Optimizing drug combination and mechanism analysis based on risk pathway crosstalk in pan cancer.

Combination therapy can greatly improve the efficacy of cancer treatment, so identifying the most effective drug combination and interaction can accelerate the development of combination therapy. Here we developed a computational network biological approach to identify the effective drug which inhibition risk pathway crosstalk of cancer, and then filtrated and optimized the drug combination for cancer treatment. We integrated high-throughput data concerning pan-cancer and drugs to construct miRNA-mediated crosstalk networks among cancer pathways and further construct networks for therapeutic drug. Screening by drug combination method, we obtained 687 optimized drug combinations of 83 first-line anticancer drugs in pan-cancer. Next, we analyzed drug combination mechanism, and confirmed that the targets of cancer-specific crosstalk network in drug combination were closely related to cancer prognosis by survival analysis. Finally, we save all the results to a webpage for query ( http://bio-bigdata.hrbmu.edu.cn/oDrugCP/ ). In conclusion, our study provided an effective method for screening precise drug combinations for various cancer treatments, which may have important scientific significance and clinical application value for tumor treatment.

Theoretical Study of the Photocyclization Reaction-Induced Dual Aggregation-Induced Emission Phenomenon.

Photochromic molecules with aggregation-induced emission (AIE) effects are of great value and prospective in various practical applications. To explore its inherent mechanism, the open isomer ap-BBTE and the closed isomer c-BBTE were chosen to perform the theoretical calculation using the quantum mechanics/molecular mechanics model combined with thermal vibration correlation function formalism. The calculations show that the photocyclization (PC) reaction from ap-BBTE to c-BBTE facilitates an improvement in the AIE effect. It is found that the fluorescence quantum yield (ΦF) enhancement of ap-BBTE is attributed to the restriction of the low-frequency rotational motion of the benzothiophene moiety and the high-frequency stretching vibrations of the C-C bond between the benzothiophene and benzylbis(thiadiazole) vinyl groups after aggregation. For c-BBTE, the increase in ΦF upon aggregation is mainly due to the suppression of the high-frequency stretching vibration of the C-C bond between the benzothiophene and the benzobis(thiadiazole) vinyl groups. In addition, the AIE effect was also enhanced from ap-BBTE to c-BBTE, which is consistent with the experimental phenomenon. The corresponding emission spectrum red-shifted from ap-BBTE to c-BBTE in both dilute solution and the crystalline state due to the improved intramolecular conjugation of c-BBTE. Moreover, the PC reaction from ap-BBTE to c-BBTE easily occurs in an excited state with a low energy barrier transition state by forming a C-C bond between benzothiophene groups effectively in dilute solution. Our calculations provide theoretical guidance for the further rational design of efficient AIE luminogens.

Nature of Hops, Coordinates, and Detailed Balance for Nonadiabatic Simulations in the Condensed Phase.

Photoinduced processes play a crucial role in a multitude of important molecular phenomena. Accurately modeling these processes in an environment other than a vacuum requires a detailed description of the electronic states involved as well as how energy flows are coupled to the surroundings. Nonadiabatic effects must also be included in order to describe the exchange of energy between electronic and nuclear degrees of freedom correctly. In this work, we revisit the ring-opening reaction 1,3-cylohexadiene (CHD) in a solvent environment. Using our newly developed Interface for Non-Adiabatic Quantum mechanics/molecular mechanics in Solvent (INAQS) we trace the evolution of the reaction via hybrid quantum mechanics/molecular mechanics (QM/MM) surface hopping with a focus on the solvent's participation in the nonadiabatic relaxation process and the long-time approach to equilibrium. We explicitly include the MM solvent contribution to the nonadiabatic coupling vector─enabling an accurate approach to equilibrium at long times─and find that in highly multidimensional systems gradients can have little or nothing to do with the nonadiabatic couplings.

Modulating the Microenvironment of Silanols in Pure-Silicon Zeolites for Boosting Vapor-phase Beckmann Rearrangement of Cyclohexanone Oxime.

Vapor-phase Beckmann rearrangement of cyclohexanone oxime (CHO) to ε-caprolactam (CPL) is still difficult to commercialize at the industrial scale due to its relatively low catalytic activity and poor lifetime. Herein, we synthesized a series of pure-silicon zeolites (including MFI, MEL, and -SVR) with three-dimensional 10-member-ring topolgies, diverse silanol status, and hierarchical porosity to investigate the synergistic effects of inner diffusivity and reactivity. S-1 zeolite of MFI-type topology with plentiful silanol nests exhibits a more preferable catalytic performance in terms of CHO conversion (99.7%) and CPL selectivity (89.7%), much higher than those of MEL- and -SVR-type zeolites mainly due to their diverse silanol distribution. With the construction of hierarchical porosity, S-1-P shows improved CPL selectivity of 94.1% owing to the enhanced diffusivity to shorten the retention time of the reactant and product molecules. The reaction mechanism and network have been further revealed by density functional theory (DFT) calculations and experimental designs, which indicate that silanol nests are major active sites due to their suitable interaction with CHO rather than terminal silanols. Particularly, the microenvironments of silanols can be modulated by alcohol solvents, ascribed to their different charge transfer and steric hindrance. Consequently, S-1-P shows superior CPL selectivity of 97.3% in ethonal solvents, which have higher adsorb energy of -0.627 eV with silanol nests than other alcohols. The present study not only provides a fundamental guide for the design of zeolite catalysts but also provides a reference for modulating the microenvironment of active sites according to the catalytic mechanism.

Stabilization of Carbocation Intermediate by Cucurbit[7]uril Enables High Photolysis Efficiency.

A cucurbit[7]uril-based host-guest strategy is employed to enhance the efficiency of photolysis reactions that release caged molecules from photoremovable protecting groups. The photolysis of benzyl acetate follows a heterolytic bond cleavage mechanism, thereby leading to the formation of a contact ion pair as the key reactive intermediate. The Gibbs free energy of the contact ion pair is lowered by 3.06 kcal/mol through the stabilization of cucurbit[7]uril, as revealed by DFT calculations, which results in a 40-fold increase in the quantum yield of the photolysis reaction. This methodology is also applicable to the chloride leaving group and the diphenyl photoremovable protecting group. We anticipate that this research presents a novel strategy to improve reactions involving active cationics, thereby enriching the field of supramolecular catalysis.

Prognostic value of the S100 calcium-binding protein family members in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a crucial public health problem around the world, and the outlook remains bleak. More accurate prediction models are urgently needed because of the great heterogeneity of HCC. The S100 protein family contains over 20 differentially expressed members, which are commonly dysregulated in cancers. In the present study, we analyzed the expression profile of S100 family members in patients with HCC based on the TCGA database. A novel prognostic risk score model, based on S100 family members, was developed using the least absolute shrinkage and selection operator regression algorithm, to analyze the clinical outcome. Our prediction model showed a powerful predictive value (1-year AUC: 0.738; 3-year AUC: 0.746; 5-year AUC: 0.813), while two former prediction models had less excellent performances than ours. And the S100 family members-based subtypes reveal the heterogeneity in many aspects, including gene mutations, phenotypic traits, tumor immune infiltration, and predictive therapeutic efficacy. We further investigated the role of S100A9, one member with the highest coefficient in the risk score model, which was mainly expressed in para-tumoral tissues. Using the Single-Sample Gene Set Enrichment Analysis algorithm and immunofluorescence staining of tumor tissue sections, we found that S100A9 may be associated with macrophages. These findings provide a new potential risk score model for HCC and support further study of S100 family members in patients, especially S100A9.

Uric acid metabolism promotes apoptosis against Bombyx mori nucleopolyhedrovirus in silkworm, Bombyx mori.

The white epidermis of silkworms is due to the accumulation of uric acid crystals. Abnormal silkworm uric acid metabolism decreases uric acid production, leading to a transparent or translucent phenotype. The oily silkworm op50 is a mutant strain with a highly transparent epidermis derived from the p50 strain. It shows more susceptibility to Bombyx mori nucleopolyhedrovirus (BmNPV) infection than the wild type; however, the underlying mechanism is unknown. This study analysed the changes in 34 metabolites in p50 and op50 at different times following BmNPV infection based on comparative metabolomics. The differential metabolites were mainly clustered in six metabolic pathways. Of these, the uric acid pathway was identified as critical for resistance in silkworms, as feeding with inosine significantly enhanced larval resistance compared to other metabolites and modulated other metabolic pathways. Additionally, the increased level of resistance to BmNPV in inosine-fed silkworms was associated with the regulation of apoptosis, which is mediated by the reactive oxygen species produced during uric acid synthesis. Furthermore, feeding the industrial strain Jingsong (JS) with inosine significantly increased the level of larval resistance to BmNPV, indicating its potential application in controlling the virus in sericulture. These results lay the foundation for clarifying the resistance mechanism of silkworms to BmNPV and provide new strategies and methods for the biological control of pests.

CellMarker 2.0: an updated database of manually curated cell markers in human/mouse and web tools based on scRNA-seq data.

CellMarker 2.0 (http://bio-bigdata.hrbmu.edu.cn/CellMarker or http://117.50.127.228/CellMarker/) is an updated database that provides a manually curated collection of experimentally supported markers of various cell types in different tissues of human and mouse. In addition, web tools for analyzing single cell sequencing data are described. We have updated CellMarker 2.0 with more data and several new features, including (i) Appending 36 300 tissue-cell type-maker entries, 474 tissues, 1901 cell types and 4566 markers over the previous version. The current release recruits 26 915 cell markers, 2578 cell types and 656 tissues, resulting in a total of 83 361 tissue-cell type-maker entries. (ii) There is new marker information from 48 sequencing technology sources, including 10X Chromium, Smart-Seq2 and Drop-seq, etc. (iii) Adding 29 types of cell markers, including protein-coding gene lncRNA and processed pseudogene, etc. Additionally, six flexible web tools, including cell annotation, cell clustering, cell malignancy, cell differentiation, cell feature and cell communication, were developed to analysis and visualization of single cell sequencing data. CellMarker 2.0 is a valuable resource for exploring markers of various cell types in different tissues of human and mouse.

DeePKS + ABACUS as a Bridge between Expensive Quantum Mechanical Models and Machine Learning Potentials.

Recently, the development of machine learning (ML) potentials has made it possible to perform large-scale and long-time molecular simulations with the accuracy of quantum mechanical (QM) models. However, for different levels of QM methods, such as density functional theory (DFT) at the meta-GGA level and/or with exact exchange, quantum Monte Carlo, etc., generating a sufficient amount of data for training an ML potential has remained computationally challenging due to their high cost. In this work, we demonstrate that this issue can be largely alleviated with Deep Kohn-Sham (DeePKS), an ML-based DFT model. DeePKS employs a computationally efficient neural network-based functional model to construct a correction term added upon a cheap DFT model. Upon training, DeePKS offers closely matched energies and forces compared with high-level QM method, but the number of training data required is orders of magnitude less than that required for training a reliable ML potential. As such, DeePKS can serve as a bridge between expensive QM models and ML potentials: one can generate a decent amount of high-accuracy QM data to train a DeePKS model and then use the DeePKS model to label a much larger amount of configurations to train an ML potential. This scheme for periodic systems is implemented in a DFT package ABACUS, which is open source and ready for use in various applications.

Molecular design of DBA-type five-membered heterocyclic rings to achieve 200% exciton utilization for electroluminescence.

Achieving high exciton utilization is a long-cherished goal in the development of organic light-emitting diode materials. Herein, a three-step mechanism is proposed to achieve 200% exciton utilization: (i) hot triplet exciton (T2) conversion to singlet S1; (ii) singlet fission from S1 into two T1; (iii) and then a Dexter energy transfer to phosphors. The requirement is that S1 should lie slightly lower than or close to T2 and twice as high as T1 in energy. For this, a scenario is put forward to design a series of donor-bridge-acceptor (DBA) type molecules with 2E(T1) ≤ E(S1) < E(T2), in which the Baird-type aromatic pyrazoline ring is used as a bridge owing to its stabilized T1 (1.30-1.74 eV) and different kinds of donors and acceptors are linked to the bridge for regulating S1 (2.35-3.87 eV) and T2 (2.44-3.96 eV). The ultrafast spectroscopy and sensitization measurements for one compound (TPA-DBPrz) fully confirm the theoretical predictions.

INAQS, a Generic Interface for Nonadiabatic QM/MM Dynamics: Design, Implementation, and Validation for GROMACS/Q-CHEM simulations.

The accurate description of large molecular systems in complex environments remains an ongoing challenge for the field of computational chemistry. This problem is even more pronounced for photoinduced processes, as multiple excited electronic states and their corresponding nonadiabatic couplings must be taken into account. Multiscale approaches such as hybrid quantum mechanics/molecular mechanics (QM/MM) offer a balanced compromise between accuracy and computational burden. Here, we introduce an open-source software package (INAQS) for nonadiabatic QM/MM simulations that bridges the sampling capabilities of the GROMACS MD package and the excited-state infrastructure of the Q-CHEM electronic structure software. The interface is simple and can be adapted easily to other MD codes. The code supports a variety of different trajectory-based molecular dynamics, ranging from Born-Oppenheimer to surface hopping dynamics. To illustrate the power of this combination, we simulate electronic absorption spectra, free-energy surfaces along a reaction coordinate, and the excited-state dynamics of 1,3-cyclohexadiene in solution.

Cavity quantum-electrodynamical time-dependent density functional theory within Gaussian atomic basis. II. Analytic energy gradient.

Following the formulation of cavity quantum-electrodynamical time-dependent density functional theory (cQED-TDDFT) models [Flick et al., ACS Photonics 6, 2757-2778 (2019) and Yang et al., J. Chem. Phys. 155, 064107 (2021)], here, we report the derivation and implementation of the analytic energy gradient for polaritonic states of a single photochrome within the cQED-TDDFT models. Such gradient evaluation is also applicable to a complex of explicitly specified photochromes or, with proper scaling, a set of parallel-oriented, identical-geometry, and non-interacting molecules in the microcavity.

Identification of optimal reference genes in Bombyx mori (Lepidoptera) for normalization of stress-responsive genes after challenge with pesticides.

Pesticides are frequently used to control pests in agriculture due to their ease of use and effectiveness, but their use causes serious economic losses to sericulture when their production overlaps with agriculture. However, no suitable internal reference genes (RGs) have been reported in the study of silkworms in response to pesticides. In this study, a standard curve was established to detect the expression levels of seven RGs in different tissues of different silkworm strains after feeding with pesticides using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), including BmGAPDH, BmActin3, BmTBP, BmRPL3, Bm28sRNA, Bmα-tubulin, and BmUBC, and the stability of them was evaluated by using NormFinder, geNorm, Delta CT, BestKeeper, and RefFinder. The results showed that BmGAPDH and Bmα-tubulin were relatively stable in the midgut after feeding with fenvalerate, BmGAPDH and Bmactin3 were relatively stable in the fat body, and Bmα-tubulin and Bmactin3 were relatively stable in the hemolymph, indicating that Bmactin3 was the most suitable RG when evaluating fenvalerate, followed by BmGAPDH and Bmα-tubulin. Besides, BmGAPDH and Bmactin3 were relatively stable in the midgut after treatment with DDVP, BmGAPDH and Bmα-tubulin were relatively stable in the fat body, and BmGAPDH and Bmα-tubulin were relatively stable in the hemolymph, indicating that Bmα-tubulin was the most stable RG when evaluating DDVP, followed by BmGAPDH and Bmactin3. Of note, BmGAPDH was shared by the two pesticides. The results will be valuable for RG selection in studying the pesticide response mechanism of silkworms and other lepidopteran insects.

Association between trace elements and preeclampsia: A retrospective cohort study.

BACKGROUND: Preeclampsia is the main cause of maternal and perinatal death. Multiple studies suggest that trace elements were associated with preeclampsia, but the results varied, and less known about early or mid-term pregnancy of trace elements and preeclampsia. We aim to explore the association between mid-term pregnancy trace elements levels and preeclampsia. METHODS: The retrospective cohort study was consecutively conducted in Foshan Fosun Chancheng Hospital, Guangdong Province, China, from August 1, 2019, to November 30, 2019. Trace elements are derived from the laboratory data system, measured in maternal whole blood during 12-27 (+6) weeks of pregnancy by flame atomic absorption spectrometer method. Preeclampsia diagnosis and covariance were ascertained from the electronic medical records system. We used multivariable logical regression to estimate odds ratios (OR) and 95% CIs. RESULTS: A total of 2186 participants were included in this study, and 59 (2.70%) women developed preeclampsia. After multivariable adjustment, the OR of Mg levels for preeclampsia was 0.35 (95%CI:0.06,2.20). The fifth quintiles of Mg were associated with 0.29 (95% CI：0.10,0.85) times lower risk of preeclampsia compared with the first quintile, with a dose-response trend (P for trend = 0.056). Per 1 µmol/L increment in Cu was associated with 11% lower risk of preeclampsia (OR=0.89; 95% CI, 0.78,1.02). Compared with the first quintile, the second, third，fourth，fifth quintile of Cu was associated with a odd ratio of 0.12 (95% CI:0.03,0.43),0.67 (95% CI:0.30,1.48),0.33 (95% CI:0.15,0.76) and 0.26 (95% CI:0.10,0.66),respectively. Null associations were observed for Zn, Fe, Ca. CONCLUSIONS: Higher blood Mg and Cu levels in mid-term pregnancy were associated with lower preeclampsia risk.

Enhanced Reverse Intersystem Crossing Promoted by Triplet Exciton-Photon Coupling.

Polaritons are hybrid light-matter states formed via strong coupling between excitons and photons inside a microcavity, leading to upper and lower polariton (LP) bands splitting from the exciton. The LP has been applied to reduce the energy barrier of the reverse intersystem crossing (rISC) process from T1, harvesting triplet energy for fluorescence through thermally activated delayed fluorescence. The spin-orbit coupling between T1 and the excitonic part of the LP was considered as the origin for such an rISC transition. Here we propose a mechanism, namely, rISC promoted by the light-matter coupling (LMC) between T1 and the photonic part of LP, which is originated from the ISC-induced transition dipole moment of T1. This mechanism was excluded in previous studies. Our calculations demonstrate that the experimentally observed enhancement to the rISC process of the erythrosine B molecule can be effectively promoted by the LMC between T1 and a photon. The proposed mechanism would substantially broaden the scope of the molecular design toward highly efficient cavity-promoted light-emitting materials and immediately benefit the illumination of related experimental phenomena.

Quantum-electrodynamical time-dependent density functional theory within Gaussian atomic basis.

Inspired by the formulation of quantum-electrodynamical time-dependent density functional theory (QED-TDDFT) by Rubio and co-workers [Flick et al., ACS Photonics 6, 2757-2778 (2019)], we propose an implementation that uses dimensionless amplitudes for describing the photonic contributions to QED-TDDFT electron-photon eigenstates. This leads to a Hermitian QED-TDDFT coupling matrix that is expected to facilitate the future development of analytic derivatives. Through a Gaussian atomic basis implementation of the QED-TDDFT method, we examined the effect of dipole self-energy, rotating-wave approximation, and the Tamm-Dancoff approximation on the QED-TDDFT eigenstates of model compounds (ethene, formaldehyde, and benzaldehyde) in an optical cavity. We highlight, in the strong coupling regime, the role of higher-energy and off-resonance excited states with large transition dipole moments in the direction of the photonic field, which are automatically accounted for in our QED-TDDFT calculations and might substantially affect the energies and compositions of polaritons associated with lower-energy electronic states.

Supramolecular engineering of charge transfer in wide bandgap organic semiconductors with enhanced visible-to-NIR photoresponse.

Organic photodetectors displaying efficient photoelectric response in the near-infrared are typically based on narrow bandgap active materials. Unfortunately, the latter require complex molecular design to ensure sufficient light absorption in the near-infrared region. Here, we show a method combining an unconventional device architecture and ad-hoc supramolecular self-assembly to trigger the emergence of opto-electronic properties yielding to remarkably high near-infrared response using a wide bandgap material as active component. Our optimized vertical phototransistors comprising a network of supramolecular nanowires of N,N'-dioctyl-3,4,9,10-perylenedicarboximide sandwiched between a monolayer graphene bottom-contact and Au nanomesh scaffold top-electrode exhibit ultrasensitive light response to monochromatic light from visible to near-infrared range, with photoresponsivity of 2 × 105 A/W and 1 × 102 A/W, at 570 nm and 940 nm, respectively, hence outperforming devices based on narrow bandgap materials. Moreover, these devices also operate as highly sensitive photoplethysmography tool for health monitoring.

Intermolecular Charge-Transfer-Induced Strong Optical Emission from Herringbone H-Aggregates.

Luminescence in molecular aggregates can be quenched either by intermolecular charge transfer or by forming a dipole-forbidden lower Frenkel exciton in H-aggregate. Taking intermolecular charge transfer and excitonic coupling into a three-state model through localized diabatization, we demonstrate that the low-lying intermolecular charge-transfer state could couple with the upper bright Frenkel exciton to form dipole-allowed S1 that lies below the dark state, which accounts for the recent experimentally discovered strong luminescence in organic light-emitting transistors (OLETs) system with DPA and dNaAnt herringbone aggregates. The condition of forming such bright state is that the electron and hole transfer integrals, te and th, are of the same sign, and should be notably larger than the excitonic coupling (J), that is , te × th > 2J2. This theoretical finding not only rationalizes recent experiments but unravels an exciting scenario where strong luminescence and high charge mobilities become compatible, which is a preferable condition for both OLETs and electrically pumped lasing.

Elucidating the Electronic Structure of a Delayed Fluorescence Emitter via Orbital Interactions, Excitation Energy Components, Charge-Transfer Numbers, and Vibrational Reorganization Energies.

Recently, Wang and co-workers carried out frontier molecule orbital engineering in the design of m-Cz-BNCz, a thermally activated delayed fluorescence (TADF) molecule that emits pure green light at an external quantum efficiency of 27%. To further understand the underlying molecular design principles, we employed four advanced electronic structure analysis tools. First, an absolutely localized molecular orbitals (ALMO-) based analysis indicates an antibonding combination between the highest occupied molecular orbitals (HOMOs) of the donor 3,6-di-tert-butylcarbazole fragment and the acceptor BNCz fragment, which raises the HOMO energy and red-shifts the fluorescence emission wavelength. Second, excitation energy component analysis reveals that the S1-T1 gap is dominated by two-electron components of the excitation energies. Third, charge transfer number analysis, which is extended to use fragment-based Hirshfeld weights, indicates that the S1 and T1 excited states of m-Cz-BNCz (within time-dependent density functional theory) have notable charge transfer characters (27% for S1 and 12% for T1). This provides a balance between a small single-triplet gap and a substantial fluorescence intensity. Last, a vibrational reorganization energy analysis pinpoints the torsional motion between the BNCz and Cz moieties of m-Cz-BNCz as the source for its wider emission peak than that of p-Cz-BNCz. These four types of analyses are expected to be very valuable in the study and design of other TADF and functional dye molecules.

Aggregation-Enhanced Thermally Activated Delayed Fluorescence Efficiency for Two-Coordinate Carbene-Metal-Amide Complexes: A QM/MM Study.

The two-coordinate carbene-metal-amide complexes have attracted a great deal of attention due to their remarkable thermally activated delayed fluorescence (TADF) properties, giving them promise in organic light-emitting diode application. To reveal the inherent mechanism, we take CAAC-Cu(I)-Cz and CAAC-Au(I)-Cz as examples to investigate the photophysical properties in solution and solid phases by combining quantum mechanics/molecular mechanics approaches for the electronic structure and the thermal vibration correlation function formalism for the excited-state decay rates. We found that both intersystem crossing (ISC) and its reverse (rISC) are enhanced by 2-4 orders of magnitude upon aggregation, leading to highly efficient TADF, because (i) the metal proportion in the frontier molecular orbitals increases, leading to an enhanced spin-orbit coupling strength between S1 and T1, and (ii) the reaction barriers for ISC and rISC are much lower in solution than in aggregate phases through a decrease in energy gap ΔEST and an increase in the relative reorganization energy through bending the angle ∠C2-Cu-N1 for T1. We propose a pump-probe time-resolved infrared spectroscopy study to verify the mechanism. These findings can clarify the ongoing dispute over the understanding of the high TADF quantum efficiency for two-coordinate metal complexes.