Single-Nucleotide Variations,Insertions/Deletions and Copy Number Variations in Myelodysplastic Syndrome during Disease Progression Revealed by a Single-Cell DNA Sequencing Platform

Simple SummaryMyelodysplastic syndrome (MDS) is a myeloid neoplasm associated with complex clonal architecture. The application of single-cell sequencing is capable of revealing the clonal dynamics of MDS during disease progression and treatment resistance. This has advantages over bulk-tumor sequencing which is limited by its resolution. In this study, we evaluated two patients with MDS for the clonal dynamics of pathogenic mutations at the single-cell level of disease progression and resistance to hypomethylating agents (HMAs). There were two key observations. First, changes in the clonal heterogeneity of the pathogenic FLT3-ITD, IDH2, EZH2, or GATA2 mutations was associated with disease progression and resistance to HMA. Secondly, disease progression and resistance to HMA was accompanied by the acquisition of copy number variations of DNMT3A, TET2, and GATA2.AbstractMyelodysplastic syndrome (MDS) is a clonal myeloid neoplasm characterized by ineffective hematopoiesis, cytopenia, dysplasia, and clonal instability, leading to leukemic transformation. Hypomethylating agents are the mainstay of treatment in higher-risk MDS. However, treatment resistance and disease transformation into acute myeloid leukemia (AML) is observed in the majority of patients and is indicative of a dismal outcome. The residual cell clones resistant to therapy or cell clones acquiring new genetic aberrations are two of the key events responsible for drug resistance. Bulk tumor sequencing often fails to detect these rare subclones that confer resistance to therapy. In this study, we employed a single-cell DNA (sc-DNA) sequencing approach to study the clonal heterogeneity and clonal evolution in two MDS patients refractory to HMA. In both patients, different single nucleotide variations (SNVs) or insertions and deletions (INDELs) were detected with bulk tumor sequencing. Rare cell clones with mutations that are undetectable by bulk tumor sequencing were detected by sc-DNA sequencing. In addition to SNVs and short INDELs, this study also revealed the presence of a clonal copy number loss of DNMT3A, TET2, and GATA2 as standalone events or in association with the small SNVs or INDELs detected during HMA resistance and disease progression.     

Adjustable Intermolecular Interactions Allowing 2D Transition Metal Dichalcogenides with Prolonged Scavenging Activity for Reactive Oxygen Species

There is an increasing demand for control over the dimensions and functions of transition metal dichalcogenides (TMDs) in aqueous solution toward biological and medical applications. Herein, an approach for the exfoliation and functionalization of TMDs in water via modulation of the hydrophobic interaction between poly(ε‐caprolactone)‐b‐poly(ethylene glycol) (PCL‐b‐PEG) and the basal planes of TMDs is reported. Decreasing the hydrophobic PCL length of PCL‐b‐PEG from 5000 g mol^?1 (PCL₅₀₀₀) to 460 g mol^?1 (PCL₄₆₀) significantly increases the exfoliation efficiency of TMD nanosheets because the polymer–TMD hydrophobic interaction becomes dominant over the polymer–polymer interaction. The TMD nanosheets exfoliated by PCL₄₆₀‐b‐PEG₅₀₀₀ (460‐WS₂, 460‐WSe₂, 460‐MoS₂, and 460‐MoSe₂) show excellent and prolonged scavenging activity for reactive oxygen species (ROS), but each type of TMD displays a different scavenging tendency against hydroxyl, superoxide, and 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) radicals. A mechanistic study based on electron paramagnetic resonance spectroscopy and density functional theory simulations suggests that radical‐mediated oxidation of TMDs and hydrogen transfer from the oxidized TMDs to radicals are crucial steps for ROS scavenging by TMD nanosheets. As‐prepared 460‐TMDs are able to effectively scavenge ROS in HaCaT human keratinocytes, and also exhibit excellent biocompatibility.     

Effects of thermal annealing in oxygen plasma for buffer layers on properties of ZnO thin films

ZnO thin films with ZnO buffer layers were grown by plasma-assisted molecular beam epitaxy (PA-MBE) on p-type Si(100) substrates. Before the growth of the ZnO thin films, the ZnO buffer layers were deposited on the Si substrates for 20 minutes and then annealed at the different substrate temperature ranging from 600 to 800 degrees C in oxygen plasma. The structural and optical properties of the ZnO thin films have been investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and room-temperature (RT) photoluminescence (PL). A narrower full width at half maximum (FWHM) of the XRD spectra for ZnO(002) and a larger grain are observed in the samples with the thermal annealed buffer layers in oxygen plasma, compared to those of the as-grown sample. The surface morphology of the samples is changed from rugged to flat surface. In the PL spectra, near-band edge emission (NBEE) at 3.2 eV (380 nm) and deep-level emission (DLE) around 1.77 to 2.75 eV (700 to 450 nm) are observed. By increasing the annealing temperatures up to 800 degrees C, the PL intensity of the NBEE peak is higher than that of the as-grown sample. These results imply that the structural and optical properties of ZnO thin films are improved by the annealing process.     

Nitric Oxide Generation and Endothelial Progenitor Cells Recruitment for Improving Hemocompatibility and Accelerating Endothelialization of Tissue Engineering Heart Valve

Tissue engineering heart valve (TEHV) offers great potential to overcome the limitations of commercial artificial valves used in clinical practice as a permanent prosthetic valve. Currently, decellularized heart valve (DHV) is the most widely used scaffold for TEHV, but showed suboptimal performance due to difficulty of endothelialization. Facilitating endothelialization of DHV is indispensable for better valve performance, and excellent hemocompatibility guarantees enough time windows for endothelialization process. Herein, a dual-functional TEHV scaffold with improving hemocompatibility and accelerating endothelialization is constructed by modifying DHV with copper ions (Cu) and growth differentiation factor 11 (GDF11). Results show the newly-constructed scaffold successfully generates endogenous nitric oxide (NO) through catalysis of Cu, and possesses improved hemocompatibility by down-regulating platelets activation and adhesion. Furthermore, GDF11 immobilization significantly accelerates scaffold endothelialization through facilitating recruitment, supporting growth, and alleviating apoptosis of endothelial progenitor cells . This TEHV scaffold shows favorable performance under in vivo hemodynamic environment with intact endothelial coverage and adaptive ECM remodeling, and without thrombus or calcification formation. This newly-constructed TEHV scaffold is expected to make up for the shortcomings of currently available prosthetic valves in clinical practice and has the potential possibility of rapid translation to the clinic as a better prosthetic valve.     

Effects of interlaminar stresses on damping of 0-degree unidirectional laminated composites

The principal aim of this paper is to formulate a general model for predicting damping in composites on the basis of the concept of strain energy-weighted dissipation. In this model, the effects of interlaminar stresses on damping have been included in addition to the effects of in-plane extension/compression and in-plane shear. Validation of the model was confirmed by performing damping measurements on 0° unidirectional composite beams with varying length and thickness. The results of theoretical predictions of damping in laminated composites were found to compare favorably with experimental data. The transverse shear (σ_xz) reveals to have a considerable effect on the damping mechanisms in 0° unidirectional polymer composites. However, the other interlaminar stresses (σ_yz, σ_z) were shown to have little influence on damping in composite beam.     

An analytical method for prediction of the damping in symmetric balanced laminated composites

To obtain the effective damping of a laminated composite beam, two different analytical methods were compared. Also, we modified the basic loss factors on the basis of experimental data. In the first method, Ni and Adams's theory was used. In the second method, new energy approach was developed to determine the damping of laminated composite beams. Five typical laminated composites with [±Θ]s, [0/±Θ]s, [0/Θ]s, [0/±Θ/90]s and [90/±Θ/0]s stacking sequences were employed for this study. The present method was favorably compared with Ni and Adams's method. In this study, we found that damping was highly influenced by fiber volume fraction, fiber orientation and stacking sequence.