SARS-CoV-2 501Y.V2 variants lack higher infectivity but do have immune escape.

The 501Y.V2 variants of SARS-CoV-2 containing multiple mutations in spike are now dominant in South Africa and are rapidly spreading to other countries. Here, experiments with 18 pseudotyped viruses showed that the 501Y.V2 variants do not confer increased infectivity in multiple cell types except for murine ACE2-overexpressing cells, where a substantial increase in infectivity was observed. Notably, the susceptibility of the 501Y.V2 variants to 12 of 17 neutralizing monoclonal antibodies was substantially diminished, and the neutralization ability of the sera from convalescent patients and immunized mice was also reduced for these variants. The neutralization resistance was mainly caused by E484K and N501Y mutations in the receptor-binding domain of spike. The enhanced infectivity in murine ACE2-overexpressing cells suggests the possibility of spillover of the 501Y.V2 variants to mice. Moreover, the neutralization resistance we detected for the 501Y.V2 variants suggests the potential for compromised efficacy of monoclonal antibodies and vaccines.

The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity.

The spike protein of SARS-CoV-2 has been undergoing mutations and is highly glycosylated. It is critically important to investigate the biological significance of these mutations. Here, we investigated 80 variants and 26 glycosylation site modifications for the infectivity and reactivity to a panel of neutralizing antibodies and sera from convalescent patients. D614G, along with several variants containing both D614G and another amino acid change, were significantly more infectious. Most variants with amino acid change at receptor binding domain were less infectious, but variants including A475V, L452R, V483A, and F490L became resistant to some neutralizing antibodies. Moreover, the majority of glycosylation deletions were less infectious, whereas deletion of both N331 and N343 glycosylation drastically reduced infectivity, revealing the importance of glycosylation for viral infectivity. Interestingly, N234Q was markedly resistant to neutralizing antibodies, whereas N165Q became more sensitive. These findings could be of value in the development of vaccine and therapeutic antibodies.

MFD-GDrug: multimodal feature fusion-based deep learning for GPCR-drug interaction prediction.

The accurate identification of drug-protein interactions (DPIs) is crucial in drug development, especially concerning G protein-coupled receptors (GPCRs), which are vital targets in drug discovery. However, experimental validation of GPCR-drug pairings is costly, prompting the need for accurate predictive methods. To address this, we propose MFD-GDrug, a multimodal deep learning model. Leveraging the ESM pretrained model, we extract protein features and employ a CNN for protein feature representation. For drugs, we integrated multimodal features of drug molecular structures, including three-dimensional features derived from Mol2vec and the topological information of drug graph structures extracted through Graph Convolutional Neural Networks (GCN). By combining structural characterizations and pretrained embeddings, our model effectively captures GPCR-drug interactions. Our tests on leading GPCR-drug interaction datasets show that MFD-GDrug outperforms other methods, demonstrating superior predictive accuracy.

Modulation of Heterotypic and Homotypic Interactions to Visualize the Evolution of Organic Aggregates in a Fluorescence Turn-on Manner.

The abnormal evolution of membrane-less organelles into amyloid fibrils is a causative factor in many neurodegenerative diseases. Fundamental research on evolving organic aggregates is thus instructive for understanding the root causes of these diseases. In-situ monitoring of evolving molecular aggregates with built-in fluorescence properties is a reliable approach to reflect their subtle structural variation. To increase the sensitivity of real-time monitoring, we presented organic aggregates assembled by TPAN-2MeO, which is a triphenyl acrylonitrile derivative. TPAN-2MeO showed a morphological evolution with distinct turn-on emission. Upon rapid nanoaggregation, it formed non-emissive spherical aggregates in the kinetically metastable state. Experimental and simulation results revealed that the weak homotypic interactions between the TPAN-2MeO molecules liberated their molecular motion for efficient non-radiative decay, and the strong heterotypic interactions between TPAN-2MeO and water stabilized the molecular geometry favorable for the non-fluorescent state. After ultrasonication, the decreased heterotypic interactions and increased homotypic interactions acted synergistically to allow access to the emissive thermodynamic equilibrium state with a decent photoluminescence quantum yield (PLQY). The spherical aggregates were eventually transformed into micrometer-sized blocklike particles. Under mechanical stirring, the co-assembly of TPAN-2MeO and Pluronic F-127 formed uniform fluorescent platelets, inducing a significant enhancement in PLQY. These results decipher the stimuli-triggered structural variation of organic aggregates with concurrent sensitive fluorescence response and pave the way for a deep understanding of the evolutionary events of biogenic aggregates.

Multifunctional Fluorescent Main-Chain Charged Polyelectrolytes Synthesized by Cascade C-H Activation/Annulation Polymerizations.

Fluorescent polyelectrolytes have attracted enormous attention as functional polymer materials. In contrast with the widely studied conjugated polyelectrolytes with ionic groups in side chains, fluorescent main-chain charged polyelectrolytes (MCCPs) have rarely been explored due to the large synthetic difficulty. Herein, we develop a facile and atom-economical N-heterocyclic carbene-directed cascade C-H activation/annulation polymerization strategy that can transform readily available imidazolium substrates and internal diynes into multifunctional fluorescent MCCPs with complex structures and high molecular weights (absolute Mn up to 135 600) in nearly quantitative yields. The presence of multisubstituted polycyclic N-heteroaromatic cations in polymer backbones endow the obtained MCCPs with excellent solution processability, high thermal stability, and dual-state efficient fluorescence in both solution and aggregate states. Benefiting from the strong electron-withdrawing capability of the cationic heterocycles in main chains, multicolored aggregate-state fluorescence can be readily achieved by modifying the substituents around the cationic ring-fused core. Taking advantage of the good photosensitivity of the fluorescent MCCP thin films, multiscale and high-resolution fluorescent photopatterns with different colors can be facilely prepared with potential applications in optical display devices and anticounterfeiting systems. Moreover, the strong electrostatic interactions of these cationic MCCPs with anionic polyelectrolytes enable them to form multicolored fluorescent interfacial polyelectrolyte complexation microfibers with directly visualized internal structures. Such flexible microfibers can be further made into diversified forms of fiber-based macroscopic patterns or painting.

Substrate-Responsive Pillar[5]arene-Based Organic Room-Temperature Phosphorescence.

Room-temperature phosphorescence (RTP) is a photophysical phenomenon typically associated with a long-lived emission that can be detected by the unaided eye. Several natural proteins display RTP, as do certain artificial polymers. In both cases, the RTP is ascribed to effective intramolecular through-space electronic communication. However, small molecules with internal electronic communication that enable RTP are relatively rare. Herein, we describe an alkyl halide-responsive RTP system consisting of a meta-formylphenyl-bearing pillar[5]arene derivative that supports effective through-space charge transfer (TSCT) within the pillararene cavity. Treatment with bromoethane, a heavy atom-containing guest for the pillar[5]arene host, serves to enhance the emission. An isomeric para-formylphenyl-bearing pillar[5]arene system proved ineffective in producing an RTP effect. Quantum chemical calculations based on single-crystal X-ray diffraction analyses provided insights into the structural determinants governing TSCT between the 1,4-dimethoxybenzene donor units and the formylphenyl groups of the pillar[5]arene, as well as the associated energy gaps and intersystem crossing channels. We believe that the present system and the associated mechanistic analysis provide the foundation for design of new small molecule with tunable RTP features.

Through-Space Interaction of Tetraphenylethylene: What, Where, and How.

Electronic conjugation through covalent bonds is generally considered as the basis for the electronic transition of organic luminescent materials. Tetraphenylethylene (TPE), an efficient fluorophore with aggregation-induced emission character, fluoresces blue emission in the aggregate state, and such photoluminescence is always ascribed to the through-bond conjugation (TBC) among the four phenyl rings and the central C═C bond. However, in this work, systematic spectroscopic studies and DFT theoretical simulation reveal that the intramolecular through-space interaction (TSI) between two vicinal phenyl rings generates the bright blue emission in TPE but not the TBC effect. Furthermore, the evaluation of excited-state decay dynamics suggests the significance of photoinduced isomerization in the nonradiative decay of TPE in the solution state. More importantly, different from the traditional qualitative description for TSI, the quantitative elucidation of the TSI is realized through the atoms-in-molecules analysis; meanwhile, a theoretical solid-state model for TPE and other multirotor systems for studying the electronic configuration is preliminarily established. The mechanistic model of TSI delineated in this work provides a new strategy to design luminescent materials beyond the traditional theory of TBC and expands the quantum understanding of molecular behavior to the aggregate level.

A platform method for plasmid isoforms analysis by capillary gel electrophoresis.

In the production of novel biological products, plasmids are often engineered into delivery vectors for target genes, which can be used directly as vaccines or as intermediate products for gene/cell therapy. Plasmid DNA exists in several topological forms such as supercoiled, linear, and open circular. As supercoiled plasmid shows the highest efficiency in transfecting eukaryotic cells, the content of supercoiled plasmids becomes an important indicator of plasmid quality. CGE is an effective analysis method for separating different topological structures of plasmids. For the purpose of providing plasmid manufacturers and regulatory agencies with an efficient and readily used tool for monitoring the quality of plasmids, this article identifies the optimal separation and detection conditions of CGE, presents a platform-based plasmid analytical method, and uses plasmid of different sizes to verify the feasibility of this method. In terms of detector, the LIF detector has obvious advantages over the ultraviolet detector in sensitivity and resolution. Using the optimal CE condition (10× gel buffer), baseline separation of different topological forms and impurities can be achieved for different plasmid sizes (5.9, 7.8, 15.4 kb). In addition, 6.5 kb plasmid was used to compare the different separation technologies such as CGE-LIF, ion exchange chromatography and agarose gel electrophoresis. The result shows that CGE-LIF can provide better resolution and quantitation accuracy than ion exchange chromatography and agarose gel electrophoresis. CGE-LIF, as a quick and convenient method to separate and quantify plasmids, has the advantages of high sensitivity, high resolution, and high quantitative accuracy. Therefore, it is ideal for analysis of plasmids with different sizes, and it can also be used as a platform method for manufacturers and regulatory agencies to monitor the purity and stability of plasmids.

Click Synthesis Enabled Sulfur Atom Strategy for Polymerization-Enhanced and Two-Photon Photosensitization.

Facile tailoring of photosensitizers (PSs) with advanced and synergetic properties is highly expected to broaden and deepen photodynamic therapy (PDT) applications. Herein, a catalyst-free thiol-yne click reaction was employed to develop the sulfur atom-based PSs by using the in situ formed sulfur "heavy atom effect" to enhance the intersystem crossing (ISC), while such an effect can be remarkably magnified by the polymerization. The introduction of a tetraphenylpyrazine-based aggregation-induced emission (AIE) unit was also advantageous in PS design by suppressing their non-radiative decay to facilitate the ISC in the aggregated state. Besides, the resulting sulfur atom electron donor, together with a double-bond π bridge and AIE electron acceptor, created a donor-π-acceptor (D-π-A) molecular system with good two-photon excitation properties. Combined with the high singlet oxygen generation efficiency, the fabricated polymer nanoparticles exhibited an excellent in vitro two-photon-excited PDT towards cancer cells, therefore possessing a huge potential for the deep-tissue disease therapy.

Hierarchical Supramolecular Self-Assembly: Fabrication and Visualization of Multiblock Microstructures.

Due to the fast dynamics and re-equilibration of supramolecular self-assembly, bottom-up molecular strategies to fabricate well-defined and controllable multiblock structures are rare. Herein, we propose a new concept for fabrication of fluorescent multiblock microcolumns containing 1 to 7 blocks via hierarchical supramolecular self-assembly based on cucurbit[8]uril (CB[8]), NaBr and an AIEgen guest. Through the complexation between CB[8] and different numbers of AIEgen guests (2, 1, 0), the competitive displacement caused by the binding of the sodium cation to the CB[8] portal, and the reversible assembly of positively charged guests in salt solutions, one-pot hierarchical supramolecular self-assembly is realized. The molecular structure of each block is analyzed by single-crystal X-ray diffraction. The AIEgen enables the self-assembly of multiblocks to be visualized, understood, and regulated.

How to Manipulate Through-Space Conjugation and Clusteroluminescence of Simple AIEgens with Isolated Phenyl Rings.

Apart from the traditional through-bond conjugation (TBC), through-space conjugation (TSC) is gradually proved as another important interaction in photophysical processes, especially for the recent observation of clusteroluminescence from nonconjugated molecules. However, unlike TBC in conjugated chromophores, it is still challenging to manipulate TSC and clusteroluminescence. Herein, simple and nonconjugated triphenylmethane (TPM) and its derivatives with electron-donating and electron-withdrawing groups were synthesized, and their photophysical properties were systematically studied. TPM was characterized with visible clusteroluminescence due to the intramolecular TSC. Experimental and theoretical results showed that the introduction of electron-donating groups into TPM could red-shift the wavelength and increase the efficiency of clusteroluminescence simultaneously, due to the increased electronic density and stabilization of TSC. However, TPM derivatives with electron-withdrawing groups showed inefficient or even quenched clusteroluminescence caused by the vigorous excited-state intramolecular motion and intermolecular photoinduced electron transfer process. This work provides a reliable strategy to manipulate TSC and clusteroluminescence.

Planar and Twisted Molecular Structure Leads to the High Brightness of Semiconducting Polymer Nanoparticles for NIR-IIa Fluorescence Imaging.

Semiconducting polymer nanoparticles (SPNs) emitting in the second near-infrared window (NIR-II, 1000-1700 nm) are promising materials for deep-tissue optical imaging in mammals, but the brightness is far from satisfactory. Herein, we developed a molecular design strategy to boost the brightness of NIR-II SPNs: structure planarization and twisting. By integration of the strong absorption coefficient inherited from planar π-conjugated units and high solid-state quantum yield (ΦPL) from twisted motifs into one polymer, a rise in brightness was obtained. The resulting pNIR-4 with both twisted and planar structure displayed improved ΦPL and absorption when compared to the planar polymer pNIR-1 and the twisted polymer pNIR-2. Given the emission tail extending into the NIR-IIa region (1300-1400 nm) of the pNIR-4 nanoparticles, NIR-IIa fluorescence imaging of blood vessels with enhanced clarity was observed. Moreover, a pH-responsive poly(ß-amino ester) made pNIR-4 specifically accumulate at tumor sites, allowing NIR-IIa fluorescence image-guided cancer precision resection. This study provides a molecular design strategy for developing highly bright fluorophores.

A visible-light-induced "on-off" one-pot synthesis of 3-arylacetylene coumarins with AIE properties.

A mild and simple one-pot stepwise method to synthesize 3-arylacetylene coumarins from alkynoates was demonstrated. This catalytic system involves photosensitizer-free photocatalysis and thermocatalysis processes. A series of alkynoates and phenylacetylenes were well tolerated in the optimized multi-catalytic system. The corresponding 3-arylacetylene coumarins were obtained in moderate to excellent yields. The results of the studies of their optical properties showed that the aromatic ring at the C4-position of coumarins is unfavorable for improving the molecular fluorescence quantum yield in solution. Based on the spectral studies and X-ray single crystal diffraction analysis, it was found that AIE activities may exist in some of the 3-arylvinyl-4-aryl-coumarins in their solid state. We expect that these molecules may have potential optical applications.

New Wine in Old Bottles: Prolonging Room-Temperature Phosphorescence of Crown Ethers by Supramolecular Interactions.

Supramolecular macrocyclic hosts have long been used in smart materials. However, their triplet emission and regulation at crystal level is rarely studied. Herein, ultralong and universal room-temperature phosphorescence (RTP) is reported for traditional crown ethers. A supramolecular strategy involving chain length adjustment and morphological locking through complexation with K+ was explored as a general method to tune the phosphorescence lifetime in the solid state. A maximum 10-fold increase of lifetime after complex formation accompanied with by invisible to visible phosphorescence was achieved. A deep encryption based on this activated RTP strategy was also facilely fabricated. This work thus opens a new world for supramolecular macrocycles and their intrinsic guest responsiveness offers a new avenue for versatile smart luminescent materials.

Time-Dependent Photodynamic Therapy for Multiple Targets: A Highly Efficient AIE-Active Photosensitizer for Selective Bacterial Elimination and Cancer Cell Ablation.

Pathogen infections and cancer are two major human health problems. Herein, we report the synthesis of an organic salt photosensitizer (PS), called 4TPA-BQ, by a one-step reaction. 4TPA-BQ presents aggregation-induced emission features. Owing to the aggregation-induced reactive oxygen species generated and a sufficiently small ΔEST , 4TPA-BQ shows a satisfactorily high 1 O2 generation efficiency of 97.8 %. In vitro and in vivo experiments confirmed that 4TPA-BQ exhibited potent photodynamic antibacterial performance against ampicillin-resistant Escherichia coli with good biocompatibility in a short time (15 minutes). When the incubation duration persisted long enough (12 hours), cancer cells were ablated efficiently, leaving normal cells essentially unaffected. This is the first reported time-dependent fluorescence-guided photodynamic therapy in one individual PS, which achieves ordered and multiple targeting simply by varying the external conditions. 4TPA-BQ reveals new design principles for the implementation of efficient PSs in clinical applications.

Restriction of Access to the Dark State: A New Mechanistic Model for Heteroatom-Containing AIE Systems.

Restriction of intramolecular motion (RIM), as the working mechanism of aggregation-induced emission (AIE), cannot fully explain some heteroatom-containing systems. Now, two excited states are taken into account and a mechanism, restriction of access to dark state (RADS), is specified to elaborate RIM and complete the picture of AIE mechanism. A nitrogen-containing molecule named APA is chosen as a model compound; its weak fluorescence in solution is ascribed to the easy access from the bright (π,π*) state to the close-lying dark (n,π*) state. By either metal complexation or aggregation, the dark state is less accessible due to restriction of the molecular motion leading to the dark state and elevation of the dark state energy, thus the bright state emission is restored. RADS is powerful in elucidating the AIE effect of molecules with excited states favoring non-radiative decay, including overlap-forbidden states such as (n,π*) and CT states, spin-forbidden triplet states, and so on.

2,2'-Diamino-6,6'-diboryl-1,1'-binaphthyl: A Versatile Building Block for Temperature-Dependent Dual Fluorescence and Switchable Circularly Polarized Luminescence.

Temperature-dependent dual fluorescence and switchable circularly polarized luminescence (CPL) are two highly pursued but challenging properties for small organic molecules (SOMs). We herein disclose a triarylborane π-system based on a 2,2'-diamino-6,6'-diboryl-1,1'-binaphthyl scaffold that can serve as a versatile building block for achieving these two properties by simply choosing different amino groups. BNMe2 -BNaph with less bulky dimethylamino groups displays temperature-dependent dual fluorescence, and can thus be used as a highly sensitive ratiometric fluorescence thermometer. On the other hand, BNPh2 -BNaph with bulky diphenylamino groups exhibits intense fluorescence in both solution and in the solid state. A change of solvent from nonpolar cyclohexane to highly polar MeCN not only shifts the CPL position to much longer wavelength but also inverts the CPL sign. In addition, the complexation of BNPh2 -BNaph with fluoride greatly enhances the CPL intensity.

Spontaneous and Fast Molecular Motion at Room Temperature in the Solid State.

The development of molecular machines requires new building blocks which are easy to characterize and visualize to realize a complexity comparable to their natural counterparts such as biological enzymes. Furthermore, with the desire to build functional nanobots capable of navigating living organisms, it is necessary that the building blocks show mobility even in the solid state. Herein we report a system which is emissive in the amorphous state but is non-fluorescent in the crystalline state due to the formation of extensive π-π interactions. This dual nature could be exploited for easy visualization of its solid-state molecular rearrangement. The emission of the amorphous film was quenched as the molecules spontaneously formed π-π interactions even in the solid state. Scratching the non-emissive film destroyed the interactions and restored the emission of the film. The emission quickly disappeared with an average lifetime of 20 s as the compound reformed the π-network even at room temperature.

Aggregation-induced emission and the working mechanism of 1-benzoyl and 1-benzyl pyrene derivatives.

Over the past decade, research studies on solid-state luminescent materials featuring aggregation-induced emission (AIE) have achieved great success. It has been proved that lots of planar ACQ (aggregation-caused quenching) chromophores can be converted to AIE luminogens (AIEgens) by combining with an AIE-active unit such as tetraphenylethene (TPE). In this work, we present a new method to create AIE luminogens just by introducing benzoyl or benzyl to a planar chromophore, pyrene. The generated 1-benzoyl and 1-benzyl pyrene derivatives exhibit weak emission when molecularly dissolved in good solvents but strong emission from pyrene dimers when aggregated in poor solvent or the solid state. Their crystal structure analysis and theoretical calculations are performed to depict the working mechanism of these new AIEgens. The results show that the structural rigidification of these 1-benzoyl pyrene derivatives is the major cause for their AIE effect. This new AIE system along with a clear working mechanism will contribute to the development of AIE-related functional materials and theories.

Strategies to Enhance the Photosensitization: Polymerization and the Donor-Acceptor Even-Odd Effect.

A particular challenge in the design of organic photosensitizers (PSs) with donor-acceptor (D-A) structures is that it is based on trial and error rather than specific rules. Now these challenges are addressed by proposing two efficient strategies to enhance the photosensitization efficiency: polymerization-facilitated photosensitization and the D-A even-odd effect. Conjugated polymers have been found to exhibit a higher 1 O2 generation efficiency than their small molecular counterparts. Furthermore, PSs with A-D-A structures show enhanced photosensitization efficiency over those with D-A-D structures. Theoretical calculations suggest an enhanced intersystem crossing (ISC) efficiency by these strategies. Both in vitro and in vivo experiments demonstrate that the resulting materials can be used as photosensitizers in image-guided photodynamic anticancer therapy. These guidelines are applicable to other polymers and small molecules to lead to the development of new PSs.