Identification and validation of a platelet-related signature for predicting survival and drug sensitivity in multiple myeloma.

Background: Significant progress has been achieved in the management of multiple myeloma (MM) by implementing high-dose therapy and stem cell transplantation. Moreover, the prognosis of patients has been enhanced due to the introduction of novel immunomodulatory drugs and the emergence of new targeted therapies. However, predicting the survival rates of patients with multiple myeloma is still tricky. According to recent researches, platelets have a significant impact in affecting the biological activity of tumors and are essential parts of the tumor microenvironment. Nonetheless, it is still unclear how platelet-related genes (PRGs) connect to the prognosis of multiple myeloma. Methods: We analyzed the expression of platelet-related genes and their prognostic value in multiple myeloma patients in this study. We also created a nomogram combining clinical metrics. Furthermore, we investigated disparities in the biological characteristics, immunological microenvironment, and reaction to immunotherapy, along with analyzing the drug susceptibility within diverse risk groups. Results: By using the platelet-related risk model, we were able to predict patients' prognosis more accurately. Subjects in the high-risk cohort exhibited inferior survival outcomes, both in the training and validation datasets, as compared to those in the low-risk cohort (p < 0.05). Moreover, there were differences in the immunological microenvironments, biological processes, clinical features, and chemotherapeutic drug sensitivity between the groups at high and low risk. Using multivariable Cox regression analyses, platelet-related risk score was shown to be an independent prognostic influence in MM (p < 0.001, hazard ratio (HR) = 2.001%, 95% confidence interval (CI): 1.467-2.730). Furthermore, the capacity to predict survival was further improved when a combined nomogram was utilized. In training cohort, this outperformed the predictive value of International staging system (ISS) alone from a 5-years area under curve (AUC) = 0.668 (95% CI: 0.611-0.725) to an AUC = 0.721 (95% CI: 0.665-0.778). Conclusion: Our study revealed the potential benefits of PRGs in terms of survival prognosis of MM patients. Furthermore, we verified its potential as a drug target for MM patients. These findings open up novel possibilities for prognostic evaluation and treatment choices for MM.

Restricting epigenetic activity promotes the reprogramming of transformed cells to pluripotency in a line-specific manner.

Somatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are resistant to reprogramming. Epigenetic barriers must block transformed cells from reprogramming, but the nature of those barriers is unclear. In this study, we generated a systematic panel of transformed mouse embryonic fibroblasts (MEFs) using oncogenic transgenes and discovered transformed cell lines compatible with reprogramming when transfected with Oct4/Sox2/Klf4/Myc. By comparing the reprogramming-capable and incapable transformed lines we identified multiple stages of failure in the reprogramming process. Some transformed lines failed at an early stage, whilst other lines seemed to progress through a conventional reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperacetylated active epigenetic state. This study reveals that diverse epigenetic barriers underly resistance to reprogramming of transformed cells.

Evaporation kinetics during containerless chemical synthesis of ZIF-8 in levitated droplets.

Zeolitic imidazolate framework-8 was synthesized in a containerless state via acoustic levitation. The cavitation effect of ultrasound affected the coordination connection of organic ligands in acoustically levitated droplets and they exhibited a conspicuous difference in the particle size distribution as compared with those under normal conditions. Herein, methanol was chosen as the solvent to investigate the influence of droplet evaporation on acoustic levitation synthesis. The kinetic parameters of droplet evaporation such as geometrical morphology transformation, concentration change and temperature evolution were measured for the levitation state. Surface evaporation resulted in the drastic deformation of the droplet during ZIF-8 synthesis and caused its vertical vibration and shape oscillation. The abrupt change of the levitation state aggravated the sound field effect on the containerless synthesis and caused a decrease of particle size distribution. A two-dimensional axis-symmetry model was used to visually simulate the sound field distribution during acoustic levitation synthesis based on the finite element method. The fabricated ZIF-8 was able to remove phthalic acid in wastewater through adsorption, and its kinetic features followed a pseudo second-order rate model.

Recent advances in precursor-derived ceramics integrated with two-dimensional materials.

The ceramization of polymeric precursors via thermal treatment represents a simple, fast and highly efficient method for producing polymer-derived ceramics (PDCs). PDCs integrating two-dimensional (2D) materials attracted special interest because they combine the diverse functionalities of 2D materials (electrical conductivity and catalytic performance) with the excellent intrinsic properties of PDCs, such as high-temperature stability, oxidation and corrosion resistance. This review focuses on recent development of the composites integrating PDC and 2D materials (PDC-2D composites). The methods used to prepare those materials and the relationship between as-prepared structures and property or functionality are discussed in detail. Then, the applications of PDC-2D composites in electromagnetic wave absorption and shielding, energy storage, hydrogen evolution, and electrothermal devices are also addressed.

Floating synthesis with enhanced catalytic performance via acoustic levitation processing.

Acoustic levitation supplies a containerless state to eliminate natural convection and heterogeneous crystal nucleation and thus provides a highly uniform and ultra clean condition in the confined levitating area. Herein, we attempt to make full use of these advantages to fabricate well dispersed metal nanoparticles. The gold nanoparticles, synthesized in an acoustically levitated droplet, exhibited a smaller size and improved catalytic performance in 4-nitrophenol reduction were synthesized in an acoustically levitated droplet. The sound field was simulated to understand the impact of acoustic levitation on gold nanoparticle growth with the aid of crystal growth theory. Chemical reducing reactions in the acoustic levitated space trend to occur in a better dispersed state because the sound field supplies continuous vibration energy. The bubble movement and the cavitation effect accelerate the nucleation, decrease the size, and the internal flow inside levitated droplet probably inhibit the particle fusion in the growth stage. These factors lead to a reduction in particle size compared with the normal wet chemical synthetic condition. The resultant higher surface area and more numerous active catalytic sites contribute to the improvement of the catalytic performance.

Toward the Controlled Synthesis of Highly Dispersed Metal Clusters Enabled by Downsizing Crystalline Porous Organic Cage Supports.

The controlled synthesis of subnanometer-sized metal clusters (MCs) presents a fascinating prospect for the research of size-dependent properties. In this study, a facile approach by employing porous racemic organic cage crystals as supports for immobilizing a broad range of noble MCs (e.g., Ru, Ir, Rh) is reported. Downsizing the support to the nanoscale leads to resultant MCs with precisely controlled sizes < 0.7 nm. Such enhanced stabilization ability is a result of enhanced metal-support interactions as well as the nanoconfinement of organic cages in controlling the growth of MCs. Moreover, the obtained MCs display excellent catalytic performance in a series of liquid-phase reactions owing to a decrease in the diffusion resistance from the substrate to MCs immobilized by the nano-sized cage support.

Anti-leukaemia effects of leonurine in vitro and in vivo.

The present study was conducted to explore the anti-acute myeloid leukaemia (AML) effects of leonurine. HL-60 and U-937 cells were used to assess the antileukaemia effect of leonurine in vitro, and HL-60 and U-937 xenograft nude mice were used to evaluate its antitumour effect in vivo. Leonurine inhibited the proliferation of HL-60 and U-937 cells in a time- and dose-dependent manner. Moreover, leonurine therapy prevented the growth of tumours in both xenograft animal models. Leonurine could induce apoptosis in HL-60 and U-937 cells. The cytotoxic effects of leonurine on HL-60 and U-937 cells were associated with an increased ratio of Bax/Bcl-2, activation of caspase-3, caspase-8 and caspase-9, and increased expression of cytochrome c in the cytoplasm. Leonurine inhibited activation of the PI3K/Akt pathway in HL-60 and U-937 cells by lowering the phosphorylation levels of PI3K and Akt. Our results indicate that leonurine is a potential anti-AML agent, and this activity may be associated with its repression of the phosphorylation of PI3K and Akt.

An Electrocatalytic Reaction As a Basis for Chemical Computing in Water Droplets.

Aqueous droplets covered with amphiphilic Janus Au/Fe3O4 nanoparticles and suspended in an organic phase serve as building blocks of droplet-based electronic circuitry. The electrocatalytic activity of these nanoparticles in a hydrogen evolution reaction (HER) underlies the droplet's ability to rectify currents with typical rectification ratios of ∼10. In effect, individual droplets act as low-frequency half-wave rectifiers, whereas several appropriately wired droplets enable full-wave rectification. When the HER-supporting droplets are combined with salt-containing "resistor" ones, the resulting ensembles can act as AND or OR gates or as inverters.

Transposable element sequence fragments incorporated into coding and noncoding transcripts modulate the transcriptome of human pluripotent stem cells.

Transposable elements (TEs) occupy nearly 40% of mammalian genomes and, whilst most are fragmentary and no longer capable of transposition, they can nevertheless contribute to cell function. TEs within genes transcribed by RNA polymerase II can be copied as parts of primary transcripts; however, their full contribution to mature transcript sequences remains unresolved. Here, using long and short read (LR and SR) RNA sequencing data, we show that 26% of coding and 65% of noncoding transcripts in human pluripotent stem cells (hPSCs) contain TE-derived sequences. Different TE families are incorporated into RNAs in unique patterns, with consequences to transcript structure and function. The presence of TE sequences within a transcript is correlated with TE-type specific changes in its subcellular distribution, alterations in steady-state levels and half-life, and differential association with RNA Binding Proteins (RBPs). We identify hPSC-specific incorporation of endogenous retroviruses (ERVs) and LINE:L1 into protein-coding mRNAs, which generate TE sequence-derived peptides. Finally, single cell RNA-seq reveals that hPSCs express ERV-containing transcripts, whilst differentiating subpopulations lack ERVs and express SINE and LINE-containing transcripts. Overall, our comprehensive analysis demonstrates that the incorporation of TE sequences into the RNAs of hPSCs is more widespread and has a greater impact than previously appreciated.

Irbesartan suppresses lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) dysfunction by inhibiting the activation of MLCK/MLC.

The basic function of the blood-brain barrier (BBB) is to selectively regulate the infiltration of solutes from the circulating blood into the central nervous system (CNS). Impaired BBB activity is related to brain damage caused by stroke, traumatic injury, neurodegenerative diseases, etc. Comprised of a monolayer of endothelial cells, the integrity of the BBB is determined by the expression of tight junction proteins and the contractile activity of the perijunctional apical actomyosin ring. Irbesartan, an AT1R antagonist, has been widely used for the treatment of hypertension. However, the pharmacological function of Irbesartan in the balance of the BBB is still unknown. In the present study, we performed both in-vivo and in-vitro experiments using lipopolysaccharide (LPS) to explore the mechanism behind the protective effects of Irbesartan against the BBB impairment. The results of our mouse model study revealed that Irbesartan could reduce BBB permeability, restore the expression of Occludin, and suppress the expression of inflammatory mediators, including interleukin-6, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. Additionally, Irbesartan improved LPS-induced depressive-like behavior. In our in vitro experiments, human brain microvascular endothelial cells (HBMVECs) stimulated with LPS demonstrated decreased endothelial permeability and increased occludin expression in response to Irbesartan treatment. Importantly, we found that the protective effects of Irbesartan were mediated through the NF-κB/MLC/MLCK signaling pathway, as blockage of NF-κB abolished the effects of Irbesartan. Our findings provide a basis for further research into the neuroprotective mechanism of Irbesartan.

Long non­coding RNA LINC00460 serves as a potential biomarker and oncogene via regulation of the miR­320b/PBX3 axis in acute myeloid leukemia.

Long non­coding RNA 00460 (LINC00460) has been reported to be involved in the tumorigenesis of various cancer types. However, the function of LINC00460 in acute myeloid leukemia (AML) remains elusive. Therefore, the present study aimed to investigate the role of LINC00460 in AML. The expression of LINC00460 in the serum of 80 diagnosed patients with AML and 67 healthy controls was measured via reverse transcription­quantitative polymerase chain reaction, and the results were compared with clinical features and patient outcomes. The expression of LINC00460 in 45 patients with cytogenetically normal­AML (CN­AML) was also assayed. Receiver operating characteristic (ROC) curves were generated to evaluate the sensitivity and specificity of serum LINC00460. In addition, the effects of LINC00460 on the viability, cell cycle distribution and apoptosis of AML cells were investigated. Bioinformatics tools were used to identify the possible mechanisms of how LINC00460 affects AML cells. It was found that the expression of LINC00460 was significantly upregulated in the serum of patients with AML and those with CN­AML. Higher expression of serum LINC00460 was positively associated with French­American­British classification and cytogenetics. Furthermore, ROC curve analyses demonstrated that serum LINC00460 could differentiate patients with AML from healthy individuals with an area under the curve of 0.8488 (95% CI, 0.7697­0.9279). The serum LINC00460 expression was also significantly decreased when the patients achieved complete remission. Kaplan­Meier analysis indicated that patients with high serum LINC00460 expression had a shorter overall survival time compared with the low serum LINC00460 expression group. Knockdown of LINC00460 inhibited viability, while inducing cell cycle arrest and apoptosis in AML cells. LINC00460 was also a decoy of microRNA (miR)­320b, which can further inhibit the expression of PBX homeobox 3 (PBX3). Collectively, the results suggested that LINC00460 may be applied as a potential diagnostic and prognostic biomarker for patients with AML. It was identified that LINC00460 may exert its effects, at least partly, via the miR­320b/PBX3 axis in AML.

The Protective Effects of Apremilast Against Oxygen-Glucose Deprivation/Reperfusion (OGD/R)-Induced Inflammation and Apoptosis in Astroglia Mediated by CREB/BDNF.

Oxygen-glucose deprivation and reoxygenation (OGD/R)-induced impairment of astrocytes may lead to neuronal dysfunction in the central nervous system (CNS). Apremilast is a phosphodiesterase 4 (PDE4) inhibitor primarily used for the treatment of psoriasis and psoriatic arthritis that has demonstrated certain neuroprotective properties. PDE4 is an isoenzyme that degrades 3'-5'-cyclic adenosine monophosphate (cAMP), which serves as a neuroprotective agent by promoting neuronal recovery through protein kinase (PKA)-mediated phosphorylation of cAMP response element-binding protein (CREB) and subsequent expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF) and anti-apoptotic B cell lymphoma (Bcl-2). However, the effects of apremilast in astrocytes have not been elucidated. In the present study, we employed an in vitro model of ischemic stroke using oxygen-glucose deprivation and reoxygenation (OGD/R)-challenged astrocytes to investigate the effects of apremilast against apoptosis (the flow cytometry assay), cell death (the lactate dehydrogenase release assay), oxidative stress (2', 7' dichlorofluorescin diacetate staining), and the expression of the key neuroprotective factors CREB and BDNF (Western blot analysis). Our findings show that treatment with apremilast could significantly reduce astrocyte apoptosis and cell death induced by OGD/R as evidenced by reduced release of glial fibrillary acidic protein (GFAP) and improvement of the Bax/Bcl-2 ratio. The results of MTT assay, measurement of lactate dehydrogenase (LDH) release, and flow cytometry confirmed the improvement in cell viability mediated by apremilast. Importantly, we found that CREB phosphorylation was required for the increases in BDNF and Bcl-2 induced by apremilast as well as the decrease in astrocyte apoptosis. These preliminary findings indicate that apremilast may have the potential to prevent astrocyte cell death and promote neuronal healing in cerebral ischemic injury. Further in vivo research will expand our understanding of these promising results.

Identifying transposable element expression dynamics and heterogeneity during development at the single-cell level with a processing pipeline scTE.

Transposable elements (TEs) make up a majority of a typical eukaryote's genome, and contribute to cell heterogeneity in unclear ways. Single-cell sequencing technologies are powerful tools to explore cells, however analysis is typically gene-centric and TE expression has not been addressed. Here, we develop a single-cell TE processing pipeline, scTE, and report the expression of TEs in single cells in a range of biological contexts. Specific TE types are expressed in subpopulations of embryonic stem cells and are dynamically regulated during pluripotency reprogramming, differentiation, and embryogenesis. Unexpectedly, TEs are expressed in somatic cells, including human disease-specific TEs that are undetectable in bulk analyses. Finally, we apply scTE to single-cell ATAC-seq data, and demonstrate that scTE can discriminate cell type using chromatin accessibly of TEs alone. Overall, our results classify the dynamic patterns of TEs in single cells and their contributions to cell heterogeneity.

On-Nanoparticle Gating Units Render an Ordinary Catalyst Substrate- and Site-Selective.

When an organometallic catalyst is tethered onto a nanoparticle and is embedded in a monolayer of longer ligands terminated in "gating" end-groups, these groups can control the access and orientation of the incoming substrates. In this way, a nonspecific catalyst can become enzyme-like: it can select only certain substrates from substrate mixtures and, quite remarkably, can also preorganize these substrates such that only some of their otherwise equivalent sites react. For a simple, copper-based click reaction catalyst and for gating ligands terminated in charged groups, both substrate- and site-selectivities are on the order of 100, which is all the more notable given the relative simplicity of the on-particle monolayers compared to the intricacy of enzymes' active sites. The strategy of self-assembling macromolecular, on-nanoparticle environments to enhance selectivities of "ordinary" catalysts presented here is extendable to other types of catalysts and gating based on electrostatics, hydrophobicity, and chirality, or the combinations of these effects. Rational design of such systems should be guided by theoretical models we also describe.

Unified Analysis of Multiple ChIP-Seq Datasets.

High-throughput sequencing technologies are increasingly used in molecular cell biology to assess genome-wide chromatin dynamics of proteins bound to DNA, through techniques such as chromatin immunoprecipitation sequencing (ChIP-seq). These techniques often rely on an analysis strategy based on identifying genomic regions with increased sequencing signal to infer the binding location or chemical modifications of proteins bound to DNA. Peak calling within individual samples has been well described, however relatively little attention has been devoted to the merging of replicate samples, and the cross-comparison of many samples. Here, we present a generalized strategy to enable the unification of ChIP-seq datasets, enabling enhanced cross-comparison of binding patterns. The strategy works by merging peak data between different (even unrelated) samples, and then using a local background to recalculate enrichment. This strategy redefines the peaks within each experiment, allowing for more accurate cross-comparison of datasets.

Accelerating Crystallization of Open Organic Materials by Poly(ionic liquid)s.

The capability to significantly shorten the synthetic period of a broad spectrum of open organic materials presents an enticing prospect for materials processing and applications. Herein we discovered 1,2,4-triazolium poly(ionic liquid)s (PILs) could serve as a universal additive to accelerate by at least one order of magnitude the growth rate of representative imine-linked crystalline open organics, including organic cages, covalent organic frameworks (COFs), and macrocycles. This phenomenon results from the active C5-protons in poly(1,2,4-triazolium)s that catalyze the formation of imine bonds, and the simultaneous salting-out effect (induced precipitation by decreasing solubility) that PILs exert on these crystallizing species.

Enhancing crystal growth using polyelectrolyte solutions and shear flow.

The ability to grow properly sized and good quality crystals is one of the cornerstones of single-crystal diffraction, is advantageous in many industrial-scale chemical processes1-3, and is important for obtaining institutional approvals of new drugs for which high-quality crystallographic data are required4-7. Typically, single crystals suitable for such processes and analyses are grown for hours to days during which any mechanical disturbances-believed to be detrimental to the process-are carefully avoided. In particular, stirring and shear flows are known to cause secondary nucleation, which decreases the final size of the crystals (though shear can also increase their quantity8-14). Here we demonstrate that in the presence of polymers (preferably, polyionic liquids), crystals of various types grow in common solvents, at constant temperature, much bigger and much faster when stirred, rather than kept still. This conclusion is based on the study of approximately 20 diverse organic molecules, inorganic salts, metal-organic complexes, and even some proteins. On typical timescales of a few to tens of minutes, these molecules grow into regularly faceted crystals that are always larger (with longest linear dimension about 16 times larger) than those obtained in control experiments of the same duration but without stirring or without polymers. We attribute this enhancement to two synergistic effects. First, under shear, the polymers and their aggregates disentangle, compete for solvent molecules and thus effectively 'salt out' (that is, induce precipitation by decreasing solubility of) the crystallizing species. Second, the local shear rate is dependent on particle size, ultimately promoting the growth of larger crystals (but not via surface-energy effects as in classical Ostwald ripening). This closed-system, constant-temperature crystallization driven by shear could be a valuable addition to the repertoire of crystal growth techniques, enabling accelerated growth of crystals required by the materials and pharmaceutical industries.

Exosomes-carried microRNA-26b-5p regulates microglia M1 polarization after cerebral ischemia/reperfusion.

Exosome and microRNAs (miRs) are implicated in ischemia/reperfusion (I/R) process. In this study, I/R mouse model was established, and exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) were isolated, identified, and injected to I/R mice to observe nerve injury and microglia M1 polarization. The differentially expressed genes in I/R microglia from databases were analyzed, and miRs differentially expressed in exosomes-treated microglia were analyzed by microarray. miR-26b-5p expression in hUCMSCs was intervened. Besides, microglia was extracted and co-cultured with SH-SY5Y or PC12 cells in oxygen-glucose deprivation/reperfusion (OGD/R) models to simulate I/R in vivo. Additionally, Toll-like receptor (TLR) activator GS-9620 was added to microglia. Exosomes alleviated nerve injury and inhibited M1 polarization in microglia. After I/R modeling, CH25H expression in microglia was upregulated but decreased after exosome treatment. miR-26b-5p was upregulated in microglia after exosome treatment and could target CH25H. Reduction in exosomal miR-26b-5p reversed the effects of hUCMSCs-exos on microglia. TLR pathway was activated in microglia after I/R but exosomes prevented its activation. Exosomal miR-26b-5p could repress M1 polarization of microglia by targeting CH25H to inactivate the TLR pathway, so as to relieve nerve injury after cerebral I/R. This investigation may offer new approaches for I/R treatment.

Poly(ionic liquid) composites.

Poly(ionic liquid)s (PILs), as an innovative class of polyelectrolytes, are composed of polymeric backbones with IL species in each repeating unit. The combined merits of the polymers and ILs make them promising materials for composites in materials science. Particularly, the integration of PILs with functional substances (PIL composites) opens up a new dimension in utilizing ionic polymers by offering novel properties and improved functions, which impacts multiple subfields of our chemical society. This review summarizes recent developments of PIL composites with a special emphasis on the preparation techniques that are based on the intrinsic properties of the PILs and the synergistic effects between the PILs and substances of interest for diverse applications.

Inhibition of microRNA-21-5p reduces keloid fibroblast autophagy and migration by targeting PTEN after electron beam irradiation.

Electron beam (EB) irradiation is useful to reduce the recurrence of keloids; however, the underlying mechanism remains unknown. MicroRNA-21 (miR-21), which regulates autophagy during cancer radiation therapy, was identified as a potential therapeutic target for keloids. Here, we investigate the regulatory mechanism(s) of miR-21-5p on keloid fibroblast autophagy and migration after EB irradiation. The microRNA expression profile of the keloid dermis was examined by performing a microRNA microarray. Levels of LC3B and Beclin-1 were detected by immunohistochemical and western blot analysis in the keloid dermis and fibroblasts. Autophagy and apoptosis were tested in keloid fibroblasts after EB irradiation or transfection with an miR-21-5p inhibitor using electron microscopy, a Cyto-ID Green Autophagy Detection Kit, and an Annexin V PE Apoptosis Detection Kit. Migration was analyzed by an in vitro scratch-wound healing assay. Mechanistic tests were performed using small interfering RNAs to phosphatase and tensin homolog (siPTEN). Levels of miR-21-5p, PTEN, programmed cell death 4 (PDCD4), p-AKT, and apoptosis- and autophagy-associated genes were examined by qRT-PCR and western blotting. LC3B expression and migration ability were enhanced in fibroblasts and the keloid margin dermis compared with those in the adjacent normal skin. Both EB irradiation and an miR-21-5p inhibitor reduced keloid fibroblast autophagy, which was accompanied by decreased expression of miR-21-5p, p-AKT, and LC3B-II and increased expression of PTEN, PDCD4, and apoptosis-related genes. MiR-21-5p downregulation inhibited migration and suppressed LC3B expression and this was reversed by PTEN reduction. In conclusion, with increasing apoptosis, EB irradiation inhibits autophagy in keloid fibroblasts by reducing miR-21-5p, which regulates migration and LC3B expression via PTEN/AKT signaling. These data suggest a potential mechanism wherein miR-21-5p inhibition regulates autophagy and migration in EB-irradiated keloid fibroblasts, effectively preventing local invasion and recurrence. Therefore, miR-21-5p could be a new therapeutic target, to replace EB irradiation, and control keloid relapse.