Theoretical investigation of distal charge separation in a perylenediimide trimer.

An exciton-phonon (ex-ph) model based on our recently developed block interaction product basis framework is introduced to simulate the distal charge separation (CS) process in aggregated perylenediimide (PDI) trimer incorporating the quantum dynamic method, i.e., the time-dependent density matrix renormalization group. The electronic Hamiltonian in the ex-ph model is represented by nine constructed diabatic states, which include three local excited (LE) states and six charge transfer (CT) states from both the neighboring and distal chromophores. These diabatic states are automatically generated from the direct products of the leading localized neutral or ionic states of each chromophore's reduced density matrix, which are obtained from ab initio quantum chemical calculation of the subsystem consisting of the targeted chromophore and its nearest neighbors, thus considering the interaction of the adjacent environment. In order to quantum-dynamically simulate the distal CS process with massive coupled vibrational modes in molecular aggregates, we used our recently proposed hierarchical mapping approach to renormalize these modes and truncate those vibrational modes that are not effectively coupled with electronic states accordingly. The simulation result demonstrates that the formation of the distal CS process undergoes an intermediate state of adjacent CT, i.e., starts from the LE states, passes through an adjacent CT state to generate the intermediates (∼200 fs), and then formalizes the targeted distal CS via further charge transference (∼1 ps). This finding agrees well with the results observed in the experiment, indicating that our scheme is capable of quantitatively investigating the CS process in a realistic aggregated PDI trimer and can also be potentially applied to exploring CS and other photoinduced processes in larger systems.

Superenhancement Photon Upconversion Nanoparticles for Photoactivated Nanocryometer.

Highly doped lanthanide luminescent nanoparticles exhibit unique optical properties, providing exciting opportunities for many ground-breaking applications, such as super-resolution microscopy, deep-tissue bioimaging, confidentiality, and anticounterfeiting. However, the concentration-quenching effect compromises their luminescence efficiency/brightness, hindering their wide range of applications. Herein, we developed a low-temperature suppression cross-relaxation strategy, which drastically enhanced upconversion luminescence (up to 2150-fold of green emission) in Er3+-rich nanosystems. The cryogenic field opens the energy transport channel of Er3+ multiphoton upconversion by further suppressing phonon-assisted cross-relaxation. Our results provide direct evidence for understanding the energy loss mechanism of photon upconversion, deepening a fundamental understanding of the upconversion process in highly doped nanosystems. Furthermore, it also suggests the potential applications of upconversion nanoparticles for extreme ambient-temperature detection and anticounterfeiting.

Palladium-Catalyzed Cascade Heck Coupling and Allylboration of Iododiboron Compounds via Diboryl Radicals.

Geminal bis(boronates) are versatile synthetic building blocks in organic chemistry. The fact that they predominantly serve as nucleophiles in the previous reports, however, has restrained their synthetic potential. Herein we disclose the ambiphilic reactivity of α-halogenated geminal bis(boronates), of which the first catalytic utilization was accomplished by merging a formal Heck cross-coupling with a highly diastereoselective allylboration of aldehydes or imines, providing a new avenue for rapid assembly of polyfunctionalized boron-containing compounds. We demonstrated that this cascade reaction is highly efficient and compatible with various functional groups, and a wide range of heterocycles. In contrast to a classical Pd(0/II) scenario, mechanistic experiments and DFT calculations have provided strong evidence for a catalytic cycle involving Pd(I)/diboryl carbon radical intermediates.

Annotation of Dipeptides and Tripeptides Derivatized via Dansylation Based on Liquid Chromatography-Mass Spectrometry and Iterative Quantitative Structure Retention Relationship.

Small peptides such as dipeptides and tripeptides show various biological activities in organisms. However, methods for identifying dipeptides/tripeptides from complex biological samples are lacking. Here, an annotation strategy involving the derivatization of dipeptides and tripeptides via dansylation was suggested based on liquid chromatography-mass spectrometry (LC-MS) and iterative quantitative structure retention relationship (QSRR) to choose dipeptides/tripeptides by using a small number of standards. First, the LC-autoMS/MS method and initial QSRR model were built based on 25 selected grid-dipeptides and 18 test-dipeptides. To achieve high-coverage detection, dipeptide/tripeptide pools containing abundant dipeptides/tripeptides were then obtained from four dansylated biological samples including serum, tissue, feces, and soybean paste by using the parameter-optimized LC-autoMS/MS method. The QSRR model was further optimized through an iterative train-by-pick strategy. Based on the specific fragments and tR tolerances, 198 dipeptides and 149 tripeptides were annotated. The dipeptides at lower annotation levels were verified by using authentic standards and grid-correlation analysis. Finally, variation in serum dipeptides/tripeptides of three different liver diseases including hepatitis B infection, liver cirrhosis, and hepatocellular carcinoma was characterized. Dipeptides with N-prolinyl, C-proline, N-glutamyl, and N-valinyl generally increased with disease severity. In conclusion, this study provides an efficient strategy for annotating dipeptides/tripeptides from complex samples.

Identification of Unknown Inverted Singlet-Triplet Cores by High-Throughput Virtual Screening.

Molecules where the energy of the lowest excited singlet state is found below the energy of the lowest triplet state (inverted singlet-triplet molecules) are extremely rare. It is particularly challenging to discover new ones through virtual screening because the required wavefunction-based methods are expensive and unsuitable for high-throughput calculations. Here, we devised a virtual screening approach where the molecules to be considered with advanced methods are pre-selected with increasingly more sophisticated filters that include the evaluation of the HOMO-LUMO exchange integral and approximate CASSCF calculations. A final set of 7 candidates (0.05% of the initial 15 000) were verified to possess inversion between singlet and triplet states with state-of-the-art multireference methods (MS-CASPT2). One of them is deemed of particular interest because it is unrelated to other proposals made in the literature.

Engineering Biomimetic Biosensor Using Dual-Targeting Multivalent Aptamer Regulated 3D DNA Walker Enables High-Performance Detection of Heterogeneous Circulating Tumor Cells.

The phenotypic heterogeneity of circulating tumor cells (CTCs) and the nonspecific adsorption of background cells impede the effective and sensitive detection of rare CTCs. Although leukocyte membrane coating approach has a good antileukocyte adhesion ability and holds great promise for addressing the challenge of capture purity, its limited specificity and sensitivity prevent its use in the detection of heterogeneous CTCs. To overcome these obstacles, a biomimetic biosensor that integrated dual-targeting multivalent aptamer/walker duplex functionalized biomimetic magnetic beads and an enzyme-powered DNA walker signal amplification strategy is designed. As compared to conventional leukocyte membrane coating, the biomimetic biosensor achieves efficient and high purity enrichment of heterogeneous CTCs with different epithelial cell adhesion molecule (EpCAM) expression while minimizing the interference of leukocytes. Meanwhile, the capture of target cells can trigger the release of walker strands to activate an enzyme-powered DNA walker, resulting in cascade signal amplification and the ultrasensitive and accurate detection of rare heterogeneous CTCs. Importantly, the captured CTCs remained viable and can be recultured in vitro with success. Overall, this work provides a new perspective for the efficient detection of heterogeneous CTCs by biomimetic membrane coating and paves the way for early cancer diagnosis.

Neoadjuvant Modified FOLFOXIRI With Selective Radiotherapy in Locally Advanced Rectal Cancer: Long-term Outcomes of Phase II Study and Propensity-Score-Matched Comparison With Chemoradiotherapy.

BACKGROUND: Neoadjuvant modified FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) chemotherapy with selective radiotherapy did not compromise pathologic complete response and tumor downstaging in locally advanced rectal cancer. OBJECTIVE: The study aimed to analyze disease-free survival and local recurrence of neoadjuvant chemotherapy with modified FOLFOXIRI (mFOLFOXIRI). DESIGN: This was a prospective single-arm phase II study. A propensity score-adjusted method was implemented to compare outcomes against historical controls of chemoradiotherapy. SETTINGS: The study was conducted at single institutions. PATIENTS: One hundred 6 patients with stage II and III rectal cancers were included. INTERVENTION: All patients received neoadjuvant mFOLFOXIRI chemotherapy before total mesorectal excision. Patients with mesorectal fascia-positive or ycT4a/b after reevaluation with MRI received radiation before surgery. Otherwise, immediate total mesorectal excision would be performed. MAIN OUTCOME AND MEASURES: The primary end point was tumor downstaging (ypStage 0-I) rate, which was reported previously. Disease-free survival and local recurrence rate were the main outcomes for the current study. RESULTS: After a median follow-up of 43.3 months, the 2-year disease-free survival rate was 85.6% and the 3-year disease-free survival rate was 78.9%. The local recurrence rate was 7.8% after surgery. After propensity score matching, 73 patients were available for comparison in each group. The pathologic complete response rate was 23.3% and 13.7% ( p = 0.14), the proportion of ypStage 0-I was 45.2% vs 39.7% ( p = 0.5), the 3-year disease-free survival was 87.6% vs 75.8% (HR = 0.46; 95% CI, 0.22-0.95, p = 0.037). The local recurrence rate in the mFOLFOXIRI group was 5.5% and in the chemoradiotherapy group was 4.1% ( p = 0.70). Patients receiving mFOLFOXIRI had a lower incidence of anastomotic fistula compared with the chemoradiotherapy group (5.5% vs 17.8%, p = 0.02). LIMITATIONS: This was a single-arm, nonrandomized phase II study. CONCLUSIONS: Neoadjuvant mFOLFOXIRI with selective radiotherapy was feasible and safe, and it improved 3-year disease-free survival compared with propensity score-matched historical controls who received chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/B989 .Trial registration: NCT02217020. FOLFOXIRI MODIFICADO NEOADYUVANTE CON RADIOTERAPIA SELECTIVA EN CNCER DE RECTO LOCALMENTE AVANZADO RESULTADOS A LARGO PLAZO DEL ESTUDIO DE FASE II Y COMPARACIN EMPAREJADA POR PUNTUACIN DE PROPENSIN CON QUIMIORRADIOTERAPIA: ANTECEDENTES:La quimioterapia neoadyuvante con FOLFOXIRI modificado (ácido folínico, 5-fluoruracilo, oxaliplatino e irinotecan) con radioterapia selectiva no comprometió la respuesta patológica completa ni la reducción del estadio del tumor en el cáncer de recto localmente avanzado.OBJETIVO:El estudio tuvo como objetivo analizar la sobrevida libre de enfermedad y la recurrencia local de la quimioterapia neoadyuvante con FOLFOXIRI modificado (mFOLFOXIRI).DISEÑO:Este fue un estudio prospectivo de fase II de un solo brazo. Se implementó un método ajustado por puntaje de propensión para comparar los resultados con los controles históricos de quimiorradioterapia.ESCENARIO:El estudio se realizó en instituciones individuales.PACIENTES:Se incluyeron 106 pacientes con cáncer de recto en estadio II y III.INTERVENCIÓN:Todos los pacientes recibieron quimioterapia neoadyuvante con mFOLFOXIRI antes de la escisión total del mesorrecto. Los pacientes con fascia mesorrectal positiva o ycT4a/b después de la reevaluación con MRI recibirían radiación antes de la cirugía. En caso contrario, se realizaría una escisión mesorrectal total inmediata.PRINCIPALES RESULTADOS Y MEDIDAS:El criterio principal de valoración fue la tasa de disminución del estadio del tumor (ypEstadio 0-I), que se informó anteriormente. La sobrevida libre de enfermedad y la tasa de recurrencia local son los principales resultados del estudio actual.RESULTADOS:Después de una mediana de seguimiento de 43,3 meses, las tasas de sobrevida libre de enfermedad a 2 y 3 años fueron del 85,6 % y 78,9 %, respectivamente. La tasa de recidiva local fue del 7,8% tras la cirugía. Después del emparejamiento por puntaje de propensión, 73 pacientes estaban disponibles para la comparación en cada grupo. La tasa de respuesta patológica completa fue de 23,3 % y de 13,7 % (p = 0,14), la proporción de ypEstadio 0-I fue del 45,2 % frente al 39,7 % (p = 0,5), la SLE a los 3 años fue del 87,6 % frente al 75,8 % (HR = 0,46, IC del 95 % 0,22-0,95, p = 0,037) y la tasa de recurrencia local fue del 5,5 % y del 4,1 % (p = 0,70) en el grupo de mFOLFOXIRI frente al grupo de quimiorradioterapia, respectivamente. Los pacientes que recibieron mFOLFOXIRI tuvieron una menor incidencia de fístula anastomótica en comparación con el grupo de quimiorradioterapia (5,5 % frente a 17,8 %, p = 0,02).LIMITACIONES:Este fue un estudio de fase II no aleatorizado de un solo brazo.CONCLUSIONES:El mFOLFOXIRI neoadyuvante con radioterapia selectiva fue factible y seguro, y mejoró la SSE a los 3 años en comparación con los controles históricos emparejados por puntaje de propensión que recibieron quimiorradioterapia. Consulte Video Resumen en http://links.lww.com/DCR/B989 . (Traducción-Dr. Felipe Bellolio ).

Manipulating the Injected Energy Flux via Host-Sensitized Nanostructure for Improving Multiphoton Upconversion Luminescence of Tm3.

Combating the concentration quenching effect by increasing the concentration of sensitized rare-earth ions in rational design upconversion nanostructure will make it easier to utilize injection energy flux and transfer it to emitters, resulting in improved upconversion luminescence (UCL). We proposed a host-sensitized nanostructure (active core@luminescent shell@inert shell) to improve multiphoton UCL of Tm3+ based on the LiLnF4 host. Yb3+ ions were isolated in the core as energy absorbents, and Tm3+ was doped in the interior LiYbF4 host shell. Compared with sandwich structured nanocrystals (Y@Y:Yb/Tm@Y), reverse structure (YbTm@Yb@Y), and fully doped structure (YbTm@YbTm@Y), the proposed structure achieved the highest efficiency of multiphoton UCL and favored a better FRET-based application performance as the Tm3+ located at an optimized spatial distribution. Furthermore, steady-state and dynamic analysis results demonstrate that by manipulating the spatial distribution of the active ions, excited energy can be tuned to enable multiphoton upconversion enhancement, overcoming the conventional limitations.

GhAP1-D3 positively regulates flowering time and early maturity with no yield and fiber quality penalties in upland cotton.

Flowering time (FTi) is a major factor determining how quickly cotton plants reach maturity. Early maturity greatly affects lint yield and fiber quality and is crucial for mechanical harvesting of cotton in northwestern China. Yet, few quantitative trait loci (QTLs) or genes regulating early maturity have been reported in cotton, and the underlying regulatory mechanisms are largely unknown. In this study, we characterized 152, 68, and 101 loci that were significantly associated with the three key early maturity traits-FTi, flower and boll period (FBP) and whole growth period (WGP), respectively, via four genome-wide association study methods in upland cotton (Gossypium hirsutum). We focused on one major early maturity-related genomic region containing three single nucleotide polymorphisms on chromosome D03, and determined that GhAP1-D3, a gene homologous to Arabidopsis thaliana APETALA1 (AP1), is the causal locus in this region. Transgenic plants overexpressing GhAP1-D3 showed significantly early flowering and early maturity without penalties for yield and fiber quality compared to wild-type (WT) plants. By contrast, the mutant lines of GhAP1-D3 generated by genome editing displayed markedly later flowering than the WT. GhAP1-D3 interacted with GhSOC1 (SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1), a pivotal regulator of FTi, both in vitro and in vivo. Changes in GhAP1-D3 transcript levels clearly affected the expression of multiple key flowering regulatory genes. Additionally, DNA hypomethylation and high levels of H3K9ac affected strong expression of GhAP1-D3 in early-maturing cotton cultivars. We propose that epigenetic modifications modulate GhAP1-D3 expression to positively regulate FTi in cotton through interaction of the encoded GhAP1 with GhSOC1 and affecting the transcription of multiple flowering-related genes. These findings may also lay a foundation for breeding early-maturing cotton varieties in the future.

Rapid calculation of internal conversion and intersystem crossing rate for organic materials discovery.

The internal conversion (IC) process from S1 to S0 and the intersystem crossing (ISC) transition from T1 to S0 are two essential processes in functional molecular material design. Despite their importance, it is currently impossible to evaluate the rate of these processes for a large set of molecules and, therefore, perform high-throughput virtual screening in large-scale data to gain more physical insight. In this work, we explore possible approaches to accelerate the calculations of IC and ISC rates based on a systematic reduction of the number of modes included in the computation and the study of the importance of the different parameters and the influence of their accuracy on the final result. The results reproduce the experimental trends with systematic errors that are ultimately due to the approximations of the theory. We noted that plausible results for ISC in planar molecules are only obtained by including the effect of Hertzberg-Teller coupling. Our method establishes the feasibility and expected accuracy of the computation of nonradiative rates in the virtual screening of molecular materials.

Perioperative platelet count in peripheral blood is associated with the early stage of PND after major orthopedic surgery: a prospective observational study.

BACKGROUND: Perioperative neurocognitive disorders (PND) are common complications of major surgery among elderly patients, remarkably decreasing patients' life quality. Platelet count has been proved to be an essential factor in inflammation. However, as far as we know, the relationship between platelet count and PND is not clear yet in the orthopedic area. PND could be a long-term disease, which sometimes lasts for several years, and it is meaningful to find a biomarker of PND at the early stage. Thus, we designed this study to find out the association between perioperative platelet count and occurrence of PND, and determine whether preoperative platelet count could be a biomarker of the early stage of PND. METHODS: A prospective observational study was performed on the patients who would take total knee arthroplasty or total hip arthroplasty. Their peripheral platelets were counted by blood routine examination 1 day before and 3 days after the surgery. And we assessed their neurocognitive functions 1 day before and 3 days after the surgery. These data were recorded and analyzed to find out the relationship between platelet count and the occurrence of PND. RESULTS: Eventually, 70 patients finished the whole process, and 14 of them developed PND. The median preoperative platelet count in the PND group was significantly higher than that in the non-PND group (239 vs 168 × 10^9/L, p = 0.009). Preoperative platelet count was an independent risk factor for PND (odds ratio = 1.014, 95% confidence interval [CI] 1.000-1.027, P = 0.043) in the logistic multivariable regression, while the area under the curve of the receiver operating characteristic curve of the prediction model was 0.796 (95% CI 0.676-0.916). CONCLUSIONS: The higher preoperative and postoperative level of platelet count in the peripheral blood were associated with the early stage of PND, and preoperative platelet count could be a potential predictor of the early stage of PND in patients undergoing major orthopedic surgeries. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000033001 , registration date: 17 May 2020.

Saquayamycin B1 Suppresses Proliferation, Invasion, and Migration by Inhibiting PI3K/AKT Signaling Pathway in Human Colorectal Cancer Cells.

Moromycin B (Mor B), saquayamycin B1 (Saq B1), saquayamycin B (Saq B), and landomycin N (Lan N), four angucyclines produced by the marine-derived actinomycete Streptomyces sp., are a class of polyketone compounds containing benzanthracene. Here, the structure-activity relationship of these four compounds was analyzed in human colorectal cancer (CRC) cells. Saq B1, which showed the strongest cytotoxicity with an IC50 of 0.18-0.84 µM for CRC cells in MTT assays, was employed to test underlying mechanisms of action in SW480 and SW620 cells (two invasive CRC cell lines). Our results showed that Saq B1 inhibited CRC cell proliferation in a dose- and time-dependent manner. Notably, lower cytotoxicity was measured in normal human hepatocyte cells (QSG-7701). Furthermore, we observed proapoptosis, antimigration, and anti-invasion activities of Saq B1 in CRC cells. At the same time, the protein and mRNA expression of important markers related to the epithelial-mesenchymal transition (EMT) and apoptosis changed, including N-cadherin, E-cadherin, and Bcl-2, in Saq B1-treated CRC cells. Surprisingly, the PI3K/AKT signaling pathway was shown to be involved in Saq B1-induced apoptosis, and in inhibiting invasion and migration. Computer docking models also suggested that Saq B1 might bind to PI3Kα. Collectively, these results indicate that Saq B1 effectively inhibited growth and decreased the motor ability of CRC cells by regulating the PI3K/AKT signaling pathway, which provides more possibilities for the development of drugs in the treatment of CRC.

Two new dinor-eudesmane sesquiterpenoids from the roots of Chloranthus multistachys.

Two new dinor-eudesmane sesquiterpenoids, named multistalin A (1), and multistalin B (2), together with three sesquiterpene glycosides (3-5), and a norlabdane-type diterpene (6) were isolated from the root extract of Chloranthus multistachys Pei. Their structures were elucidated on the basis of spectroscopic analysis including 1D, 2D NMR techniques and HR-ESI-MS. In addition, the cytotoxicity activities of the isolated compounds against selected cancer cells (Hela and A-549) were evaluated by MTT assay.

Suppressing Non-Radiative Relaxation through Single-Atom Metal Modification for Enhanced Fluorescence Efficiency in Molybdenum Disulfide Quantum Dots.

To enhance the fluorescence efficiency of semiconductor nanocrystal quantum dots (QDs), strategies via enhancing photo-absorption and eliminating non-radiative relaxation have been proposed. In this study, we demonstrate that fluorescence efficiency of molybdenum disulfide quantum dots (MoS2 QDs) can be enhanced by single-atom metal (Au, Ag, Pt, Cu) modification. Four-fold enhancement of the fluorescence emission of MoS2 QDs is observed with single-atom Au modification. The underlying mechanism is ascribed to the passivation of non-radiative surface states owing to the new defect energy level of Au in the forbidden band that can trap excess electrons in n-type MoS2 , increasing the recombination probability of conduction band electrons with valence band holes of MoS2 . Our results open an avenue for enhancing the fluorescence efficiency of QDs via the modification of atomically dispersed metals, and extend their scopes and potentials in a fundamental way for economic efficiency and stability of single-atom metals.

miR-128 participates in the pathogenesis of chronic constipation by regulating the p38α/M-CSF inflammatory signaling pathway.

Chronic constipation (CC) is a gastrointestinal disorder that adversely affects the quality of life. MicroRNAs are involved in the pathogenesis of functional gastrointestinal disorders. This study aims to investigate the molecular mechanism of microRNA-128 in CC. Here, we successfully constructed a murine model of CC based on morphine and rhubarb. The expression of stem cell factor (SCF) and neuron-specific enolase (NSE) was low in the models. Using miRNA array and bioinformatic analysis, we predicted and confirmed the expression of miR-128 and its downstream target genes in CC model. Compared with the control group, CC group showed a significant downregulation of miR-128 and upregulation of p38α and macrophage colony-stimulating factors (M-CSFs). Moreover, we observed elevated inflammatory cytokine and decreased anti-inflammatory cytokine levels in colonic tissues. Furthermore, coculture assays indicated that regulating expression of miR-128 in colonic epithelial cells induced the secretion of IL-6 and TNF-α by macrophages. In conclusion, our study demonstrated that miR-128 regulated the p38α/M-CSF signaling pathway to promote chronic inflammatory responses and changes in the immune microenvironment of the colon, thereby offering potential insights into the pathogenesis of CC and therapeutic targets for its treatment.NEW & NOTEWORTHY In this study, we constructed a murine model and identified a novel signaling mechanism involved in the chronic constipation progression. Our findings on the role of miR-128/p38α/M-CSF axis provide new insights into the treatment of chronic constipation.

Inside-Out-Oriented Cell Membrane Biomimetic Magnetic Nanoparticles for High-Performance Drug Lead Discovery.

Biomimetic cell membrane-coated nanoparticles have been broadly applied because of their superior biochemical properties. The right-side-out cell membrane coating manner provides nanoparticles with an immune-evasive stealth function in vivo. However, this acts as a drag for drug discovery when the drug targets are the intracellular domain of transmembrane receptors. Herein, inside-out-oriented cell membrane-coated nanoparticles were prepared for screening tyrosine kinase inhibitors, which specifically interacted with the intracellular kinase domain of the epidermal growth factor receptor. Biotinylated human lung adenocarcinoma epithelial cell membranes specifically interacted with streptavidin-immobilized Fe3O4 magnetic nanoparticles and then formed inside-out-oriented cell membrane-coated magnetic nanoparticles (IOCMMNPs). The cell membrane orientation of the IOCMMNPs was successfully confirmed by immunogold electron microscopy, fluorescently labeled confocal microscopy, sialic acid quantification assay, and the adsorption capacity assay. Moreover, IOCMMNPs possessed satisfactory binding capacity, selectivity, and high sensitivity (limit of detection = 0.4 × 10-3 µg mL-1). Ultimately, IOCMMNPs successfully targeted two main compounds from Strychnos nux-vomica whose potential antitumor activities were further validated by pharmacological studies. The application of the inside-out cell membrane coating strategy further enhances the drug screening efficiency and broadens the insight and methodologies for drug lead discovery. This inside-out cell membrane coating concept also provides a method for the future development of engineered cell membrane-coated nanotechnology.

HBeAg mediates inflammatory functions of macrophages by TLR2 contributing to hepatic fibrosis.

BACKGROUND: We and others have confirmed activation of macrophages plays a critical role in liver injury and fibrogenesis during HBV infection. And we have also proved HBeAg can obviously induce the production of macrophage inflammatory cytokines compared with HBsAg and HBcAg. However, the receptor and functional domain of HBeAg in macrophage activation and its effects and mechanisms on hepatic fibrosis remain elusive. METHODS: The potentially direct binding receptors of HBeAg were screened and verified by Co-IP assay. Meanwhile, the function domain and accessible peptides of HBeAg for macrophage activation were analyzed by prediction of surface accessible peptide, construction, and synthesis of truncated fragments. Furthermore, effects and mechanisms of the activation of hepatic stellate cells induced by HBeAg-treated macrophages were investigated by Transwell, CCK-8, Gel contraction assay, Phospho Explorer antibody microarray, and Luminex assay. Finally, the effect of HBeAg in hepatic inflammation and fibrosis was evaluated in both human and murine tissues by immunohistochemistry, immunofluorescence, ELISA, and detection of liver enzymes. RESULTS: Herein, we verified TLR-2 was the direct binding receptor of HBeAg. Meanwhile, C-terminal peptide (122-143 aa.) of core domain in HBeAg was critical for macrophage activation. But arginine-rich domain of HBcAg hided this function, although HBcAg and HBeAg shared the same core domain. Furthermore, HBeAg promoted the proliferation, motility, and contraction of hepatic stellate cells (HSCs) in a macrophage-dependent manner, but not alone. PI3K-AKT-mTOR and p38 MAPK signaling pathway were responsible for motility phenotype of HSCs, while the Smad-dependent TGF-ß signaling pathway for proliferation and contraction of them. Additionally, multiple chemokines and cytokines, such as CCL2, CCL5, CXCL10, and TNF-α, might be key mediators of HSC activation. Consistently, HBeAg induced transient inflammation response and promoted early fibrogenesis via TLR-2 in mice. Finally, clinical investigations suggested that the level of HBeAg is associated with inflammation and fibrosis degrees in patients infected with HBV. CONCLUSIONS: HBeAg activated macrophages via the TLR-2/NF-κB signal pathway and further exacerbated hepatic fibrosis by facilitating motility, proliferation, and contraction of HSCs with the help of macrophages.

LncRNA ENSG00000254615 Modulates Proliferation and 5-FU Resistance by Regulating p21 and Cyclin D1 in Colorectal Cancer.

5-Fluorouracil (5-FU) resistance is an urgent problem of colorectal cancer (CRC) chemotherapy that needs to be resolved. To investigate 5-FU-associated lncRNAs for CRC might be of great significant. LncRNA ENSG00000254615 was detected by RNA-sequencing. ENSG00000254615 were detected highly expressed in 5-FU-sensitive CRC cells and tissue specimens, and inhibited cell proliferation and attenuated 5-FU resistance in vitro and in vivo. Furthermore, ENSG00000254615 participated in the regulation of p21 and Cyclin D1. Taken together, we proposed that ENSG00000254615 inhibits proliferation and attenuates 5-FU resistance of CRC by regulating p21 and Cyclin D1 expression.

Gadobenate dimeglumine-enhanced biliary imaging from the hepatobiliary phase can predict progression in patients with liver cirrhosis.

OBJECTIVES: To determine the value of gadobenate dimeglumine (Gd-BOPTA)-enhanced biliary imaging from the hepatobiliary phase in predicting hepatic decompensation and insufficiency for patients with cirrhosis. METHODS: This single-center retrospective study included 270 patients who underwent Gd-BOPTA-enhanced magnetic resonance imaging. The relative enhancement ratios of the biliary system (REB) and liver parenchyma (REL) in patients with normal liver function without underlying chronic liver disease and three groups of patients with Child-Pugh A, Child-Pugh B, and Child-Pugh C disease were measured. After a mean follow-up of 38.5 ± 22.5 months, prognostic factors were evaluated using the Cox proportional hazards regression model. Receiver operating characteristic (ROC) curve analyses were performed to assess the capacity of the REB and REL to predict the development of hepatic decompensation and insufficiency. RESULTS: During the follow-up period, nine of 79 patients with Child-Pugh A disease developed hepatic decompensation. The REB was a significant predictive factor (hazard ratio (HR) = 0.40 (0.19-0.84); p = 0.016), but the REL showed no association with hepatic decompensation. Moreover, the areas under the ROC curves (AUCs) were 0.83 and 0.52 for the REB and REL, respectively. Thirty-eight of 207 patients with cirrhosis developed hepatic insufficiency. The REB was a significant predictive factor (HR = 0.24 (0.13-0.46); p < 0.0001), but the REL did not show statistically significant association with hepatic insufficiency. The AUCs were 0.82 and 0.57 for the REB and REL, respectively. CONCLUSIONS: Gd-BOPTA-enhanced biliary imaging from the hepatobiliary phase was valuable in predicting hepatic decompensation and insufficiency for cirrhotic patients. KEY POINTS: • Gd-BOPTA-enhanced biliary imaging was a significant predictive factor for hepatic decompensation in patients with cirrhosis. • Gd-BOPTA-enhanced biliary imaging was a significant predictive factor for hepatic insufficiency in patients with cirrhosis. • Gd-BOPTA-enhanced biliary imaging showed superior predictive values for adverse clinical outcomes compared to liver parenchymal imaging at the hepatobiliary phase.

Solvent-Directed Transition Metal-Free C-C Bond Cleavage by Azido-1,3,5-triazines and Their Stability-Reactivity Paradox.

We report a solvent-directed and regioselective carbon-carbon bond cleavage of aryl ketones by azido-1,3,5-triazines (ATs), which is typically completed within 10 min in DMSO at room temperature, without using transition metal catalysts. The cleavage is driven by the steric hindrance in the adducts of aryl ketones and ATs, which is substantiated by DFT calculation. Our recent results showed that ATs present high reactivity in solution and high stability in solid state. This "stability-reactivity paradox" has been explained in light of the molecular and crystal structures of ATs.