Unveiling the role of UPF3B in hepatocellular carcinoma: Potential therapeutic target.

RNA-binding proteins can regulate nucleotide metabolism and gene expression. UPF3B regulator of nonsense mediated mRNA decay (UPF3B) exhibits dysfunction in cancers. However, its role in the progression of hepatocellular carcinoma (HCC) is still insufficiently understood. Here, we found that UPF3B was markedly upregulated in HCC samples and associated with adverse prognosis in patients. UPF3B dramatically promoted HCC growth both in vivo and in vitro. Mechanistically, UPF3B was found to bind to PPP2R2C, a regulatory subunit of PP2A, boosting its mRNA degradation and activating the PI3K/AKT/mTOR pathway. E2F transcription factor 6 (E2F6) directly binds to the UPF3B promoter to facilitate its transcription. Together, the E2F6/UPF3B/PPP2R2C axis promotes HCC growth through the PI3K/AKT/mTOR pathway. Hence, it could be a promising therapeutic target for treating HCC.

TGF-ß1-Induced LINC01094 promotes epithelial-mesenchymal transition in hepatocellular carcinoma through the miR-122-5p/TGFBR2-SAMD2-SMAD3 Axis.

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. It has been proven that long non-coding RNAs (lncRNAs) play an essential role in regulating HCC progression. However, the involvement of LINC01094 in regulating epithelial-mesenchymal transition (EMT) in HCC remains unclear. LINC01094 expression in HCC patients was retrieved from the Cancer Genome Atlas database. Overexpressing and downregulating LINC01094 were conducted to investigate its biological functions using Hep3B, SNU-387, and HuH-7 cells. Western blotting and morphological observation were performed to study the EMT in HCC cells. Transwell assay was adopted to determine the migration and invasion of HCC cells. The underlying mechanism of competitive endogenous RNAs (ceRNAs) was investigated using bioinformatics analysis, quantitative reverse-transcription polymerase chain reaction, and rescue experiments. Elevated LINC01094 expression was observed in HCC and associated with a poor prognosis. Knockdown of LINC01094 expression in SNU-387 and HuH-7 cells could inhibit migration, invasion, and EMT markers. Overexpression of LINC01094 indicated that LINC01094 promoted EMT via the TGF-ß/SMAD signaling pathway. The bioinformatics analysis revealed that miR-122-5p was a target of LINC01094. The miRWalk database analysis showed that TGFBR2, SMAD2, and SMAD3 were downstream targets of miR-122-5p. Mechanically, LINC01094 acted as a ceRNA that facilitated HCC metastasis by sponging miR-122-5p to regulate the expression of TGFBR2, SMAD2, and SMAD3. Further, TGF-ß1 could enhance the expression of LINC01094, forming a positive feedback loop. TGF-ß1-induced LINC01094 expression promotes HCC cell migration and invasion by targeting the miR-122-5p/TGFBR2-SMAD2-SMAD3 axis. LINC01094 may be a potential prognostic biomarker and therapeutic target for HCC metastasis.

CarveMix: A simple data augmentation method for brain lesion segmentation.

Brain lesion segmentation provides a valuable tool for clinical diagnosis and research, and convolutional neural networks (CNNs) have achieved unprecedented success in the segmentation task. Data augmentation is a widely used strategy to improve the training of CNNs. In particular, data augmentation approaches that mix pairs of annotated training images have been developed. These methods are easy to implement and have achieved promising results in various image processing tasks. However, existing data augmentation approaches based on image mixing are not designed for brain lesions and may not perform well for brain lesion segmentation. Thus, the design of this type of simple data augmentation method for brain lesion segmentation is still an open problem. In this work, we propose a simple yet effective data augmentation approach, dubbed as CarveMix, for CNN-based brain lesion segmentation. Like other mixing-based methods, CarveMix stochastically combines two existing annotated images (annotated for brain lesions only) to obtain new labeled samples. To make our method more suitable for brain lesion segmentation, CarveMix is lesion-aware, where the image combination is performed with a focus on the lesions and preserves the lesion information. Specifically, from one annotated image we carve a region of interest (ROI) according to the lesion location and geometry with a variable ROI size. The carved ROI then replaces the corresponding voxels in a second annotated image to synthesize new labeled images for network training, and additional harmonization steps are applied for heterogeneous data where the two annotated images can originate from different sources. Besides, we further propose to model the mass effect that is unique to whole brain tumor segmentation during image mixing. To evaluate the proposed method, experiments were performed on multiple publicly available or private datasets, and the results show that our method improves the accuracy of brain lesion segmentation. The code of the proposed method is available at https://github.com/ZhangxinruBIT/CarveMix.git.

Thiele's Fluorocarbons: Stable Diradicaloids with Efficient Visible-to-Near-Infrared Fluorescence from a Zwitterionic Excited State.

Thiele's hydrocarbon was the first synthesized diradicaloid in the search for stable open-shell structures, but it remains sensitive to oxygen and light. We here report the synthesis of Thiele's fluorocarbon (TFC) and its derivatives exhibiting exceptional thermal, oxidative, and photostability. TFCs have remarkable luminescent properties with yellow to NIR fluorescence and up to 100% quantum yields. X-ray crystallography and ESR spectroscopy confirm their closed-shell quinoidal ground state. As expected from their symmetric nonpolar structure, the TFCs' absorption spectra show no solvent effect, but their emission reveals an extraordinarily large Stokes shift which increases with solvent polarity (from 0.9 eV in cyclohexane to 1.5 eV in acetonitrile). We show that this behavior is a result of sudden polarization, leading to a zwitterionic excited state.

Development of a TNF-α-mediated Trojan Horse for bacteria-based cancer therapy.

Tumor necrosis factor α (TNF-α) is upregulated in a chronic inflammatory environment, including tumors, and has been recognized as a pro-tumor factor in many cancers. Applying the traditional TNF-α antibodies that neutralize TNF-α activity, however, only exerts modest anti-tumor efficacy in clinical studies. Here, we develop an innovative approach to target TNF-α that is distinct from the neutralization mechanism. We employed phage display and yeast display to select non-neutralizing antibodies that can piggyback on TNF-α and co-internalize into cells through receptor ligation. When conjugating with toxins, the antibody exhibited cytotoxicity to cancer cells in a TNF-α-dependent manner. We further implemented the immunotoxin to an E. coli vehicle specially engineered for a high secretion level. In a syngeneic murine melanoma model, the bacteria stimulated TNF-α expression that synergized with the secreted immunotoxin and greatly inhibited tumor growth. The treatment also dramatically remodeled the tumor microenvironment in favor of several anti-tumor immune cells, including N1 neutrophils, M1 macrophages, and activated CD4+ and CD8+ lymphocytes. We anticipate that our new piggyback strategy is generalizable to targeting other soluble ligands and/or conjugates with different drugs for managing a diverse set of diseases.

Integrated barium titanate electro-optic modulators operating at CMOS-compatible voltage.

We propose monolithically integrated electro-optical modulators based on thin-film x-cut barium titanate that exhibit large modulation bandwidth and operate at voltages compatible with complementary metal-oxide-semiconductor technology. The optical and radio frequency parameters of the modulator are systematically simulated, calculated, and optimized, respectively. Our simulation includes the evaluation of single-mode conditions, the separation distance between the electrode edge and the waveguide edge, bending loss, optical field distribution, and half-wave voltage-length product for optical parameters, and characteristic impedance, attenuation constant, radio frequency effective index, and -3d B modulation bandwidth for radio frequency parameters. By engineering both the microwave and photonic circuits, we have achieved high electro-optical efficiencies and group-velocity matching simultaneously. Our numerical simulation and theoretical analysis show that the half-wave voltage-length product was 0.48 V·cm, and the -3d B modulation bandwidths with a device length of 5 mm and 10 mm were 262 GHz and 107 GHz, respectively. Overall, our study highlights the potential of the proposed modulators for low driving voltage and high-performance optical communication systems.

Blood tau-PT217 contributes to the anesthesia/surgery-induced delirium-like behavior in aged mice.

INTRODUCTION: Blood phosphorylated tau at threonine 217 (tau-PT217) is a newly established biomarker for Alzheimer's disease and postoperative delirium in patients. However, the mechanisms and consequences of acute changes in blood tau-PT217 remain largely unknown. METHODS: We investigated the effects of anesthesia/surgery on blood tau-PT217 in aged mice, and evaluated the associated changes in B cell populations, neuronal excitability in anterior cingulate cortex, and delirium-like behavior using positron emission tomography imaging, nanoneedle technology, flow cytometry, electrophysiology, and behavioral tests. RESULTS: Anesthesia/surgery induced acute increases in blood tau-PT217 via enhanced generation in the lungs and release from B cells. Tau-PT217 might cross the blood-brain barrier, increasing neuronal excitability and inducing delirium-like behavior. B cell transfer and WS635, a mitochondrial function enhancer, mitigated the anesthesia/surgery-induced changes. DISCUSSION: Acute increases in blood tau-PT217 may contribute to brain dysfunction and postoperative delirium. Targeting B cells or mitochondrial function may have therapeutic potential for preventing or treating these conditions.

Simulation framework for fringe projection profilometry using ray tracing and light transport coefficient measurement.

Fringe projection profilometry is widely used in optical metrology, and fringe analysis is important to improve measurement accuracy. However, the fringe images captured by cameras are influenced by many factors, an analytical study of which, to characterize the imaging process, is difficult to perform. We propose a method to accurately simulate the real imaging system in the virtual environment using ray tracing algorithm. The light transport coefficients of the cameras are measured to simulate defocus instead of using Gaussian function. Experimental results show that the proposed method can simulate a physical system in the virtual environment more accurately than the Gaussian function at large defocus condition.

RetroGNN: Fast Estimation of Synthesizability for Virtual Screening and De Novo Design by Learning from Slow Retrosynthesis Software.

De novo molecule design algorithms often result in chemically unfeasible or synthetically inaccessible molecules. A natural idea to mitigate this problem is to bias these algorithms toward more easily synthesizable molecules using a proxy score for synthetic accessibility. However, using currently available proxies can still result in highly unrealistic compounds. Here, we propose a novel approach, RetroGNN, to estimate synthesizability. First, we search for routes using synthesis planning software for a large number of random molecules. This information is then used to train a graph neural network to predict the outcome of the synthesis planner given the target molecule, in which the regression task can be used as a synthesizability scorer. We highlight how RetroGNN can be used in generative molecule-discovery pipelines together with other scoring functions. We evaluate our approach on several QSAR-based molecule design benchmarks, for which we find synthesizable molecules with state-of-the-art scores. Compared to the virtual screening of 5 million existing molecules from the ZINC database, using RetroGNNScore with a simple fragment-based de novo design algorithm finds molecules predicted to be more likely to possess the desired activity exponentially faster, while maintaining good druglike properties and being easier to synthesize. Importantly, our deep neural network can successfully filter out hard to synthesize molecules while achieving a 105 times speedup over using retrosynthesis planning software.

Pressure-Controlled Encapsulation of Graphene Quantum Dots into Liposomes by the Reverse-Phase Evaporation Method.

Ultrasmall nanoparticles (USNPs) with sizes below 10 nm have shown great potentials in medical applications owing to their outstanding physical, chemical, optical, and biological properties. However, they suffer from a rapid renal clearance and biodegradation rate in the biological environment due to the small size. Liposomes are one of the most promising delivery nanocarriers for loading USNPs because of their excellent biocompatibility and lipid bilayer structure. Encapsulation of USNPs into liposomes in an efficient and controllable manner remains a challenge. In this study, we achieved a high loading of graphene quantum dots (GQDs, ∼4 nm), a typical USNP, into the aqueous core of liposomes (45.68 ± 1.44%), which was controllable by the pressure. The GQDs-loaded liposomes (GQDs-LPs) exhibited a very good aqueous stability for over a month. Furthermore, indocyanine green (ICG), an efficient near-infrared (NIR) photothermal agent, was introduced in the GQDs-LP system that could convert NIR laser energy into thermal energy and break down the liposomes, causing the release of GQDs in 6 min. Moreover, this NIR light-controlled release system (GQDs-ICG-LPs) also exhibited a good photothermal therapeutic performance in vitro, and 75% of cancer cells were killed at a concentration of 200 µg/mL. Overall, the successful development of the NIR light-controlled release system has laid a solid foundation for the future biomedical application of USNPs-loaded liposomes.

Assessment of indocyanine green tracer-guided lymphadenectomy in laparoscopic gastrectomy after neoadjuvant chemotherapy for locally advanced gastric cancer: results from a multicenter analysis based on propensity matching.

BACKGROUND: This study evaluated the safety, effectiveness, and feasibility of indocyanine green (ICG) tracing in guiding lymph-node (LN) dissection during laparoscopic D2 radical gastrectomy in patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC). METHOD: We retrospectively analyzed data on 313 patients with clinical stage of cT1-4N0-3M0 who underwent laparoscopic radical gastrectomy after NAC between February 2010 and October 2020 from two hospitals in China. Grouped according to whether ICG was injected. For the ICG group (n = 102) and non-ICG group (n = 211), 1:1 propensity matching analysis was used. RESULTS: After matching, there was no significant difference in the general clinical pathological data between the two groups (ICG vs. non-ICG: 94 vs. 94). The average number of total LN dissections was significantly higher in the ICG group and lower LN non-compliance rate than in the non-ICG group. Subgroup analysis showed that among patients with LN and tumor did not shrink after NAC, the number of LN dissections was significantly more and LN non-compliance rate was lower in the ICG group than in the non-ICG group. Intraoperative blood loss was significantly lesser in the ICG group than in the non-ICG group, while the recovery and complications of the two groups were similar. CONCLUSION: For patients with poor NAC outcomes, ICG tracing can increase the number of LN dissections during laparoscopic radical gastrectomy, reduce the rate of LN non-compliance, and reduce intraoperative bleeding. Patients with AGC should routinely undergo ICG-guided laparoscopic radical gastrectomy.

Combining Proximity Labeling and Cross-Linking Mass Spectrometry for Proteomic Dissection of Nuclear Envelope Interactome.

Proximity labeling (PL) and chemical cross-linking (XL) mass spectrometry are two powerful methods to dissect protein-protein interactions (PPIs) in cells. Although PL typically captures neighboring proteins within a range of 10-20 nm of a single bait protein, chemical XL defines direct protein-protein contacts within 1 nm in a systemic manner. Here, we develop a new method, named PL/XL-MS, to harness the advantages of both PL and XL. PL/XL-MS can enrich a subcellular compartment by PL and simultaneously identify PPIs of multiple proteins from XL data. We applied PL/XL-MS to dissect the human nuclear envelope interactome. PL/XL-MS successfully enriched the nuclear envelope proteins and identified most known inner nuclear membrane proteins. By searching the cross-linked peptides, we successfully observed 109 literature-curated PPIs of 14 nuclear envelope proteins. Based on the homoprotein XL data, we experimentally characterized a nuclear matrix protein, Matrin-3, and observed its preferential localization near the nuclear envelope. PL/XL-MS is a simple and general method for studying protein networks in a subproteome of interest.

Transformation between 2D and 3D Covalent Organic Frameworks via Reversible [2 + 2] Cycloaddition.

We report the first transformation between crystalline vinylene-linked two-dimensional (2D) polymers and crystalline cyclobutane-linked three-dimensional (3D) polymers. Specifically, absorption-edge irradiation of the 2D poly(arylenevinylene) covalent organic frameworks (COFs) results in topological [2 + 2] cycloaddition cross-linking of the π-stacked layers in 3D COFs. The reaction is reversible, and heating to 200 °C leads to a cycloreversion while retaining the COF crystallinity. The resulting difference in connectivity is manifested in the change of mechanical and electronic properties, including exfoliation, blue-shifted UV-vis absorption, altered luminescence, modified band structure, and different acid-doping behavior. The Li-impregnated 2D and 3D COFs show a significant room-temperature ion conductivity of 1.8 × 10-4 S/cm and 3.5 × 10-5 S/cm, respectively. Even higher room-temperature proton conductivity of 1.7 × 10-2 S/cm and 2.2 × 10-3 S/cm was found for H2SO4-treated 2D and 3D COFs, respectively.

Superionic Conductors via Bulk Interfacial Conduction.

Superionic conductors with ionic conductivity on the order of mS cm-1 are expected to revolutionize the development of solid-state batteries (SSBs). However, currently available superionic conductors are limited to only a few structural families such as garnet oxides and sulfide-based glass/ceramic. Interfaces in composite systems such as alumina in lithium iodide have long been identified as a viable ionic conduction channel, but practical superionic conductors employing the interfacial conduction mechanism are yet to be realized. Here we report a novel method that creates continuous interfaces in the bulk of composite thin films. Ions can conduct through the interface, and consequently, the inorganic phase can be ionically insulating in this type of bulk interface superionic conductors (BISCs). Ionic conductivities of lithium, sodium, and magnesium ion BISCs have reached 1.16 mS cm-1, 0.40 mS cm-1, and 0.23 mS cm-1 at 25 °C in 25 µm thick films, corresponding to areal conductance as high as 464 mS cm-2, 160 mS cm-2, and 92 mS cm-2, respectively. Ultralow overpotential and stable long-term cycling for up to 5000 h were obtained for solid-state Li metal symmetric batteries employing Li ion BISCs. This work opens new structural space for superionic conductors and urges for future investigations on detailed conduction mechanisms and material design principles.

A Two-Dimensional Poly(azatriangulene) Covalent Organic Framework with Semiconducting and Paramagnetic States.

The black crystalline (aza)triangulene-based covalent organic framework TANG-COF was synthesized from its trinitro-TANG precursor via a one-pot, two-step reaction involving Pd-catalyzed hydrogenation and polycondensation with an aromatic dialdehyde. High crystallinity and permanent porosity of the layered two-dimensional (2D) structure were established. The rigid, electron-rich trioxaazatriangulene (TANG) building block enables strong π-electron interactions manifested in broad absorptions across the visible and NIR regions (Eg ≈ 1.2 eV). The high HOMO energy of TANG-COF (-4.8 eV) enables facile p doping, resulting in electrical conductivity of up to 10-2 S/cm and room-temperature paramagnetic behavior with a spin concentration of ∼10%. DFT calculations reveal dispersion of the highest occupied band both within the 2D polymer layers (0.28 eV) and along their π-stacked direction (0.95 eV).

Understanding the Photovoltaic Behavior of A-D-A Molecular Semiconductors through a Permutation of End Groups.

The facile synthesis of a series of benzodithiophene (BDT)- and indacenodithiophene (IDT)-based A-D-A oligomers with different end groups is reported, and their properties are studied by optical spectroscopy, electrochemistry, and density functional theory calculations. The permutation of central and terminal units tunes the optoelectronic properties and photovoltaic device characteristics in a predictable way, aiding in the rational design of small molecule semiconducting materials. Among the three rhodanine-derived terminal groups, N-alkylthiazolonethione revealed the strongest electron-withdrawing character, resulting in the lowest band gap, the highest stability, and the best photovoltaic device performance. The crystallographic analysis of two IDT derivatives yielded a highly unusual three-dimensional packing of the conjugated backbone, which is likely responsible for the remarkable photovoltaic performance of such A-D-A semiconductors.

Advanced Lithium Metal-Carbon Nanotube Composite Anode for High-Performance Lithium-Oxygen Batteries.

The low Coulombic efficiency and hazardous dendrite growth hinder the adoption of lithium anode in high-energy density batteries. Herein, we report a lithium metal-carbon nanotube (Li-CNT) composite as an alternative to the long-term untamed lithium electrode to address the critical issues associated with the lithium anode in Li-O2 batteries, where the lithium metal is impregnated in a porous carbon nanotube microsphere matrix (CNTm) and surface-passivated with a self-assembled monolayer of octadecylphosphonic acid as a tailor-designed solid electrolyte interphase (SEI). The high specific surface area of the Li-CNT composite reduces the local current density and thus suppresses the lithium dendrite formation upon cycling. Moreover, the tailor-designed SEI effectively separates the Li-CNT composite from the electrolyte solution and prevents the latter's further decomposition. When the Li-CNT composite anode is coupled with another CNTm-based O2 cathode, the reversibility and cycle life of the resultant Li-O2 batteries are drastically elevated.

[Determination of ten kinds of α-hydroxy acids in cosmetics with quantitative analysis of multi-components by single marker].

OBJECTIVE: To establish a method for determination of ten kinds of α-hydroxy acids in cosmetics with quantitative analysis of multi-components by single marker(QAMS). METHODS: The analytes were separated by high performance liquid chromatography on a Venusil XBP C_8 column(4. 6 mm×250 mm, 5 µm), with the mobile phases of ammonium dihydrogen phosphate buffer-methonal under a gradient elution. The components were detected at the wavelengths of 214 nm using a diode array detector. Citric acid was used as the internal standard to determine the relative correction factors(RCFs) of the nine other α-hydroxy acids, in order to calculate their contents in samples by their RCFs. RESULTS: Good linearity with correlation coefficients greater than 0. 9994 was obtained for all the analytes. Stabilities within 24 h and precision of ten α-hydroxy acids were all good. Recoveries of the method were from 89. 3% to 105. 0% at three concentration levels, with the relative standard deviation(RSD) from 1. 0% to 2. 9%. Nine batches of samples were determined by QAMS, as well as the standard curve method(SCM). The relative average deviations(RAD) were below 3. 2% between the result of the two method, which showed good feasibility and accuracy of QAMS. CONCLUSION: The method is simple, accurate and beneficial to the saving of reference substances, which is suitable for the determination of ten kinds of α-hydroxy acids in cosmetics.

A Pure-Red Doublet Emission with 90 % Quantum Yield: Stable, Colorless, Iodinated Triphenylmethane Solid.

Red luminescence is found in off-white tris(iodoperchlorophenyl)methane (3I-PTMH ) crystals which is characterized by a high photoluminescence quantum yield (PLQY 91 %) and color purity (CIE coordinates 0.66, 0.34). The emission originates from the doublet excited state of the neutral radical 3I-PTMR , which is spontaneously formed and becomes embedded in the 3I-PTMH matrix. The radical defect can also be deliberately introduced into 3I-PTMH crystals which maintain a high PLQY with up to 4 % radical concentration. The immobilized iodinated radical demonstrates excellent photostability (estimated half-life >1 year under continuous irradiation) and intriguing luminescent lifetime (69 ns). TD-DFT calculations demonstrate that electron-donating iodine atoms accelerate the radiative transition while the rigid halogen-bonded matrix suppresses the nonradiative decay.

Strong Enhancement of π-Electron Donor/Acceptor Ability by Complementary DD/AA Hydrogen Bonding.

π-Conjugated organic materials possess a wide range of tunable optoelectronic properties which are dictated by their molecular structure and supramolecular arrangement. While many efforts have been put into tuning the molecular structure to achieve the desired properties, rational supramolecular control remains a challenge. Here, we report a novel series of supramolecular materials formed by the co-assembly of weak π-electron donor (indolo[2,3-a]carbazole) and acceptor (aromatic o-quinones) molecules via complementary hydrogen bonding. The resulting polarization creates a drastic perturbation of the molecular energy levels, causing strong charge transfer in the weak donor-acceptor pairs. This leads to a significant lowering (up to 1.5 eV) of the band gaps, intense absorption in the near-IR region, very short π-stacking distances (≥3.15 Å), and strong ESR signals in the co-crystals. By varying the strength of the acceptor, the characteristics of the complexes can be tuned between intrinsic, gate-, or light-induced semiconductivity with a p-type or ambipolar transport mechanism.