KDM4C promotes mouse hippocampal neural stem cell proliferation through modulating ApoE expression.

KDM4C is implicated in the regulation of cell proliferation, differentiation, and maintenance in various stem cell types. However, its function in neural stem cells (NSCs) remains poorly understood. Therefore, this study aims to investigate the role and regulatory mechanism of KDM4C in NSCs. Primary hippocampal NSCs were isolated from neonatal mice, and both in vivo and in vitro lentivirus-mediated overexpression of KDM4C were induced in these hippocampal NSCs. Staining results revealed a significant increase in BrdU- and Ki-67-positive cells, along with an elevated number of cells in S phases due to KDM4C overexpression. Subsequently, RNA-seq was employed to analyze gene expression changes following KDM4C upregulation. GO enrichment analysis, KEGG analysis, and GSEA highlighted KDM4C-regulated genes associated with development, cell cycle, and neurogenesis. Protein-protein interaction analysis uncovered that ApoE protein interacts with several genes (top 10 upregulated and downregulated) regulated by KDM4C. Notably, knocking down ApoE mitigated the proliferative effect induced by KDM4C overexpression in NSCs. Our study demonstrates that KDM4C overexpression significantly upregulates ApoE expression, ultimately promoting proliferation in mouse hippocampal NSCs. These findings provide valuable insights into the molecular mechanisms governing neurodevelopment, with potential implications for therapeutic strategies in neurological disorders.

Patterning axon targeting of olfactory receptor neurons by coupled hedgehog signaling at two distinct steps.

We present evidence for a coupled two-step action of Hedgehog signaling in patterning axon targeting of Drosophila olfactory receptor neurons (ORNs). In the first step, differential Hedgehog pathway activity in peripheral sensory organ precursors creates ORN populations with different levels of the Patched receptor. Different Patched levels in ORNs then determine axonal responsiveness to target-derived Hedgehog in the brain: only ORN axons that do not express high levels of Patched are responsive to and require a second step of Hedgehog signaling for target selection. Hedgehog signaling in the imaginal sensory organ precursors thus confers differential ORN responsiveness to Hedgehog-mediated axon targeting in the brain. This mechanism contributes to the spatial coordination of ORN cell bodies in the periphery and their glomerular targets in the brain. Such coupled two-step signaling may be more generally used to coordinate other spatially and temporally segregated developmental events.

Elucidation of the key role of Pt···Pt interactions in the directional self-assembly of platinum(II) complexes.

Here, we report the use of an amphiphilic Pt(II) complex, K[Pt{(O3SCH2CH2CH2)2bzimpy}Cl] (PtB), as a model to elucidate the key role of Pt···Pt interactions in directing self-assembly by combining temperature-dependent ultraviolet-visible (UV-Vis) spectroscopy, stopped-flow kinetic experiments, quantum mechanics (QM) calculations, and molecular dynamics (MD) simulations. Interestingly, we found that the self-assembly mechanism of PtB in aqueous solution follows a nucleation-free isodesmic model, as revealed by the temperature-dependent UV-Vis experiments. In contrast, a cooperative growth is found for the self-assembly of PtB in acetone­water (7:1, vol/vol) solution, which is further verified by the stopped-flow experiments, which clearly indicates the existence of a nucleation phase in the acetone­water (7:1, vol/vol) solution. To reveal the underlying reasons and driving forces for these self-assembly processes, we performed QM calculations and show that the Pt···Pt interactions arising from the interaction between the pz and dz2 orbitals play a crucial role in determining the formation of ordered self-assembled structures. In subsequent oligomer MD simulations, we demonstrate that this directional Pt···Pt interaction can indeed facilitate the formation of linear structures packed in a helix-like fashion. Our results suggest that the self-assembly of PtB in acetone­water (7:1, vol/vol) solution is predominantly driven by the directional noncovalent Pt···Pt interaction, leading to the cooperative growth and the formation of fibrous nanostructures. On the contrary, the self-assembly in aqueous solution forms spherical nanostructures of PtB, which is primarily due to the predominant contribution from the less directional hydrophobic interactions over the directional Pt···Pt and π−π interactions that result in an isodesmic growth.

Two Key Descriptors for Designing Second Near-Infrared Dyes and Experimental Validation.

Second near-infrared (NIR-II) optical imaging technology has emerged as a powerful tool for diagnostic and image-guided surgery due to its higher imaging contrast. However, a general strategy for efficiently designing NIR-II organic molecules is still lacking, because NIR-II dyes are usually difficult to synthesize, which has impeded the rapid development of NIR-II bioprobes. Herein, based on the theoretical calculations on 62 multiaryl-pyrrole (MAP) systems with spectra ranging from the visible to the NIR-II region, a continuous red shift of the spectra toward the NIR-II region could be achieved by adjusting the type and site of substituents on the MAPs. Two descriptors (ΔEgs and µgs) were identified as exhibiting strong correlations with the maximum absorption/emission wavelengths, and the descriptors could be used to predict the emission spectrum in the NIR-II region only if ΔEgs ≤ 2.5 eV and µgs ≤ 22.55 D. The experimental absorption and emission spectra of ten MAPs fully confirmed the theoretical predictions, and biological imaging in vivo of newly designed MAP23-BBT showed high spatial resolution in the NIR-II region in deep tissue angiography. More importantly, both descriptors of ΔEgs and µgs have shown general applicability to most of the reported donor-acceptor-donor-type non-MAP NIR-II dyes. These results have broad implications for the efficient design of NIR-II dyes.

Advances in Nanoplatforms for Immunotherapy Applications Targeting the Tumor Microenvironment.

Cancer immunotherapy is a treatment method that activates or enhances the autoimmune response of the body to fight tumor growth and metastasis, has fewer toxic side effects and a longer-lasting efficacy than radiotherapy and chemotherapy, and has become an important means for the clinical treatment of cancer. However, clinical results from immunotherapy have shown that most patients lack responsiveness to immunotherapy and cannot benefit from this treatment strategy. The tumor microenvironment (TME) plays a critical role in the response to immunotherapy. The TME typically prevents effective lymphocyte activation, reducing their infiltration, and inhibiting the infiltration of effector T cells. According to the characteristic differences between the TME and normal tissues, various nanoplatforms with TME targeting and regulation properties have been developed for more precise regulation of the TME and have the ability to codeliver a variety of active pharmaceutical ingredients, thereby reducing systemic toxicity and improving the therapeutic effect of antitumor. In addition, the precise structural design of the nanoplatform can integrate specific functional motifs, such as surface-targeted ligands, degradable backbones, and TME stimulus-responsive components, into nanomedicines, thereby reshaping the tumor microenvironment, improving the body's immunosuppressive state, and enhancing the permeability of drugs in tumor tissues, in order to achieve controlled and stimulus-triggered release of load cargo. In this review, the physiological characteristics of the TME and the latest research regarding the application of TME-regulated nanoplatforms in improving antitumor immunotherapy will be described. Furthermore, the existing problems and further applications perspectives of TME-regulated platforms for cancer immunotherapy will also be discussed.

Exploring causal association between circulating inflammatory cytokines and functional outcomes following ischemic stroke: A bidirectional Mendelian randomization study.

OBJECTIVES: Previous observational studies have indicated correlations between various inflammatory cytokines and functional outcomes following ischemic stroke (IS); however, the causality remains unclear. We aimed to further evaluate the causal association between 41 circulating inflammatory cytokines and functional outcomes following IS. METHODS: Two-sample bidirectional Mendelian randomization (MR) analysis was used in this study. The genetic variation of 41 circulating inflammatory cytokines were derived from genome-wide association study (GWAS) data of European ancestry (n = 8293). The corresponding genetic association of functional outcomes following IS were derived from European ancestry GWAS data (n = 6021). RESULTS: Inverse variance weighted (IVW) analysis showed that genetically predicted increased levels of regulation and activation in normal T-cell expression and secretion factor (RANTES/CCL5) and eosinophilic chemotactic factor (EOTAXIN/CCL11) were positively correlated with the increased adverse functional outcomes (modified Rankin Scale [mRS≥3] following IS (OR: 1.40, 95% CI: 1.002-1.96, p = 0.049; OR: 1.33, 95% CI: 1.15-1.54, p = 0.0001). Interleukin 18 (IL-18) level might be the downstream consequence of adverse functional outcomes following IS (ß: -0.09, p = 0.039). Other inflammatory cytokines and functional outcomes following IS did not appear to be causally related. CONCLUSIONS: This study suggests a causality between inflammation and adverse functional outcomes following IS. RANTES (CCL5) and EOTAXIN (CCL11) may be the upstream factors of adverse functional outcomes following IS, while IL-18 may be the downstream effect of adverse functional outcomes following IS. Whether these cytokines can be used to predict or improve adverse functional outcomes after IS requires further researches.

Turnover of Murine Cytomegalovirus-Expanded CD8+ T Cells Is Similar to That of Memory Phenotype T Cells and Independent of the Magnitude of the Response.

The potential of memory T cells to provide protection against reinfection is beyond question. Yet, it remains debated whether long-term T cell memory is due to long-lived memory cells. There is ample evidence that blood-derived memory phenotype CD8+ T cells maintain themselves through cell division, rather than through longevity of individual cells. It has recently been proposed, however, that there may be heterogeneity in the lifespans of memory T cells, depending on factors such as exposure to cognate Ag. CMV infection induces not only conventional, contracting T cell responses, but also inflationary CD8+ T cell responses, which are maintained at unusually high numbers, and are even thought to continue to expand over time. It has been proposed that such inflating T cell responses result from the accumulation of relatively long-lived CMV-specific memory CD8+ T cells. Using in vivo deuterium labeling and mathematical modeling, we found that the average production rates and expected lifespans of mouse CMV-specific CD8+ T cells are very similar to those of bulk memory-phenotype CD8+ T cells. Even CMV-specific inflationary CD8+ T cell responses that differ 3-fold in size were found to turn over at similar rates.

Host-guest interaction induced room-temperature phosphorescence enhancement of organic dyes: a computational study.

To achieve the effective regulation of organic room temperature phosphorescence (RTP) in supramolecular systems, the elucidation of host-guest interactions in RTP is of vital importance. Herein, we employed two organic dyes (PYCl and PYBr) and their four host-guest complexes with CB[6] and CB[7] and explored the mechanism of host-guest interaction induced RTP enhancement using quantum mechanics/molecular mechanics (QM/MM) approach. For the two organic dyes, we found that the better RTP performance of PYBr than PYCl is attributed to intersystem crossing (ISC) augmentation induced by the heavy atom effect. Binding to CB[6] through host-guest interactions can simultaneously accelerate the radiative decay process by increasing the transition dipole moment of T1 → S0 (µT1→S0), block the nonradiative decay process, and promote the ISC process, eventually leading to a remarkably boosted RTP. Upon complexation, the conversion of S1 from 1(n, π*) to 1(π, π*) is key to µT1→S0 enhancement; reduced reorganization energies reflect the suppression of the nonradiative decay process by restricting the rotation of rings A and B in organic dyes. In addition, the promoted ISC process is due to the activation of more ISC channels between S1 and high-lying triplet states with large spin-orbital coupling constants and small energy gap. The case of CB[7]-type complexes is much different, because of the extremely large cavity size of CB[7] for encapsulation. This work proposes the mechanism of host-guest interaction-induced RTP enhancement of organic dyes, thus laying a solid foundation for the rational design of advanced RTP materials based on supramolecular assemblies.

Pressure effects on both fluorescent emission and charge transport properties of organic semiconductors: a computational study.

External pressure can regulate the photophysical property and charge transport performance of organic semiconductors, however, the underlying mechanism at the microscopic level is still elusive. Using thermal vibrational correlation function coupled quantum mechanics/molecular mechanics and full quantum charge transfer rate theory, we systematically explore the influence of pressure on fluorescence emission and charge transport behaviours of representative cyclooctatetrathiophene (COTh). It is found that, upon pressurization, the intramolecular configurations of COTh became more twisted, leading to the blue-shifted emission. The fluorescence quantum efficiency (FQE) of COTh crystals decreases monotonically in a wide pressure range of 0-4.38 GPa, because the increase of intermolecular electronic energy transfer rate constant (keet) is larger than the decrease of internal conversion rate constant (kic), and the variation of keet is dominant. The decrease in kic is attributed to the decreasing reorganization energy, reflecting the suppression of the low-frequency flipping vibrations of four thiophene rings and the high-frequency stretching vibrations of central cyclooctatetraene, while the keet increase is due to the simultaneous increase in exciton coupling and spectra overlap. Moreover, we predicted that the hole mobility of COTh increases monotonically by nearly an order of magnitude from 0.39 to 3.00 cm2 V-1 s-1 upon compression, because of the increase in transfer integral and the decrease of charged reorganization energy. Furthermore, its hole mobility exhibits obvious anisotropy. Our work systematically builds the external pressure, molecular packing, luminescence and transport properties relationships of organic semiconductors and provides theoretical guidance for the rational design of pressure responsive organic semiconductors with excellent photoelectric performance.

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.

Translation, cultural adaptation, and validation of the Chinese standardized outcomes in nephrology-hemodialysis fatigue (C-SONG-HD fatigue) scale: a study of Chinese patients undergoing hemodialysis.

OBJECTIVE: This study aimed to translate and culturally adapt the standardized outcomes in nephrology-hemodialysis fatigue (SONG-HD fatigue) scale and to assess the psychometric properties of the Chinese version of the SONG-HD fatigue (C-SONG-HD fatigue) scale. METHODS: Forward and back translations were used to translate the SONG-HD fatigue scale into Chinese. We used the C-SONG-HD fatigue scale to survey Chinese patients undergoing hemodialysis (HD) in China. We examined the distribution of responses and floor and ceiling effects. Cronbach's alpha and McDonald's omega coefficient, intraclass coefficients, and Spearman correlations were used to assess internal consistency reliability, test-retest reliability, and convergent validity, respectively. Responsiveness was also evaluated. RESULTS: In total, 489 participants across southeast China, northwest China, and central China completed the study. The C-SONG-HD fatigue scale had good internal consistency (Cronbach's alpha coefficient 0.861, omega coefficient 0.916), test-retest reliability (intraclass correlation coefficient 0.695), and convergent validity (Spearman correlation 0.691). The analysis of all first-time HD patients did not show notable responsiveness, and only patients with temporary vascular access had good responsiveness with an effect size (ES) of 0.54, a standardized response mean (SRM) of 0.85, and a standard error of measurement (SEM) of 0.77. CONCLUSION: The Chinese version of the SONG-HD fatigue scale showed satisfactory reliability and validity in patients undergoing hemodialysis (HD) in China. It could be used as a tool to measure the fatigue of Chinese HD patients.

Prediction of influenza outbreaks in Fuzhou, China: comparative analysis of forecasting models.

BACKGROUND: Influenza is a highly contagious respiratory disease that presents a significant challenge to public health globally. Therefore, effective influenza prediction and prevention are crucial for the timely allocation of resources, the development of vaccine strategies, and the implementation of targeted public health interventions. METHOD: In this study, we utilized historical influenza case data from January 2013 to December 2021 in Fuzhou to develop four regression prediction models: SARIMA, Prophet, Holt-Winters, and XGBoost models. Their predicted performance was assessed by using influenza data from the period from January 2022 to December 2022 in Fuzhou. These models were used for fitting and prediction analysis. The evaluation metrics, including Mean Squared Error (MSE), Root Mean Squared Error (RMSE), and Mean Absolute Error (MAE), were employed to compare the performance of these models. RESULTS: The results indicate that the epidemic of influenza in Fuzhou exhibits a distinct seasonal and cyclical pattern. The influenza cases data displayed a noticeable upward trend and significant fluctuations. In our study, we employed SARIMA, Prophet, Holt-Winters, and XGBoost models to predict influenza outbreaks in Fuzhou. Among these models, the XGBoost model demonstrated the best performance on both the training and test sets, yielding the lowest values for MSE, RMSE, and MAE among the four models. CONCLUSION: The utilization of the XGBoost model significantly enhances the prediction accuracy of influenza in Fuzhou. This study makes a valuable contribution to the field of influenza prediction and provides substantial support for future influenza response efforts.

Synthesis of π-Conjugated Chiral Organoborane Macrocycles with Blue to Near-Infrared Emissions and the Diradical Character of Cations.

Highly emissive π-conjugated macrocycles with tunable circularly polarized luminescence (CPL) have sparked theoretical and synthetic interests in recent years. Herein, we report a synthetic approach to obtain new chiral organoborane macrocycles (CMC1, CMC2, and CMC3) that are built on the structurally chiral [5]helicenes and highly luminescent triarylborane/amine moieties embedded into the cyclic systems. These rarely accessible B/N-doped main-group chiral macrocycles show a unique topology dependence of the optoelectronic and chiroptical properties. CMC1 and CMC2 show a higher luminescence dissymmetry factor (glum) together with an enhanced CPL brightness (BCPL) as compared with CMC3. Electronic effects were also tuned and resulted in bathochromic shifts of their emission and CPL responses from blue for CMC1 to the near-infrared (NIR) region for CMC3. Furthermore, chemical oxidations of the N donor sites in CMC1 gave rise to a highly stable radical cation (CMC1·+SbF6-) and diradical dication species (CMC12·2+2SbF6-) that serve as a rare example of a positively charged open-shell chiral macrocycle.

TNEA therapy promotes the autophagic degradation of NLRP3 inflammasome in a transgenic mouse model of Alzheimer's disease via TFEB/TFE3 activation.

BACKGROUND: The impairment in the autophagy-lysosomal pathway (ALP) and the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome represent two molecular events leading to neurodegeneration and neuroinflammation in Alzheimer's disease (AD), a devastating neurodegenerative disorder without a cure. Previously we demonstrated the cognitive-enhancing effect of a combined electroacupuncture (EA) therapy termed TNEA in a transgenic mouse model of AD, involving activation of transcription factor EB (TFEB), a master regulator of ALP. However, whether and how TNEA inhibits NLRP3 inflammasome via TFEB-mediated ALP in AD remains to be investigated. METHODS: 5xFAD mice overexpressing amyloid-ß (Aß) were treated with TNEA or EA on its composing acupoints (GB13 and GV24). The changes in the signaling pathways regulating NLRP3 inflammasome, the association of NLRP3 inflammasome with ALP, and the roles of TFEB/TFE3 in mice brains were determined by immunoblots, immunohistochemistry and AAV-mediated knockdown assays. RESULTS: TNEA inhibits the activation of NLRP3 inflammasome and the release of active interleukin 1ß (IL1B) in the hippocampi of 5xFAD mice. Mechanistically, TNEA promoted the autophagic degradation of inflammasome components via activating both TFEB and TFE3 by modulating kinases including AMPK and AKT. The composing acupoints in TNEA showed synergistic effects on regulating these molecular events and memory improvement. CONCLUSION: Our findings suggest that TNEA attenuates AD-associated memory impairment via promoting TFEB/TFE3-mediated autophagic clearance of Aß and NLRP3 inflammasome, and partially reveal the molecular basis of combined acupoints therapy originated from ancient wisdom.

Wildfire-Derived Nitrogen Aerosols Threaten the Fragile Ecosystem in Himalayas and Tibetan Plateau.

Himalayas and Tibetan Plateau (HTP) is important for global biodiversity and regional sustainable development. While numerous studies have revealed that the ecosystem in this unique and pristine region is changing, their exact causes are still poorly understood. Here, we present a year-round (23 March 2017 to 19 March 2018) ground- and satellite-based atmospheric observation at the Qomolangma monitoring station (QOMS, 4276 m a.s.l.). Based on a comprehensive chemical and stable isotope (15N) analysis of nitrogen compounds and satellite observations, we provide unequivocal evidence that wildfire emissions in South Asia can come across the Himalayas and threaten the HTP's ecosystem. Such wildfire episodes, mostly occurring in spring (March-April), not only substantially enhanced the aerosol nitrogen concentration but also altered its composition (i.e., rendering it more bioavailable). We estimated a nitrogen deposition flux at QOMS of ∼10 kg N ha-1 yr-1, which is approximately twice the lower value of the critical load range reported for the Alpine ecosystem. Such adverse impact is particularly concerning, given the anticipated increase of wildfire activities in the future under climate change.

Exosomal hsa_circRNA_047733 integrated with clinical features for preoperative prediction of lymph node metastasis risk in oral squamous cell carcinoma.

BACKGROUND: To evaluate whether exosomal circRNAs could serve as diagnostic biomarkers for the accurate preoperative prediction of lymph node metastasis (LNM) risk in oral squamous cell carcinoma (OSCC) patients. METHODS: A combinative strategy of exosomal circRNAs microarray and qRT-PCR verification was employed to dig LNM-related circRNA signatures. Then, a dynamic nomogram was developed based on candidate circRNAs and preoperative clinical features and the calibration, discrimination, and clinical use of the nomogram were evaluated. RESULTS: According to the microarray, three circRNAs derived from the tumor were associated with preoperative LNM risk, including hsa_circRNA_047733, hsa_circRNA_024144 and hsa_circRNA_403472. The hsa_circRNA_047733 was further verified to be significantly downregulated in patients with LNM (+) as compared with those with LNM (-) (p = 0.007). Patients with the higher expression of hsa_circRNA_047733 showed a lower risk of LNM (multivariate-adjusted OR = 0.22, 95%CI: 0.06-0.83). The bioinformatics prediction showed that hsa_circRNA_047733 might sponge miR-4464/miR-4748 to regulate RPS21 expression. A dynamic nomogram integrating exosomal hsa_circRNA_047733 with five clinicopathological characteristics (tumor site, leukocyte level, maximum tumor diameter, and LNM reported by MRI and preoperative biopsy differentiation) was developed. The model displayed an excellent discrimination ability (AUC = 0.868, 95%CI: 0.781-0.955) and great calibration. The decision curve revealed a higher net benefit superior to the baseline model at an 80% threshold probability. CONCLUSION: The data provide preliminary evidence that exosomal hsa_circRNA_047733 might be a novel biomarker for the LNM of OSCC. The hsa_circRNA_047733-based dynamic nomogram could serve as a convenient preoperative assessment tool to predict the risk of LNM for OSCC patients.

Complete mitochondrial genome of Penicillidia jenynsii (Diptera: Hippoboscoidea: Nycteribiidae) and phylogenetic relationship.

In recent years, bat-associated pathogens, such as 2019 novel coronavirus, have been ravaging the world, and ectoparasites of bats have received increasing attention. Penicillidia jenynsii is a member of the family Nycteribiidae which is a group of specialized ectoparasites of bats. In this study, the complete mitochondrial genome of P. jenynsii was sequenced for the first time and a comprehensive phylogenetic analysis of the superfamily Hippoboscoidea was conducted. The complete mitochondrial genome of P. jenynsii is 16 165 base pairs (bp) in size, including 13 protein-coding genes (PCGs), 22 transfer RNA genes, 2 ribosomal RNA genes and 1 control region. The phylogenetic analysis based on 13 PCGs of the superfamily Hippoboscoidea known from the NCBI supported the monophyly of the family Nycteribiidae, and the family Nycteribiidae was a sister group with the family Streblidae. This study not only provided molecular data for the identification of P. jenynsii, but also provided a reference for the phylogenetic analysis of the superfamily Hippoboscoidea.

Elucidation of the key role of isomerization in the self-assembly and luminescence properties of AIEgens.

Due to the hierarchical nature of the self-assembly process, it is effective to control assembled nanostructures by tuning the spatial configurations of the building blocks through Z-/E-isomerization. A pair of AIE stereoisomers termed (Z)-/(E)-TPE-UPy was reported with different self-assembly mechanisms, morphologies and luminescence properties. In this study, we present a multiscale modeling combining MD simulations, hybrid QM/MM calculations and the PCM model, to systematically clarify the molecular configuration-molecular assembly-photophysical property relationship of (Z)-/(E)-TPE-UPy. Our study shows that (Z)-TPE-UPy follows a concentration-dependent ring-chain polymerization mechanism. At low concentration, (Z)-TPE-UPy tends to form ring-like (Z)-close-dimers with all H-bond sites occupied, while at high concentration, the H-bond backbone in the chain-like structures is more planar and stronger, making the zig-zag chain-like conformations more favorable. For the (E)-isomer, the H-bond backbone is quite planar and rigid, which makes it linearly elongate one-by-one at the whole range of concentrations via the isodesmic polymerization mechanism. (Z)-TPE-UPy oligomers exhibit large flexibility and diverse conformations, leading to sharply enhanced viscosity at high concentration in experiments. Moreover, the fluorescence spectrum of (Z)-/(E)-TPE-UPy aggregate is conformation-dependent and the enhanced emission in the aggregated state is attributed to the restriction of the low-frequency intramolecular rotations of the phenyl rings and the distortion of the CC plane, as well as the reduction of electron-vibration couplings. Our work not only offers valuable insights into the key role of stereoisomerism in assembled morphologies and luminescence properties, but also provides a theoretical basis for the rational design of new building blocks based on stereoisomers.

Theoretical prediction of nanomolar and sequence-selective binding of synthetic supramolecular cucurbit[7]uril to N-terminal Leu-containing tripeptides.

Molecular recognition towards peptides and proteins with high affinity by synthetic supramolecular hosts is important but challenging. In this work, we investigate the molecular recognition of the synthetic cucurbit[7]uril (CB[7]) to 17 designed N-terminal Leu-containing tripeptides in aqueous medium by molecular dynamics (MD) simulation and screen out tripeptides with high binding affinity. It is found that, compared to LGG, only the third residue is Arg (R), the binding affinity of CB[7] to LGR reaches nanomolar level with binding equilibrium constant (Ka) of 1.1 × 109 M-1. The CB[7] recognition to the N-terminal Leu-containing tripeptides is highly sequence dependent; whether changing the sequence order (from LGR to LRG) or increasing the sequence length (from LGR to LGGR), Ka decreases by about three orders of magnitude. Interestingly, substituting N-terminal Leu for its isomer Ile, the binding of CB[7] to tripeptides weakens significantly with Ka decreasing by 3-8 orders of magnitude. Thus CB[7] can effectively distinguish N-terminal Leu-containing tripeptides from N-terminal Ile-containing tripeptides. Importantly, we predict that when R is as C-terminus, regardless of N-terminal residue being of aromatic type or Leu, the binding strength is always close to the nanomolar level. Therefore, R can be introduced to rationally design novel peptides with high binding affinity to CB[7] in practical applications.

Theoretical insights into the AIE mechanism of assembles.

Fluorophores in aggregated state are commonly used in optoelectronic devices, and the molecular packing are complex and diverse, including crystal, amorphous aggregate in solution, thin film, ordered supramolecular assemblies, and highly ordered cell membrane. In addition, the luminous behavior of the aggregated state can be precisely regulated by external stimuli such as hydrostatic pressure. In this review, we summarize the representative progress on the application of multiscale modeling protocol to illustrate the underlying mechanism of fluorescent emission of organic dyes in different assembles. The aim is to obtain the molecular packing in different forms of assembles and then to understand their underlying mechanism of stimuli-responsive fluorescent behavior at the molecular level. This is essential for the rational design, synthesis, and efficient application of fluorescent dyes.