Unraveling sources of emission heterogeneity in Silicon Vacancy color centers with cryo-cathodoluminescence microscopy.

Diamond color centers have proven to be versatile quantum emitters and exquisite sensors of stress, temperature, electric and magnetic fields, and biochemical processes. Among color centers, the silicon-vacancy (SiV[Formula: see text]) defect exhibits high brightness, minimal phonon coupling, narrow optical linewidths, and high degrees of photon indistinguishability. Yet the creation of reliable and scalable SiV[Formula: see text]-based color centers has been hampered by heterogeneous emission, theorized to originate from surface imperfections, crystal lattice strain, defect symmetry, or other lattice impurities. Here, we advance high-resolution cryo-electron microscopy combined with cathodoluminescence spectroscopy and 4D scanning transmission electron microscopy (STEM) to elucidate the structural sources of heterogeneity in SiV[Formula: see text] emission from nanodiamond with sub-nanometer-scale resolution. Our diamond nanoparticles are grown directly on TEM membranes from molecular-level seedings, representing the natural formation conditions of color centers in diamond. We show that individual subcrystallites within a single nanodiamond exhibit distinct zero-phonon line (ZPL) energies and differences in brightness that can vary by 0.1 meV in energy and over 70% in brightness. These changes are correlated with the atomic-scale lattice structure. We find that ZPL blue-shifts result from tensile strain, while ZPL red shifts are due to compressive strain. We also find that distinct crystallites host distinct densities of SiV[Formula: see text] emitters and that grain boundaries impact SiV[Formula: see text] emission significantly. Finally, we interrogate nanodiamonds as small as 40 nm in diameter and show that these diamonds exhibit no spatial change to their ZPL energy. Our work provides a foundation for atomic-scale structure-emission correlation, e.g., of single atomic defects in a range of quantum and two-dimensional materials.

PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6.

Ataxin-2 (Atx2) is a polyglutamine (polyQ) tract-containing RNA-binding protein, while its polyQ expansion may cause protein aggregation that is implicated in the pathogenesis of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2). However, the molecular mechanism underlying how Atx2 aggregation contributes to the proteinopathies remains elusive. Here, we investigated the influence of Atx2 aggregation on the assembly and functionality of cellular processing bodies (P-bodies) by using biochemical and fluorescence imaging approaches. We have revealed that polyQ-expanded (PQE) Atx2 sequesters the DEAD-box RNA helicase (DDX6), an essential component of P-bodies, into aggregates or puncta via some RNA sequences. The N-terminal like-Sm (LSm) domain of Atx2 (residues 82-184) and the C-terminal helicase domain of DDX6 are responsible for the interaction and specific sequestration. Moreover, sequestration of DDX6 may aggravate pre-mRNA mis-splicing, and interfere with the assembly of cellular P-bodies, releasing the endoribonuclease MARF1 that promotes mRNA decay and translational repression. Rescuing the DDX6 protein level can recover the assembly and functionality of P-bodies, preventing targeted mRNA from degradation. This study provides a line of evidence for sequestration of the P-body components and impairment of the P-body homeostasis in dysregulating RNA metabolism, which is implicated in the disease pathologies and a potential therapeutic target.

Stretchable ionic-electronic bilayer hydrogel electronics enable in situ detection of solid-state epidermal biomarkers.

Continuous and in situ detection of biomarkers in biofluids (for example, sweat) can provide critical health data but is limited by biofluid accessibility. Here we report a sensor design that enables in situ detection of solid-state biomarkers ubiquitously present on human skin. We deploy an ionic-electronic bilayer hydrogel to facilitate the sequential dissolution, diffusion and electrochemical reaction of solid-state analytes. We demonstrate continuous monitoring of water-soluble analytes (for example, solid lactate) and water-insoluble analytes (for example, solid cholesterol) with ultralow detection limits of 0.51 and 0.26 nmol cm-2, respectively. Additionally, the bilayer hydrogel electrochemical interface reduces motion artefacts by a factor of three compared with conventional liquid-sensing electrochemical interfaces. In a clinical study, solid-state epidermal biomarkers measured by our stretchable wearable sensors showed a high correlation with biomarkers in human blood and dynamically correlated with physiological activities. These results present routes to universal platforms for biomarker monitoring without the need for biofluid acquisition.

Serine/threonine-protein kinase D2-mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression.

Desmoglein-2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell-cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine-protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2-T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2-mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

miTDS: Uncovering miRNA-mRNA interactions with deep learning for functional target prediction.

MicroRNAs (miRNAs) are vital in regulating gene expression through binding to specific target sites on messenger RNAs (mRNAs), a process closely tied to cancer pathogenesis. Identifying miRNA functional targets is essential but challenging, due to incomplete genome annotation and an emphasis on known miRNA-mRNA interactions, restricting predictions of unknown ones. To address those challenges, we have developed a deep learning model based on miRNA functional target identification, named miTDS, to investigate miRNA-mRNA interactions. miTDS first employs a scoring mechanism to eliminate unstable sequence pairs and then utilizes a dynamic word embedding model based on the transformer architecture, enabling a comprehensive analysis of miRNA-mRNA interaction sites by harnessing the global contextual associations of each nucleotide. On this basis, miTDS fuses extended seed alignment representations learned in the multi-scale attention mechanism module with dynamic semantic representations extracted in the RNA-based dual-path module, which can further elucidate and predict miRNA and mRNA functions and interactions. To validate the effectiveness of miTDS, we conducted a thorough comparison with state-of-the-art miRNA-mRNA functional target prediction methods. The evaluation, performed on a dataset cross-referenced with entries from MirTarbase and Diana-TarBase, revealed that miTDS surpasses current methods in accurately predicting functional targets. In addition, our model exhibited proficiency in identifying A-to-I RNA editing sites, which represents an aberrant interaction that yields valuable insights into the suppression of cancerous processes.

The crotonylated and succinylated proteins of jujube involved in phytoplasma-stress responses.

BACKGROUND: Protein posttranslational modifications (PTMs) are fast and early responses to environmental changes, including pathogen infection. Jujube witches' broom (JWB) is a phytoplasma disease causing great economic loss in jujube production. After phytoplasma infection, the transcriptional, translational, and metabolic levels in jujube were activated, enabling it to survive during phytoplasma invasion. However, no study has yet reported on PTMs in jujube. Lysine crotonylation (Kcr) and lysine succinylation (Ksu) have been popular studies in recent years and their function in plant phytoplasma-stress responses remains unclear. RESULTS: Here, 1656 crotonylated and 282 succinylated jujube proteins were first identified under phytoplasma-stress, of which 198 were simultaneously crotonylated and succinylated. Comparative analysis revealed that 656 proteins, 137 crotonylated and 43 succinylated proteins in jujube were regulated by phytoplasma infection, suggesting that Kcr was more universal than Ksu. Kcr differentially expressed proteins (DEPs) were related to ribosomes, photosynthetic and carbon metabolism, while Ksu DEPs were mainly involved in carbon metabolism, the TCA cycle and secondary metabolite biosynthesis. The crosstalk network among proteome, crotonylome and succinylome showed that DEPs related to ribosomal, peroxidases and glutathione redox were enriched. Among them, ZjPOD51 and ZjPHGPX2 significantly increased at the protein and Kcr level under phytoplasma-stress. Notably, 7 Kcr sites were identified in ZjPHGPX2, a unique antioxidant enzyme. After inhibitor nicotinamide (NAM) treatment, GPX enzyme activity in jujube seedlings was reduced. Further, site-directed mutagenesis of key Kcr modification sites K130 and/or K135 in ZjPHGPX2 significantly reduced its activity. CONCLUSIONS: This study firstly provided large-scale datasets of Kcr and Ksu in phytoplasma-infected jujube and revealed that Kcr modification in ZjPHGPX2 positively regulates its activity.

Design of a Thermally Stable Heat-Resistant (Al2O3+Al3Ti)/Al Composite with Excellent High-Temperature Mechanical Properties: Multimechanism Synergistic Strengthening Strategy.

The effectiveness of the room-temperature strengthening strategy for aluminum (Al) is compromised at increased temperatures due to grain and precipitate phase coarsening. Overcoming the heightened activity of grain boundaries and dislocations poses a significant challenge in enhancing the high-temperature strength through traditional precipitation strengthening. This study presents novel strengthening strategies that integrate intergranular reinforcements, intragranular reinforcements, refined grain, and stacking faults within an (Al2O3+Al3Ti)/Al composite prepared using sol-gel and powder metallurgy technology. Excellent high-temperature tensile properties are achieved; also, a remarkable fatigue performance at increased temperatures that surpasses those of other existing Al alloys and composites is revealed. These superior characteristics can be attributed to its exceptionally stable microstructure and the synergistic strengthening mechanisms mentioned above. This work offers new insights into designing and fabricating thermally stable Al matrix composites for high-temperature applications.

Quantitative susceptibility mapping through model-based deep image prior (MoDIP).

The data-driven approach of supervised learning methods has limited applicability in solving dipole inversion in Quantitative Susceptibility Mapping (QSM) with varying scan parameters across different objects. To address this generalization issue in supervised QSM methods, we propose a novel training-free model-based unsupervised method called MoDIP (Model-based Deep Image Prior). MoDIP comprises a small, untrained network and a Data Fidelity Optimization (DFO) module. The network converges to an interim state, acting as an implicit prior for image regularization, while the optimization process enforces the physical model of QSM dipole inversion. Experimental results demonstrate MoDIP's excellent generalizability in solving QSM dipole inversion across different scan parameters. It exhibits robustness against pathological brain QSM, achieving over 32 % accuracy improvement than supervised deep learning methods. It is also 33 % more computationally efficient and runs 4 times faster than conventional DIP-based approaches, enabling 3D high-resolution image reconstruction in under 4.5 min.

Risk-based lung cancer screening in heavy smokers: a benefit-harm and cost-effectiveness modeling study.

BACKGROUND: Annual screening through low-dose computed tomography (LDCT) is recommended for heavy smokers. However, it is questionable whether all individuals require annual screening given the potential harms of LDCT screening. This study examines the benefit-harm and cost-effectiveness of risk-based screening in heavy smokers and determines the optimal risk threshold for screening and risk-stratified screening intervals. METHODS: We conducted a comparative cost-effectiveness analysis in China, using a cohort-based Markov model which simulated a lung cancer screening cohort of 19,146 heavy smokers aged 50 ~ 74 years old, who had a smoking history of at least 30 pack-years and were either current smokers or had quit for < 15 years. A total of 34 risk-based screening strategies, varying by different risk groups for screening eligibility and screening intervals (1-year, 2-year, 3-year, one-off, non-screening), were evaluated and were compared with annual screening for all heavy smokers (the status quo strategy). The analysis was undertaken from the health service perspective with a 30-year time horizon. The willingness-to-pay (WTP) threshold was adopted as three times the gross domestic product (GDP) of China in 2021 (CNY 242,928) per quality-adjusted life year (QALY) gained. RESULTS: Compared with the status quo strategy, nine risk-based screening strategies were found to be cost-effective, with two of them even resulting in cost-saving. The most cost-effective strategy was the risk-based approach of annual screening for individuals with a 5-year risk threshold of ≥ 1.70%, biennial screening for individuals with a 5-year risk threshold of 1.03 ~ 1.69%, and triennial screening for individuals with a 5-year risk threshold of < 1.03%. This strategy had the highest incremental net monetary benefit (iNMB) of CNY 1032. All risk-based screening strategies were more efficient than the status quo strategy, requiring 129 ~ 656 fewer screenings per lung cancer death avoided, and 0.5 ~ 28 fewer screenings per life-year gained. The cost-effectiveness of risk-based screening was further improved when individual adherence to screening improved and individuals quit smoking after being screened. CONCLUSIONS: Risk-based screening strategies are more efficient in reducing lung cancer deaths and gaining life years compared to the status quo strategy. Risk-stratified screening intervals can potentially balance long-term benefit-harm trade-offs and improve the cost-effectiveness of lung cancer screenings.

All Roads Lead to Rome: Comparing Nanoparticle- and Small Molecule-Driven Cell Autophagy.

Autophagy, vital for removing cellular waste, is triggered differently by small molecules and nanoparticles. Small molecules, like rapamycin, non-selectively activate autophagy by inhibiting the mTOR pathway, which is essential for cell regulation. This can clear damaged components but may cause cytotoxicity with prolonged use. Nanoparticles, however, induce autophagy, often causing oxidative stress, through broader cellular interactions and can lead to a targeted form known as "xenophagy." Their impact varies with their properties but can be harnessed therapeutically. In this review, the autophagy induced by nanoparticles is explored and small molecules across four dimensions: the mechanisms behind autophagy induction, the outcomes of such induction, the toxicological effects on cellular autophagy, and the therapeutic potential of employing autophagy triggered by nanoparticles or small molecules. Although small molecules and nanoparticles each induce autophagy through different pathways and lead to diverse effects, both represent invaluable tools in cell biology, nanomedicine, and drug discovery, offering unique insights and therapeutic opportunities.

Evaluation of an E6/E7 PCR-capillary electrophoresis fragment analysis in the genotyping of human papillomavirus in archival FFPE samples of oropharyngeal cancer.

Accumulating evidence has demonstrated that high-risk human papillomaviruses (HR-HPVs) are involved in the etiology of a subset of oropharyngeal squamous cell carcinoma (OPSCC). In this regard, the International Agency for Research on Cancer (IARC) has recommended direct molecular HPV testing. So far, there is no agreement on the most appropriate method for HPV detection on OPSCC formalin-fixed paraffin-embedded (FFPE) materials. In this study, we aimed to evaluate the performance of the high-sensitive SureX HPV assay in OPSCC FFPE tissues compared with LiPA-25 and p16ink4a immunostaining. A retrospective series of FFPE primary OPSCC cases were diagnosed between 2008 and 2019 and provided by the Henan Cancer Hospital, China. The level of agreement of two assays was determined using Cohen's Kappa (κ) statistics. A total of 230 FFPE OPSCC samples from tumor resections (n = 160) and diagnostic biopsies (n = 70) were detected. Sixty-six (28.7%) and 70 (30.4%) samples were identified as HPV-DNA-positive by LiPA-25 and SureX, respectively, of which HPV16 was largely the most common type (95.5% vs 94.3%). We found a perfect concordance between LiPA-25 and SureX for HPV-DNA status (κ = 0.906, 95% CI: 0.875-0.937) and for HPV16 (κ = 0.925, 95% CI: 0.897-0.953). In addition, SureX and p16ink4a immunostaining had a perfect concordance (κ = 0.917, 95% CI: 0.888-0.946). Moreover, the HPV-driven fraction, based on double positivity for HPV-DNA and p16ink4a, was similar between SureX (63 of 230, 27.4%) and LiPA-25 (60 of 230, 26.1%). Similar results were found in samples from resections and biopsies. SureX and LiPA-25 are comparable. SureX could be used for routine HPV-DNA detection and genotyping on archival OPSCC FFPE tissues.

Investigation of unidirectional coupling of dipole emitters in valley photonic heterostructure waveguides.

Photonic heterostructure has recently become a promising platform to study topological photonics with the introduction of mode width degree of freedom (DOF). However, there is still a lack of comprehensive analysis on the coupling of dipole emitters in photonic heterostructures, which constrains the development of on-chip quantum optics based on chiral dipole sources. We systematically analyze the unidirectional coupling mechanism between dipole emitters and valley photonic heterostructure waveguides (VPHWs). With the eigenmode calculations and full-wave simulations, the Stokes parameters are obtained to compare the coupling performance of two types of valley-interface VPHWs. Simulation results show that compared to the zigzag interface with inversion symmetry, the strategy of bearded interface with glide symmetry is easier to realize high-efficiency coupling. By adjusting the position and chirality of dipole emitters in VPHWs, the transmission of light reverses with guided modes coupled to different directions. Furthermore, a topological beam modulator is realized based on VPHWs, which maintains the robustness to large-area potential barriers and sharp corners. Our work supplies a powerful guide for chiral light-matter interaction, which is expected to be applied to increasingly compact and efficient on-chip optical platforms in the future.

Treatment for locally resectable stage IIIC1r cervical cancer: surgery or chemoradiotherapy?

OBJECTIVE: The aim of this study was to compare the therapeutic value and treatment-related complications of radical hysterectomy with those of concurrent chemoradiotherapy (CCRT) for locally resectable (T1a2-T2a1) stage IIIC1r cervical cancer. METHODS: A total of 213 patients with locally resectable stage IIIC1r cervical cancer who had been treated at Jiangxi Maternal and Child Health Care Hospital between January 2013 and December 2021 were included in the study and classified into two groups: surgery (148 patients) and CCRT (65 patients). The disease-free survival (DFS) rate, overall survival (OS) rate, side effects, and economic costs associated with the two groups were compared. RESULTS: 43.9% (65/148) patients in the surgical group had no pelvic lymph node metastasis, and 21of them did not require supplementary treatment after surgery due to a low risk of postoperative pathology. The median follow-up time was 46 months (range: 7-108 months). The five-year DFS and OS rates of the surgery group were slightly higher than those of the CCRT group (80.7% vs. 75.1% and 81.6% vs. 80.6%, respectively; p > 0.05). The incidences of grade III-IV gastrointestinal reactions in the surgery and CCRT groups were 5.5% and 9.2%, respectively (p = 0.332). Grade III-IV myelosuppression was identified in 27.6% of the surgery group and 26.2% of the CCRT group (p = 0.836). The per capita treatment cost was higher for the surgery group than for the CCRT group (RMB 123, 918.6 0 vs. RMB 101, 880.90, p = 0.001). CONCLUSION: The therapeutic effects and treatment-related complications of hysterectomy and CCRT are equivalent in patients with locally resectable stage IIIC1r cervical cancer, but surgery can provide accurate lymph node information and benefit patients with unnecessary radiation.

Comparative characteristics of early-onset vs. late-onset advanced colorectal cancer: a nationwide study in China.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC, diagnosed in patients under the age of 50 years) has been increasing around the world. Here, we aimed to systematically identify distinctive features of EOCRC. METHODS: From 2020 to 2021, we conducted a nationwide survey in 19 hospitals, collecting data on advanced CRC patients' demographics, clinical features, disease knowledge, medical experiences, expenditures, and health-related quality of life (HRQOL). We compared these features between EOCRC and late-onset colorectal cancer (LOCRC, ≥ 50 years old) groups and analyzed the association between EOCRC and HRQOL using multivariate linear regression. FINDINGS: In total, 991 patients with EOCRC and 3581 patients with LOCRC were included. Compared to the LOCRC group, the EOCRC group had higher levels of education, were more informed about the risk factors for CRC, were more likely to have widespread metastases throughout the body, were more inclined to undergo gene testing, and were more likely to opt for targeted therapy, radiotherapy, and chemotherapy. However, HRQOL in the EOCRC group was similar to that of the LOCRC group, and no significant association was observed between EOCRC and HRQOL (beta: -0.753, P value: 0.307). INTERPRETATION: In Chinese patients, EOCRC patients had more aggressive features. Despite undergoing more intensified treatments and gene testing, they had similar HRQOL compared with LOCRC. These findings advocate for a more tailored approach to treatment, especially for young CRC patients with advanced TNM stages and metastasis.

Predicting the multivariate zero-inflated counts: A novel model averaging method under Pearson loss.

Excessive zeros in multivariate count data are often observed in scenarios of biomedicine and public health. To provide a better analysis on this type of data, we first develop a marginalized multivariate zero-inflated Poisson (MZIP) regression model to directly interpret the overall exposure effects on marginal means. Then, we define a multiple Pearson residual for our newly developed MZIP regression model by simultaneously taking heterogeneity and correlation into consideration. Furthermore, a new model averaging prediction method is introduced based on the multiple Pearson residual, and the asymptotical optimality of this model averaging prediction is proved. Simulations and two empirical applications in medicine are used to illustrate the effectiveness of the proposed method.

Pd(II)/N,N'-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Synthesis of Cyclic Quaternary Centers and Mechanistic Investigations.

A Pd(II)/N,N'-disulfonyl bisimidazoline-catalyzed asymmetric 1,4-conjugate addition reaction of low-cost arylboronic acids with readily available ß-substituted cyclic enones is described, providing a straightforward way of constructing cyclic all-carbon quaternary stereocenters with high enantioselectivity, in which ≥96% ee was obtained in most cases. The reaction proceeded without the protection of inert gas, making the operation process simple. Theoretical calculations have been applied to understand the origins of enantioselectivity.

Visible Light-Induced Regioselective Intermolecular [2 + 2]-Cycloaddition of Alkyne and 2(1H)-Quinolone Derivatives.

We have developed a visible light-induced intermolecular [2 + 2]-cycloaddition reaction between alkenes and alkynes using thioxanthone and Cu(OTf)2 as cocatalysts. Various quinolin-2(1H)-ones, featuring diverse substituted groups, were successfully employed in this reaction, resulting in the synthesis of a series of 4,8b-dihydrocyclobuta[c]quinolin-3(2aH)-ones. Our methodology presents a novel synthetic approach for alkene-alkyne [2 + 2]-cycloaddition, delivering cyclobutene derivatives with exceptional regioselectivity.

Lithium Pollution and Its Associated Health Risks in the Largest Lithium Extraction Industrial Area in China.

Lithium (Li) is an important resource that drives sustainable mobility and renewable energy. Its demand is projected to continue to increase in the coming decades. However, the risk of Li pollution has also emerged as a global concern. Here, we investigated the pollution characteristics, sources, exposure levels, and associated health risks of Li in the Jinjiang River basin, the largest area for Li2CO3 production in China. Our results revealed the dominant role of Li extraction activities in the pollution of the river, with over 95% of dissolved Li in downstream river water being emitted from this source. Moreover, the Li concentration in aquatic plants (i.e., water hyacinth) and animals (i.e., fish) significantly increased from upstream to downstream areas, indicating a significant risk to local aquatic ecosystems. More importantly, our study found that local residents were suffering potential chronic noncarcinogenic health risks primarily from consuming contaminated water and vegetables. We also investigated the pollution characteristics of associated elements present in Li ores (e.g., Rb, Cs, Ni, and F-). By uncovering the remarkable impact of Li extraction activities on the Li content in ecosystems for the first time, our study emphasizes the importance of evaluating Li pollution from Li-related industrial activities, including mining, extraction, and recovery.

Molecular Engineering Strategies of Spectral Matching and Structure Optimization for Efficient Metal-Free Organic Dyes in Dye-Sensitized Solar Cells: A Theoretical Study.

Metal-free organic dyes are promising dyes that can be applied widely in dye-sensitized solar cells (DSSCs). The rational design and selection of dyes with complementary absorption can promote the development of methods that can enhance the utilization of incident light by DSSCs, such as cosensitization and tandem devices. Based on these opinions, the structure of the reported high-performance metal-free organic dye ZL003 is used as a template to design two new metal-free organic dyes, HX-1 and HX-2, by replacing its donor unit with a 2-phenothiazine-phenylamine unit and fusing its three independent π-bridge units into a whole with the aim of driving the red shift and the blue shift of the absorption spectra of ZL003, respectively. Through theoretical investigation, it is demonstrated that the perfect complementary optical absorption of HX-1 and HX-2 can be realized as the shift of the absorption spectra of ZL003 to different directions, which means their feasibility to the application in cosensitization or tandem dye-sensitized solar cells (T-DSSCs). Furthermore, it is hypothesized that HX-1 may be the dye with better photovoltaic performance than ZL003 by modeling their intramolecular charge-transfer (ICT) processes, TiO2 surface adsorption, and photovoltaic parameters. The short-circuit current density (Jsc) and photoelectric conversion efficiency (PCE) of HX-1 are 23.10 mA·cm-2 and 21.26% in theory, compared to those of 20.68 mA·cm-2 and 19.64% in ZL003 at the same computational level, respectively. In view of the complementary optical properties, the combination of HX-1 with HX-2 may be a reasonable option for dyes for the development of a highly efficient cosensitization system or T-DSSCs in the future. In terms of such findings, these two novel metal-free organic dyes may have bright prospects in the research of highly efficient DSSCs, and this work can provide a reference for the design of dyes with complementary absorption through simple structural adjustments of the realistic dyes with high photovoltaic performance.

Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation.

Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.