuits. This work presents a new scheme to realize stable p-type doping for WS2 with excellent layer controllability, wafer-level uniformity, and high reproducibility at the same time. The p-type WS2 was produced by introducing substitutional doping of sulfur with nitrogen atoms during the sulfurization of WOxNy film. Nitrogen atoms acted as acceptors moving the Fermi level of WS2 toward the valance band. Both experimental and theoretical investigations were designed to study the physical properties of the films fabricated. The WS2 based field-effect transistors exhibited a well-defined p-type behavior with a large on/off current ratio of ∼105 and a high hole mobility of ∼18.8 cm2 V-1 s-1. This opens up a promising method to realize stable p-type doping of 2D materials, which is very attractive for future large-scale 2D CMOS device applications.

Lipid Regulated Intramolecular Conformational Dynamics of SNARE-Protein Ykt6.

Cellular informational and metabolic processes are propagated with specific membrane fusions governed by soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNARE). SNARE protein Ykt6 is highly expressed in brain neurons and plays a critical role in the membrane-trafficking process. Studies suggested that Ykt6 undergoes a conformational change at the interface between its longin domain and the SNARE core. In this work, we study the conformational state distributions and dynamics of rat Ykt6 by means of single-molecule Förster Resonance Energy Transfer (smFRET) and Fluorescence Cross-Correlation Spectroscopy (FCCS). We observed that intramolecular conformational dynamics between longin domain and SNARE core occurred at the timescale ~200 µs. Furthermore, this dynamics can be regulated and even eliminated by the presence of lipid dodecylphoshpocholine (DPC). Our molecular dynamic (MD) simulations have shown that, the SNARE core exhibits a flexible structure while the longin domain retains relatively stable in apo state. Combining single molecule experiments and theoretical MD simulations, we are the first to provide a quantitative dynamics of Ykt6 and explain the functional conformational change from a qualitative point of view.

Absorption of Pt clusters and the induced magnetic properties of graphene.

First-principles total energy calculations are performed to investigate the formation and structures of Pt clusters on graphene. It is found that the formation energy of Pt on graphene increases with increasing Pt coverage. The structures of the absorbed Pt are that it is at the bridge site for a single Pt atom absorption, but form a dimerized cluster when two atoms are absorbed on graphene. For three- and four-Pt-atom absorption, linear and tetrahedral structures form, respectively, and the three-dimensional tetrahedral Pt(4) cluster is most stable in all the configurations investigated. There is a strong interatomic interaction among Pt atoms and so they tend to form clusters. While no magnetic behavior is expected after a single Pt atom is absorbed on graphene, the absorption of tetrahedral Pt(4) leads to Fermi level shifting to the valence band and the spin waves of C atoms in graphene become asymmetric and so they exhibit magnetism. The magnetic properties can thus be tuned by Pt absorption on graphene. The ultimate aim is to apply it in catalytic activity and electronic devices.