InferLoop: leveraging single-cell chromatin accessibility for the signal of chromatin loop.

Deciphering cell-type-specific 3D structures of chromatin is challenging. Here, we present InferLoop, a novel method for inferring the strength of chromatin interaction using single-cell chromatin accessibility data. The workflow of InferLoop is, first, to conduct signal enhancement by grouping nearby cells into bins, and then, for each bin, leverage accessibility signals for loop signals using a newly constructed metric that is similar to the perturbation of the Pearson correlation coefficient. In this study, we have described three application scenarios of InferLoop, including the inference of cell-type-specific loop signals, the prediction of gene expression levels and the interpretation of intergenic loci. The effectiveness and superiority of InferLoop over other methods in those three scenarios are rigorously validated by using the single-cell 3D genome structure data of human brain cortex and human blood, the single-cell multi-omics data of human blood and mouse brain cortex, and the intergenic loci in the GWAS Catalog database as well as the GTEx database, respectively. In addition, InferLoop can be applied to predict loop signals of individual spots using the spatial chromatin accessibility data of mouse embryo. InferLoop is available at https://github.com/jumphone/inferloop.

ARID1A loss promotes RNA editing of CDK13 in an ADAR1-dependent manner.

BACKGROUND: ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is thought to play a significant role both in tumor suppression and tumor initiation, which is highly dependent upon context. Previous studies have suggested that ARID1A deficiency may contribute to cancer development. The specific mechanisms of whether ARID1A loss affects tumorigenesis by RNA editing remain unclear. RESULTS: Our findings indicate that the deficiency of ARID1A leads to an increase in RNA editing levels and alterations in RNA editing categories mediated by adenosine deaminases acting on RNA 1 (ADAR1). ADAR1 edits the CDK13 gene at two previously unidentified sites, namely Q113R and K117R. Given the crucial role of CDK13 as a cyclin-dependent kinase, we further observed that ADAR1 deficiency results in changes in the cell cycle. Importantly, the sensitivity of ARID1A-deficient tumor cells to SR-4835, a CDK12/CDK13 inhibitor, suggests a promising therapeutic approach for individuals with ARID1A-mutant tumors. Knockdown of ADAR1 restored the sensitivity of ARID1A deficient cells to SR-4835 treatment. CONCLUSIONS: ARID1A deficiency promotes RNA editing of CDK13 by regulating ADAR1.

FitDevo: accurate inference of single-cell developmental potential using sample-specific gene weight.

The quantification of developmental potential is critical for determining developmental stages and identifying essential molecular signatures in single-cell studies. Here, we present FitDevo, a novel method for inferring developmental potential using scRNA-seq data. The main idea of FitDevo is first to generate sample-specific gene weight (SSGW) and then infer developmental potential by calculating the correlation between SSGW and gene expression. SSGW is generated using a generalized linear model that combines sample-specific information and gene weight learned from a training dataset covering scRNA-seq data of 17 previously published datasets. We have rigorously validated FitDevo's effectiveness using a testing dataset with scRNA-seq data from 28 existing datasets and have also demonstrated its superiority over current methods. Furthermore, FitDevo's broad application scope has been illustrated using three practical scenarios: deconvolution analysis of epidermis, spatial transcriptomic data analysis of hearts and intestines, and developmental potential analysis of breast cancer. The source code and related data are available at https://github.com/jumphone/fitdevo.

Edge Length-Programmed Single-Stranded RNA Origami for Predictive Innate Immune Activation and Therapy.

Ligands targeting nucleic acid-sensing receptors activate the innate immune system and play a critical role in antiviral and antitumoral therapy. However, ligand design for in situ stability, targeted delivery, and predictive immunogenicity is largely hampered by the sophisticated mechanism of the nucleic acid-sensing process. Here, we utilize single-stranded RNA (ssRNA) origami with precise structural designability as nucleic acid sensor-based ligands to achieve improved biostability, organelle-level targeting, and predictive immunogenicity. The natural ssRNAs self-fold into compact nanoparticles with defined shapes and morphologies and exhibit resistance against RNase digestion in vitro and prolonged retention in macrophage endolysosomes. We find that programming the edge length of ssRNA origami can precisely regulate the degree of macrophage activation via a toll-like receptor-dependent pathway. Further, we demonstrate that the ssRNA origami-based ligand elicits an anti-tumoral immune response of macrophages and neutrophils in the tumor microenvironment and retards tumor growth in the mouse pancreatic tumor model. Our ssRNA origami strategy utilizes structured RNA ligands to achieve predictive immune activation, providing a new solution for nucleic acid sensor-based ligand design and biomedical applications.

Selamectin increases cisplatin sensitivity by inhibiting cisplatin-resistant genes expression and autophagy in uveal melanoma.

Cisplatin resistance is the main reason for uveal melanoma (UM) treatment failure. Thus, developing strategy that increasing cisplatin sensitivity is needed. In this study, we performed drug repositioning analysis with the Connectivity Map database using a panel of previously identified cisplatin sensitivity-associated genes and cisplatin resistance-associated genes as the signature and obtained the antiparasitic drug selamectin. We demonstrated that the selamectin and cisplatin combination showed a synergistic effect on inhibiting UM cell growth. Experiments in tumor-bearing nude mice further showed that selamectin and cisplatin have synergistic effects in reducing tumor growth. Previous studies have linked increased autophagy with tumor resistance to chemotherapy. We found that selamectin inhibited the expression of the autophagy-related gene ATG9B, thus reducing autophagy. The cisplatin resistance-associated genes PDGFRB, DUSP1, MAST1 and IL11 were significantly downregulated in UM cells treated with selamectin. In summary, our study shows that selamectin enhanced the sensitivity of UM to cisplatin, through the mechanism of inhibiting cisplatin resistance-associated gene expression and autophagy. These findings may provide a new strategy for the treatment of UM.

Metal ions and nanometallic materials in antitumor immunity: Function, application, and perspective.

The slightest change in the extra/intracellular concentration of metal ions results in amplified effects by signaling cascades that regulate both cell fate within the tumor microenvironment and immune status, which influences the network of antitumor immunity through various pathways. Based on the fact that metal ions influence the fate of cancer cells and participate in both innate and adaptive immunity, they are widely applied in antitumor therapy as immune modulators. Moreover, nanomedicine possesses the advantage of precise delivery and responsive release, which can perfectly remedy the drawbacks of metal ions, such as low target selectivity and systematic toxicity, thus providing an ideal platform for metal ion application in cancer treatment. Emerging evidence has shown that immunotherapy applied with nanometallic materials may significantly enhance therapeutic efficacy. Here, we focus on the physiopathology of metal ions in tumorigenesis and discuss several breakthroughs regarding the use of nanometallic materials in antitumor immunotherapeutics. These findings demonstrate the prominence of metal ion-based nanomedicine in cancer therapy and prophylaxis, providing many new ideas for basic immunity research and clinical application. Consequently, we provide innovative insights into the comprehensive understanding of the application of metal ions combined with nanomedicine in cancer immunotherapy in the past few years.

Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex.

ATP-dependent chromatin remodeling complexes alter chromatin structure through interactions with chromatin substrates such as DNA, histones, and nucleosomes. However, whether chromatin remodeling complexes have the ability to regulate nonchromatin substrates remains unclear. Saccharomyces cerevisiae checkpoint kinase Mec1 (ATR in mammals) is an essential master regulator of genomic integrity. Here we found that the SWI/SNF chromatin remodeling complex is capable of regulating Mec1 kinase activity. In vivo, Mec1 activity is reduced by the deletion of Snf2, the core ATPase subunit of the SWI/SNF complex. SWI/SNF interacts with Mec1, and cross-linking studies revealed that the Snf2 ATPase is the main interaction partner for Mec1. In vitro, SWI/SNF can activate Mec1 kinase activity in the absence of chromatin or known activators such as Dpb11. The subunit requirement of SWI/SNF-mediated Mec1 regulation differs from that of SWI/SNF-mediated chromatin remodeling. Functionally, SWI/SNF-mediated Mec1 regulation specifically occurs in S phase of the cell cycle. Together, these findings identify a novel regulator of Mec1 kinase activity and suggest that ATP-dependent chromatin remodeling complexes can regulate nonchromatin substrates such as a checkpoint kinase.

PARP mediated DNA damage response, genomic stability and immune responses.

Poly(ADP-ribose) polymerase (PARP) enzymes, especially PARP1, play important roles in the DNA damage response and in the maintenance of genome stability, which makes PARPis a classic synthetic lethal therapy for BRCA-deficient tumors. Conventional mechanisms suggest that PARPis exert their effects via catalytic inhibition and PARP-DNA trapping. Recently, PARP1 has been found to play a role in the immune modulation of tumors. The blockade of PARP1 is able to induce innate immunity through a series of molecular mechanisms, thus allowing the prediction of the feasibility of PARPis combined with immune agents in the treatment of tumors. PARPis combined with immunomodulators may have a stronger tumor suppressive effect on inhibiting tumor growth and blocking immune escape.

In Situ Electrochemical Transformation toward Structure Optimized VEG@MXene Cathode for Enhanced Zinc-Ion Storage.

Vanadium-based derivatives, featuring affordable cost and high theoretical capacity, have gathered widespread interest in the context of aqueous zinc-ion batteries (ZIBs). However, the further application of vanadium-based materials is hindered by the limited electrical conductivity and cycling lifespan. Herein, 1D chain-like structure vanadyl ethylene glycolate (VEG, (VO(CH2 O)2 )), growing on the Ti3 C2 Tx MXene nanosheets, is synthesized via a one-step oil-bath heating process as cathode materials for ZIBs. Benefiting from the hybrid structure with high conductivity and abundant reactive sites, the VEG@MXene cathode exhibits a remarkable specific capacity (360.3 mAh g-1 at 0.5 A g-1 ), and impressive capacity retention (up to 85.2% after 3000 cycles at 10 A g-1 ). Mechanism analysis reveals a gradual phase transition from the original VEG on MXene to the stable Zn3 V2 O7 (OH)2 ·2H2 O nanoflakes accompanied by continuous zinc ion intercalation/deintercalation, offering more pathways for zinc ion transport. This work suggests that engineering conductivity-enhanced vanadium-based materials is a rational approach for developing promising cathode materials of ZIBs.

Ultrastable Zinc Anode by Simultaneously Manipulating Solvation Sheath and Inducing Oriented Deposition with PEG Stability Promoter.

Aqueous zinc-ion batteries are a low-cost and safe energy storage system, but suffer from detrimental side reactions and Zn dendrites due to the strong interactions between Zn2+ and water molecules in the electrolytes, and random Zn2+ deposition on the anode surface. Here, an electrolyte involving a dual-functional additive of polyethylene glycol (PEG) to bypass these issues is reported. The electrolyte can not only tailor the solvation sheath of Zn2+ but also enable favorably oriented deposition of Zn2+ on the anode surface. The dendrite-free Zn anode in Zn//Zn cells is obtained with high Columbic efficiency (98.8%) and long cycling lifespan (1500 h), six times longer than that of electrolyte without PEG at 0.25 mA cm-2 . What is more, the excellent cycling stability of the prepared batteries (Zn//V2 O5 ·1.6 H2 O) suggests that the developed tailoring strategy may propel a promising pathway for stabilizing Zn metal anodes.

Pt Edge-Doped MoS2 : Activating the Active Sites for Maximized Hydrogen Evolution Reaction Performance.

The demand of clean energy calls for efficient and low-cost hydrogen evolution reaction electrocatalysts. Fabricating hybrid catalysts from noble/non-noble catalysts is a practical route to reducing the consumption of noble metals and enhancing catalytic efficiency. Here, 2H-MoS2 is etched and edge-doped with Pt nanoparticles using focused ion beam and photoreduction techniques. Precise comparison of as-prepared samples demonstrates that the enhancement of catalytic performance can be controlled through tuning the catalyst defect length. On this basis, remarkably high performance is obtained by designing a specific defect array that is superior to commercial Pt/C with less Pt loading and higher mass activity. It has been proved by experimentation and COMSOL Multiphysics simulations that the promotion of catalytic activity not only benefits from the synergistic effect of Pt and edge active sites, but also contributes to the increased potential at the edges of the designed defect. This study sheds light on the mechanism of understanding nanoscale edge-doped hybrid catalysts and provides a feasible strategy for the full utilization of noble metals.

A Polymer/Graphene Composite Cathode with Active Carbonyls and Secondary Amine Moieties for High-Performance Aqueous Zn-Organic Batteries Involving Dual-Ion Mechanism.

Aqueous zinc-ion batteries (AZIBs) are regarded as one of the most promising alternative technology to lithium-ion batteries on account of their low flammability and cost-benefits. Among various cathode materials in AZIBs, environment-friendly and sustainable organic electrode materials stand out owing to their structural diversity and tunability. However, their limited rate capability and cycle stability remain the obstacles to their further application in AZIBs. Herein, a mixed cathode design strategy including polymerization and carbon materials hybridization is adopted to assemble high-rate and durable AZIBs. Specifically, a polymer/graphene composite cathode with active carbonyls and secondary amine moieties is prepared to construct high-performance aqueous Zn-organic batteries. Furthermore, a hybrid energy storage mechanism involving dual-ion mechanism is confirmed by various ex situ characterization techniques, providing promising battery chemistry. Thus, this work opens up a new path to high performance AZIBs through a rational cathode design.

Small ring has big potential: insights into extrachromosomal DNA in cancer.

Recent technical advances have led to the discovery of novel functions of extrachromosomal DNA (ecDNA) in multiple cancer types. Studies have revealed that cancer-associated ecDNA shows a unique circular shape and contains oncogenes that are more frequently amplified than that in linear chromatin DNA. Importantly, the ecDNA-mediated amplification of oncogenes was frequently found in most cancers but rare in normal tissues. Multiple reports have shown that ecDNA has a profound impact on oncogene activation, genomic instability, drug sensitivity, tumor heterogeneity and tumor immunology, therefore may offer the potential for cancer diagnosis and therapeutics. Nevertheless, the underlying mechanisms and future applications of ecDNA remain to be determined. In this review, we summarize the basic concepts, biological functions and molecular mechanisms of ecDNA. We also provide novel insights into the fundamental role of ecDNA in cancer.

Precursor-Transformation Strategy Preparation of CuPx Nanodots-Decorated CoP3 Nanowires Hybrid Catalysts for Boosting pH-Universal Electrocatalytic Hydrogen Evolution.

The development of earth-abundant, low cost, and versatile electrocatalysts for producing hydrogen from water electrolysis is still challenging. Herein, based on high hydrogen evolution reaction (HER) activity of transition metal phosphides, a CoP3 nanowire decorated with copper phosphides (denoted as CuPx ) nanodots structures synthesized through a simple and easily scalable precursor-transformation strategy is reported as a highly efficient HER catalyst. By decorating with CuPx nanodots, the optimized CoP3 nanowires electrode exhibits excellent catalytic activity and long-term durability for HER in alkaline conditions, achieving a low overpotential of 49.5 mV at a geometrical catalytic current density of 10 mA cm-2 with a small Tafel slope of 58.0 mV dec-1 , while also performing quite well in neutral and acidic media. Moreover, its overall performance exceeds most of the reported state-of-the-art catalysts, especially under high current density of 100 mA cm-2 , demonstrating its potential as a promising versatile pH universal electrocatalyst for efficient water electrolysis. These results indicate that the incorporation of earth-abundant stable element copper can significantly enhance catalytic activity, which widens the application range of copper and provides a new path for design and selection of HER catalysts.

Amorphous Sn/Crystalline SnS2 Nanosheets via In Situ Electrochemical Reduction Methodology for Highly Efficient Ambient N2 Fixation.

Electrochemical nitrogen reduction reaction (NRR) as a new strategy for synthesizing ammonia has attracted ever-growing attention, due to its renewability, flexibility, and sustainability. However, the lack of efficient electrocatalysts has hampered the development of such reactions. Herein, a series of amorphous Sn/crystalline SnS2 (Sn/SnS2 ) nanosheets by an L-cysteine-based hydrothermal process, followed by in situ electrochemical reduction, are synthesized. The amount of reduced amorphous Sn can be adjusted by selecting electrolytes with different pH values. The optimized Sn/SnS2 catalyst can achieve a high ammonia yield of 23.8 µg h-1 mg-1 , outperforming most reported noble-metal NRR electrocatalysts. According to the electrochemical tests, the conversion of SnS2 to an amorphous Sn phase leads to the substantial increase of its catalytic activity, while the amorphous Sn is identified as the active phase. These results provide a guideline for a rational design of low-cost and highly active Sn-based catalysts thus paving a wider path for NRR.

Triangle Trocar Configuration in Laparoscopic Totally Extraperitoneal Inguinal Hernia Repair: A Prospective Randomized Controlled Study.

BACKGROUND: In totally extraperitoneal (TEP) operation, when trocars are arranged with midline configuration, operative instruments can easily interfere with each other because of the small operative angle. The triangle trocar configuration, which creates a large operative angle, may minimize interference. Therefore, we evaluated the use of triangle trocar configuration in TEP inguinal hernia repair. METHODS: A prospective randomized controlled study was conducted in 113 patients of laparoscopic TEP inguinal hernia repair in the Department of Hernia and Abdominal Wall Surgery, Shanghai East Hospital, between July 2016 and June 2017. Patients were randomly assigned to TEP laparoscopic inguinal hernioplasty with triangle trocar configuration (study group, n = 59) or midline trocar configuration (control group, n = 54). Perioperative outcomes (operative time, operative complications, postoperative pain, hospital stay, and costs), early postoperative complications (seroma/hematoma and uroschesis), and mid-term outcomes (late postoperative complications and recurrence) were observed and compared. RESULTS: After a mean follow-up of 10.21 ± 2.32 mo, there was no significant difference in operative time, operative complications, postoperative pain, postoperative hospital stay, costs, postoperative complications, and recurrence rate between the two groups. The indirect hernia sac dissection time was shorter in the study group than in the control group. CONCLUSIONS: Triangle trocar configuration in TEP laparoscopic hernia repair is safe and reliable and is an option for hernia surgeons. The technique creates a large operative angle and avoids interference between endo-instruments, which facilitates TEP and decreases the indirect hernia sac dissection time.

Cationic supercapacitance of carbon nanotubes covered with copper hexacyanoferrate.

Carbon nanotubes (CNT) are uniformly covered with copper hexacyanoferrate (CuHCF) via coprecipitation to form a core shell structure. The CuHCF thickness can be tuned from 10 nm to 30 nm by changing the CuHCF loading in the hybrids from 25% to 58%. The capacitive behavior is affected by the hydrated cation radius. In 1 mol l-1 KCl solution, CuHCF/CNT hybrids (46% CuHCF loading) show the largest specific capacitance of up to 989 F g-1 at a discharge density of 1 A g-1. The hybrids also possess superior rate capability with only 8.2% capacitance loss when increasing the discharge current from 1 to 20 A g-1. The superior capacitive performance of the hybrids in the K+-ion solution can be attributed to the smaller hydrated radius of the K+ ion, which will favor the diffusion of the cation within the CuHCF lattice, leading to a larger faradic current. Besides, the cyclic stability of the hybrids is surprising, with 89.7% capacitance retention after 10000 discharge/charge cycles. The CuHCF/CNT hybrids are combined with the reduced graphene oxides (RGOs) to construct an asymmetrical supercapacitor, and its potential window can reach up to 2.0 V. More importantly, this supercapacitor exhibits a high energy density of 60.4 Wh kg-1 at the power density of 0.5 kW kg-1.

One-pot synthesis of a PtPd dendritic nanocube cage superstructure on graphenes as advanced catalysts for oxygen reduction.

How to use Pt economically and efficiently in the oxygen reduction reaction (ORR) is of theoretical and practical significance for the industrialization of the proton-exchange membrane fuel cells. In order to minimize Pt consumption and optimize the ORR performance, the ORR catalysts are recommended to be designed as a porous nanostructure. Herein, we report a one-pot solvothermal strategy to prepare PtPd dendritic nanocube cages via a galvanic replacement mechanism triggered by an I- ion. These PtPd alloy crystals are nanoporous, and uniformly dispersed on reduced graphene oxides (RGOs). The size of the PtPd dendritic nanocube cages can be easily tuned from 20-80 nm by controlling their composition. Their composition is optimized to be 1:5 Pt/Pd atomic ratio for these RGO-supported PtPd dendritic nanocages. This catalyst shows superior ORR performance with a specific activity of 2.01 mA  cm-2 and a mass activity of 4.45 A  mg-1 Pt, far above those for Pt/C catalysts (0.288 mA  cm-2 for specific activity, and 0.21 A  mg-1 Pt for mass activity). In addition to ORR activity, it also exhibits robust durability with almost negligible decay in ORR mass activity after 10 000 voltammetric cycling.

Surface Tension Components Based Selection of Cosolvents for Efficient Liquid Phase Exfoliation of 2D Materials.

A proper design of direct liquid phase exfoliation (LPE) for 2D materials as graphene, MoS2 , WS2 , h-BN, Bi2 Se3 , MoSe2 , SnS2 , and TaS2 with common cosolvents is carried out based on considering the polar and dispersive components of surface tensions of various cosolvents and 2D materials. It has been found that the exfoliation efficiency is enhanced by matching the ratio of surface tension components of cosolvents to that of the targeted 2D materials, based on which common cosolvents composed of IPA/water, THF/water, and acetone/water can be designed for sufficient LPE process. In this context, the library of low-toxic and low-cost solvents with low boiling points for LPE is infinitely enlarged when extending to common cosolvents. Polymer-based composites reinforced with a series of different 2D materials are compared with each other. It is demonstrated that the incorporation of cosolvents-exfoliated 2D materials can substantially improve the mechanical and thermal properties of polymer matrices. Typically, with the addition of 0.5 wt% of such 2D material as MoS2 nanosheets, the tensile strength and Young's modulus increased up to 74.85% and 136.97%, respectively. The different enhancement effect of 2D materials is corresponded to the intrinsic properties and LPE capacity of 2D materials.

One-pot synthesis of single-crystal Pt nanoplates uniformly deposited on reduced graphene oxide, and their high activity and stability on the electrocalalytic oxidation of methanol.

We demonstrate a one-pot thermoreduction approach towards the preparation of single-crystal Pt nanoplates, which were uniformly deposited on the reduced graphene oxide (RGO) using polyvinylpyrrolidone (PVP) as a stabilizer. The size of Pt nanoplates can be tuned from 6.8 to 10.1 nm by controlling Pt loading. The as-prepared Pt/PVP/RGO catalysts show high stability and activity towards the methanol oxidation reaction (MOR). Their MOR current can reach up to 401 mA mg(-1) Pt and MOR current can maintain 89.4% of its initial value after 10 000 potential cycles.