Structural insights into the transcription activation mechanism of the global regulator GlnR from actinobacteria.

In actinobacteria, an OmpR/PhoB subfamily protein called GlnR acts as an orphan response regulator and globally coordinates the expression of genes responsible for nitrogen, carbon, and phosphate metabolism in actinobacteria. Although many researchers have attempted to elucidate the mechanisms of GlnR-dependent transcription activation, progress is impeded by lacking of an overall structure of GlnR-dependent transcription activation complex (GlnR-TAC). Here, we report a co-crystal structure of the C-terminal DNA-binding domain of GlnR (GlnR_DBD) in complex with its regulatory cis-element DNA and a cryo-EM structure of GlnR-TAC which comprises Mycobacterium tuberculosis RNA polymerase, GlnR, and a promoter containing four well-characterized conserved GlnR binding sites. These structures illustrate how four GlnR protomers coordinate to engage promoter DNA in a head-to-tail manner, with four N-terminal receiver domains of GlnR (GlnR-RECs) bridging GlnR_DBDs and the RNAP core enzyme. Structural analysis also unravels that GlnR-TAC is stabilized by complex protein-protein interactions between GlnR and the conserved ß flap, σAR4, αCTD, and αNTD domains of RNAP, which are further confirmed by our biochemical assays. Taken together, these results reveal a global transcription activation mechanism for the master regulator GlnR and other OmpR/PhoB subfamily proteins and present a unique mode of bacterial transcription regulation.

Genetic adaptation of skin pigmentation in highland Tibetans.

Strong ultraviolet (UV) radiation at high altitude imposes a serious selective pressure, which may induce skin pigmentation adaptation of indigenous populations. We conducted skin pigmentation phenotyping and genome-wide analysis of Tibetans in order to understand the underlying mechanism of adaptation to UV radiation. We observe that Tibetans have darker baseline skin color compared with lowland Han Chinese, as well as an improved tanning ability, suggesting a two-level adaptation to boost their melanin production. A genome-wide search for the responsible genes identifies GNPAT showing strong signals of positive selection in Tibetans. An enhancer mutation (rs75356281) located in GNPAT intron 2 is enriched in Tibetans (58%) but rare in other world populations (0 to 18%). The adaptive allele of rs75356281 is associated with darker skin in Tibetans and, under UVB treatment, it displays higher enhancer activities compared with the wild-type allele in in vitro luciferase assays. Transcriptome analyses of gene-edited cells clearly show that with UVB treatment, the adaptive variant of GNPAT promotes melanin synthesis, likely through the interactions of CAT and ACAA1 in peroxisomes with other pigmentation genes, and they act synergistically, leading to an improved tanning ability in Tibetans for UV protection.

Bioinspired Surface Ligand Engineering Regulates Electron Transfers in Gold Clusterzymes to Enhance the Catalytic Activity for Improving Sensing Performance.

Metal nanoclusters feature a hierarchical structure, facilitating their ability to mimic enzyme-catalyzed reactions. However, the lack of true catalytic centers, compounded by tightly bound surface ligands hindering electron transfers to substrates, underscores the need for universal rational design methodologies to emulate the structure and mechanisms of natural enzymes. Motivated by the electron transfer in active centers with specific chemical structures, by integrating the peroxidase cofactor Fe-TCPP onto the surface of glutathione-stabilized gold nanoclusters (AuSG), we engineered AuSG-Fe-TCPP clusterzymes with a remarkable 39.6-fold enhancement in peroxidase-like activity compared to AuSG. Fe-TCPP not only mimics the active center structure, enhancing affinity to H2O2, but also facilitates the electron transfer process, enabling efficient H2O2 activation. By exemplifying the establishment of a detecting platform for trace H2O2 produced by ultrasonic cleaners, we substantiate that the bioinspired surface-ligand-engineered electron transfer can improve sensing performance with a wider linear range and lower detection limit.

Rational Design of Tetrahedral Derivatives as Efficient Light-Emitting Materials Based on "Super Atom" Perspective.

Traditional semiconductor quantum dots of groups II-VI are key ingredients of next-generation display technology. Yet, the majority of them contain toxic heavy-metal elements, thus calling for alternative light-emitting materials. Herein, we have explored three novel categories of multicomponent compounds, namely, tetragonal II-III2-VI4 porous ternary compounds, cubic I2-II3-VI4 ternary compounds, and cubic I-II-III3-V4 quaternary compounds. This is achieved by judicious introduction of a "super atom" perspective and concurrently varying the solid-state lattice packing of involved super atoms or the population of surrounding counter cations. Based on first-principles calculations of 392 candidate materials with designed crystal structures, 53 highly stable materials have been screened. Strikingly, 34 of them are direct-bandgap semiconductors with emitting wavelengths covering the near-infrared and visible-light regions. This work provides a comprehensive database of highly efficient light-emitting materials, which may be of interest for a broad field of optoelectronic applications.

Structural basis of transcription activation by Rob, a pleiotropic AraC/XylS family regulator.

Rob, which serves as a paradigm of the large AraC/XylS family transcription activators, regulates diverse subsets of genes involved in multidrug resistance and stress response. However, the underlying mechanism of how it engages bacterial RNA polymerase and promoter DNA to finely respond to environmental stimuli is still elusive. Here, we present two cryo-EM structures of Rob-dependent transcription activation complex (Rob-TAC) comprising of Escherichia coli RNA polymerase (RNAP), Rob-regulated promoter and Rob in alternative conformations. The structures show that a single Rob engages RNAP by interacting with RNAP αCTD and σ70R4, revealing their generally important regulatory roles. Notably, by occluding σ70R4 from binding to -35 element, Rob specifically binds to the conserved Rob binding box through its consensus HTH motifs, and retains DNA bending by aid of the accessory acidic loop. More strikingly, our ligand docking and biochemical analysis demonstrate that the large Rob C-terminal domain (Rob CTD) shares great structural similarity with the global Gyrl-like domains in effector binding and allosteric regulation, and coordinately promotes formation of competent Rob-TAC. Altogether, our structural and biochemical data highlight the detailed molecular mechanism of Rob-dependent transcription activation, and provide favorable evidences for understanding the physiological roles of the other AraC/XylS-family transcription factors.

Structural basis of three different transcription activation strategies adopted by a single regulator SoxS.

Transcription activation is established through extensive protein-protein and protein-DNA interactions that allow an activator to engage and remodel RNA polymerase. SoxS, a global transcription activator, diversely regulates subsets of stress response genes with different promoters, but the detailed SoxS-dependent transcription initiation mechanisms remain obscure. Here, we report cryo-EM structures of three SoxS-dependent transcription activation complexes (SoxS-TACI, SoxS-TACII and SoxS-TACIII) comprising of Escherichia coli RNA polymerase (RNAP), SoxS protein and three representative classes of SoxS-regulated promoters. The structures reveal that SoxS monomer orchestrates transcription initiation through specific interactions with the promoter DNA and different conserved domains of RNAP. In particular, SoxS is positioned in the opposite orientation in SoxS-TACIII to that in SoxS-TACI and SoxS-TACII, unveiling a novel mode of transcription activation. Strikingly, two universally conserved C-terminal domains of alpha subunit (αCTD) of RNAP associate with each other, bridging SoxS and region 4 of σ70. We show that SoxS interacts with RNAP directly and independently from DNA, remodeling the enzyme to activate transcription from cognate SoxS promoters while repressing transcription from UP-element containing promoters. Our data provide a comprehensive summary of SoxS-dependent promoter architectures and offer new insights into the αCTD contribution to transcription control in bacteria.

Deep-Learning-Enhanced Diffusion Imaging Assay for Resolving Local-Density Effects on Membrane Receptors.

G-protein-coupled receptor (GPCR) density at the cell surface is thought to regulate receptor function. Spatially resolved measurements of local-density effects on GPCRs are needed but technically limited by density heterogeneity and mobility of membrane receptors. We now develop a deep-learning (DL)-enhanced diffusion imaging assay that can measure local-density effects on ligand-receptor interactions in the plasma membrane of live cells. In this method, the DL algorithm allows the transformation of 100 ms exposure images to density maps that report receptor numbers over any specified region with ∼95% accuracy by 1 s exposure images as ground truth. With the density maps, a diffusion assay is further established for spatially resolved measurements of receptor diffusion coefficient as well as to express relationships between receptor diffusivity and local density. By this assay, we scrutinize local-density effects on chemokine receptor CXCR4 interactions with various ligands, which reveals that an agonist prefers to act with CXCR4 at low density while an inverse agonist dominates at high density. This work suggests a new insight into density-dependent receptor regulation as well as provides an unprecedented assay that can be applicable to a wide variety of receptors in live cells.

Inhibiting Osteolytic Breast Cancer Bone Metastasis by Bone-Targeted Nanoagent via Remodeling the Bone Tumor Microenvironment Combined with NIR-II Photothermal Therapy.

Bone is one of the prone metastatic sites of patients with advanced breast cancer. The "vicious cycle" between osteoclasts and breast cancer cells plays an essential role in osteolytic bone metastasis from breast cancer. In order to inhibit bone metastasis from breast cancer, NIR-II photoresponsive bone-targeting nanosystems (CuP@PPy-ZOL NPs) are designed and synthesized. CuP@PPy-ZOL NPs can trigger the photothermal-enhanced Fenton response and photodynamic effect to enhance the photothermal treatment (PTT) effect and thus achieve synergistic anti-tumor effect. Meanwhile, they exhibit a photothermal enhanced ability to inhibit osteoclast differentiation and promote osteoblast differentiation, which reshaped the bone microenvironment. CuP@PPy-ZOL NPs effectively inhibited the proliferation of tumor cells and bone resorption in the in vitro 3D bone metastases model of breast cancer. In a mouse model of breast cancer bone metastasis, CuP@PPy-ZOL NPs combined with PTT with NIR-II significantly inhibited the tumor growth of breast cancer bone metastases and osteolysis while promoting bone repair to achieve the reversal of osteolytic breast cancer bone metastases. Furthermore, the potential biological mechanisms of synergistic treatment are identified by conditioned culture experiments and mRNA transcriptome analysis. The design of this nanosystem provides a promising strategy for treating osteolytic bone metastases.

The charge effects on the hydrogen evolution reaction activity of the defected monolayer MoS2.

Doping engineering has proven to be an effective way to tune the hydrogen evolution reaction (HER) activity of MoS2. Introducing these defects could cause the overall charge imbalance of MoS2, which makes MoS2 charged. In order to understand the effect of charge on the HER activity of the defected MoS2, we systematically investigate the formation energies, hydrogen adsorption Gibbs free energy (), and electronic structures of 3d, 4d, and 5d transition metal (TM) doped monolayer MoS2 with S vacancies (Svac) based on the density functional theory (DFT) calculations. According to the formation energy calculation, Svac in the 0 and -1 charge states (S0vac and Svac1-) is found to be stable. of Svac1- is -0.16 eV, suggesting its HER catalytic activity is lower than that of Pt (), which is consistent with the experimental results. By substituting the Mo atom with TM atoms, we found that the TM atoms in groups VB-VIIB can promote the generation of Svac, forming defect complexes (TMMoSvac). is greatly affected by the charge state of defects; TMMoSvac defects (TM = V, Nb, Ta, Cr, W, Mn, and Re) in -1 charge states exhibited excellent HER activity (). Significantly, W and Re doping can promote the HER activity of MoS2 independent of the charge state and the Fermi level, which suggests that W and Re doping are most beneficial to improve the HER activity of MoS2. Therefore, the HER activity of defected MoS2 is not only influenced by as previously thought, but also by formation energies, charge state and Fermi level position of defects. The underlying physics could be deduced from the charge-induced changes in electronic structures. Our work highlights the defect charge effects on the electrochemical reactions and offers plausible mechanisms of defect charge effects.

Carbon Dot Blinking Fingerprint Uncovers Native Membrane Receptor Organizations via Deep Learning.

Oligomeric organization of G protein-coupled receptors is proposed to regulate receptor signaling and function, yet rapid and precise identification of the oligomeric status especially for native receptors on a cell membrane remains an outstanding challenge. By using blinking carbon dots (CDs), we now develop a deep learning (DL)-based blinking fingerprint recognition method, named deep-blinking fingerprint recognition (BFR), which allows automatic classification of CD-labeled receptor organizations on a cell membrane. This DL model integrates convolutional layers, long-short-term memory, and fully connected layers to extract time-dependent blinking features of CDs and is trained to a high accuracy (∼95%) for identifying receptor organizations. Using deep blinking fingerprint recognition, we found that CXCR4 mainly exists as 87.3% monomers, 12.4% dimers, and <1% higher-order oligomers on a HeLa cell membrane. We further demonstrate that the heterogeneous organizations can be regulated by various stimuli at different degrees. The receptor-binding ligands, agonist SDF-1α and antagonist AMD3100, can induce the dimerization of CXCR4 to 33.1 and 20.3%, respectively. In addition, cytochalasin D, which inhibits actin polymerization, similarly prompts significant dimerization of CXCR4 to 30.9%. The multi-pathway organization regulation will provide an insight for understanding the oligomerization mechanism of CXCR4 as well as for elucidating their physiological functions.

Nanoscopic Imaging of Nucleolar Stress Enabled by Protein-Mimicking Carbon Dots.

The nucleolus is a central hub for coordinating cellular stress responses during cancer development and treatment. Accurate identification of nucleolar stress response is crucially desired for nucleolus-based diagnostics and therapeutics but technically challenging due to the need to address the ultrastructural analysis. Here, we report a protein-like CD with the integration of fluorescent blinking domains and RNA-binding motifs, which offers the ability to perform enhanced super-resolution imaging of the nucleolar ultrastructure. This image allows extraction of multidimensional information from the nucleolus for accurate distinguishment of different cells from the same cell types. Furthermore, we demonstrate for the first time this CD-depicted nucleolar ultrastructure as a sensitive hallmark to identify and discriminate subtle responses to various stressors as well as to afford RNA-related information that has been inaccessible by conventional immunofluorescence methods. This protein-mimicking CD could become a broadly useful probe for nucleolar stress studies in cell diagnostics and therapeutics.

[Regularity of prescriptions for intermediate and advanced lung cancer based on latent structure combined with association rules].

The present study explored the regularity of prescriptions for the treatment of intermediate and advanced lung cancer to provide references for clinical medication. CNKI, Wanfang, VIP, and CBM were searched for the research papers on the treatment of lung cancer by Chinese medicine published from database inception to May 31, 2021. The relevant information of qualified papers was extracted to establish a database. The Chinese medicines with frequency >3% underwent analysis of the latent structure and association rules by Lantern 5.0 and SPSS Molder 14.1, respectively, and the prescription regularity in the treatment of intermediate and advanced lung cancer was analyzed based on the frequency description. A total of 713 papers were included, involving 327 Chinese medicines with a cumulative frequency of 12 794 and 106 prescriptions with a cumulative frequency of 824. The commonly used Chinese medicines were dominated by deficiency-tonifying, heat-clearing, phlegm-resolving, and cough/dyspnea-relieving drugs, such as Astragali Radix, Atractylodis Macrocephalae Rhizoma, Glycyrrhizae Radix et Rhizoma, Ophiopogonis Radix, Poria, and Hedyotis Diffusa, which are cold, warm, and plain in nature and sweet, bitter, and pungent in flavor, and mainly act on lung, spleen, and stomach meridians. Commonly used prescriptions included Shashen Maidong Decoction, Liujunzi Decoction, and Baihe Gujin Decoction. The latent structure analysis revealed 32 latent variables and 65 hidden classes. Six comprehensive clustering models and 11 core prescriptions were obtained by professional knowledge inference. The common syndromes of intermediate and advanced lung cancer were inferred to be Qi and Yin deficiency in the lung, Qi deficiency in the lung and spleen, Yin deficiency in the liver and kidney, combined phlegm and stasis, phlegm-heat obstructing lung, and Qi stagnation and blood stasis. Forty-four strong associations were screened out by association rules analysis, including four pairwise strong associations(Polygonati Odorati Rhizoma→Ophiopogonis Radix, Polygonati Odorati Rhizoma→Glehniae Radix, Amomi Fructus→Atractylodis Macrocephalae Rhizoma, and Polygonati Rhizoma→Astragali Radix) and 40 triplet strong associations(such as Trichosanthis Radix+Glehniae Radix→Ophiopogonis Radix, Polygonati Odorati Rhizoma+Glehniae Radix→Ophiopogonis Radix, Trichosanthis Radix+Ophiopogonis Radix→Glehniae Radix, and Scutellariae Barbatae Herba+Codonopsis Radix→Hedyotis Diffusa). In the treatment of intermediate and advanced lung cancer, Qi-replenishing and Yin-nourishing drugs are mainly employed, assisted with cancer-resisting, toxin-removing, spleen-invigorating, phlegm/stasis-resolving, and blood-activating drugs based on syndrome differentiation. The roots were treated following the principles of tonifying lungs and replenishing the spleen, and symptoms following the principles of removing the toxin, dispelling stasis, and resolving phlegm.

Deep-Learning-Assisted Single-Molecule Tracking on a Live Cell Membrane.

Single-molecule fluorescence imaging is a powerful tool to study protein function by tracking molecular position and distribution, but the precise and rapid identification of dynamic molecules remains challenging due to the heterogeneous distribution and interaction of proteins on the live cell membrane. We now develop a deep-learning (DL)-assisted single-molecule imaging method that can precisely distinguish the monomer and complex for rapid and real-time tracking of protein interaction. This DL-based model, which comprises convolutional layers, max pooling layers, and fully connected layers, is trained to reach an accuracy of >98% for identifying monomer and complex. We use this method to investigate the dynamic process of chemokine receptor CXCR4 on the live cell membrane during the early signaling stage. The results show that, upon ligand activation, the CXCR4 undergoes a dynamic process of forming a receptor complex. We further demonstrate that the CXCR4 complex tends to be internalized at 2.5-fold higher rate into the cell interior than the monomer via the clathrin-dependent pathway. This study is the first example to scrutinize the early signaling process of CXCR4 at the single-molecule level on the live cell membrane. We envision that this DL-assisted imaging method would be a broadly useful technique to study more protein families for elucidating their physiological and pathological functions.

ER stress and its PERK branch enhance TCR-induced activation in regulatory T cells.

Although accumulating evidence indicates participation of endoplasmic reticulum (ER) stress pathway or the unfolded protein response (UPR) in immunity, there still exists little information linking ER stress to regulatory T cells (Tregs). To evaluate the potential contribution of the UPR, we tested the effects of thapsigargin (TG), an ER stress inducer, on the function of Tregs. Here we reported that TG stimulation induced the up-regulation of the endoplasmic reticulum (ER)-stress chaperon Glucose-Regulated Protein 78 (GRP78), which is a master regulator of the UPR, the phosphorylation of eukaryotic initiation factor 2 alpha (elF2α) and the induction of activating transcription factor 4 (ATF4), which are both protein kinase R (PKR)-like ER kinase (PERK) downstream targets in Tregs. Simultaneously, we demonstrated that, under ER stress conditions, Tregs presented enhanced functional activity upon TCR stimulation, as illustrated with forkhead box transcription factor (Foxp3) expression, interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß) production and suppressive functional analysis. Notably, pretreatment with GSK2656157, a potent and selective PERK inhibitor, markedly diminished the TG-induced hyperresponsiveness of Tregs upon T cell antigen receptor (TCR) stimulation. Therefore, our findings illustrated the inter-connection and coordination of the evolutionarily conserved ER stress response and TCR signaling in Tregs and uncover a critical new role of the PERK branch of UPR in the regulation of Tregs function.

Effects of exercise-based pulmonary rehabilitation on adults with asthma: a systematic review and meta-analysis.

BACKGROUND: Pulmonary rehabilitation (PR) has been proposed as an effective method for many respiratory diseases. However, the effects of exercise-based PR on asthma are currently inconclusive. This review aimed to investigate the effects of exercise-based PR on adults with asthma. METHODS: The PubMed, Embase, Cochrane Library, Web of Science, International Clinical Trials Registry Platform and ClinicalTrials.gov databases were searched from inception to 31 July 2019 without language restriction. Randomized controlled trials (RCTs) investigating the effects of exercise-based PR on adults with asthma were included. Study selection, data extraction and risk of bias assessment were performed by two investigators independently. Meta-analysis was conducted by RevMan software (version 5.3). Evidence quality was rated by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: Ten literatures from nine studies (n = 418 patients) were identified. Asthma quality of life questionnaire total scores (MD = 0.39, 95% CI: 0.02 to 0.76) improved significantly in the experimental group compared to control group, including activity domain scores (MD = 0.58, 95% CI: 0.21 to 0.94), symptom domain scores (MD = 0.52, 95% CI: 0.19 to 0.85), emotion domain scores (MD = 0.53, 95% CI: - 0.03 to 1.09) and environment domain scores (MD = 0.56, 95% CI: 0.00 to 1.11). Both the 6-min walk distance (MD = 34.09, 95% CI: 2.51 to 65.66) and maximum oxygen uptake (MD = 4.45, 95% CI: 3.32 to 5.58) significantly improved. However, improvements in asthma control questionnaire scores (MD = - 0.25, 95% CI: - 0.51 to 0.02) and asthma symptom-free days (MD = 3.35, 95% CI: - 0.21 to 6.90) were not significant. Moreover, there was no significant improvement (MD = 0.10, 95% CI: - 0.08 to 0.29) in forced expiratory volume in 1 s. Nonetheless, improvements in forced vital capacity (MD = 0.23, 95% CI: 0.08 to 0.38) and peak expiratory flow (MD = 0.39, 95% CI: 0.21 to 0.57) were significant. CONCLUSIONS: Exercise-based PR may improve quality of life, exercise tolerance and some aspects of pulmonary function in adults with asthma and can be considered a supplementary therapy. RCTs of high quality and large sample sizes are required. CLINICAL TRIAL REGISTRATION: The review was registered with PROSPERO (The website is https://www.crd.york.ac.uk/prospero/ , and the ID is CRD42019147107).

N- and O-Doped Carbon Dots for Rapid and High-Throughput Dual Detection of Trace Amounts of Iron in Water and Organic Phases.

In this work, we report a dual use of highly fluorescent N- and O-doped carbon dots (CDs) for rapid and high-throughput trace analysis of iron in water and organic phases. The CDs are rapidly synthesized in a sealed vessel via microwave irradiation within 5 min, and they exhibit high quantum yields of 80% with sensitive quenching responses to iron contents. Combined with a microplate fluorescence reader, a rapid and high-throughput assay for ions is further developed. The whole process from the CD synthesis to the detection output can be accomplished within 15 min. The limits of detection for Fe3+ in aqueous solution and ferrocene in organic gasoline are determined down to 0.05 mM. Furthermore, this method has been successfully used to determine the level of irons in real gasoline for quality evaluation. The results have an excellent agreement with atomic absorption spectrophotometric measurements. The CD-based facile assay with lower cost, use of less sample, and higher-throughput holds great promise as a powerful tool for iron detection in water and organic phase samples.

An impurity intermediate band due to Pb doping induced promising thermoelectric performance of Ca5In2Sb6.

Band engineering is one of the effective approaches for designing ideal thermoelectric materials. Introducing an intermediate band in the band gap of semiconducting thermoelectric compounds may largely increase the carrier concentration and improve the electrical conductivity of these compounds. We test this hypothesis by Pb doping in Zintl Ca5In2Sb6. In the current work, we have systematically investigated the electronic structure and thermoelectric performances of substitutional doping with Pb on In sites at a doping level of 5% (0.2 e per cell) for Ca5In2Sb6 by using density functional theory combined with semi-classical Boltzmann theory. It is found that in contrast to Zn doping, Pb doping introduces a partially filled intermediate band in the band gap of Ca5In2Sb6, which originates from the Pb s states by weakly hybridizing with the Sb p states. Such an intermediate band dramatically increases the electrical conductivity of Ca5In2Sb6 and has little detrimental effect on its Seebeck coefficient, which may increase its thermoelectric figure of merit, ZT. Interestingly, a maximum ZT value of 2.46 may be achieved at 900 K for crystalline Pb-doped Ca5In2Sb6 when the carrier concentration is optimized. Therefore, Pb-doped Ca5In2Sb6 may be a promising thermoelectric material.

Theoretical Insights on the Charge State and Bifunctional OER/ORR Electrocatalyst Activity in 4d-Transition-Metal-Doped g-C3N4 Monolayers.

Exploring efficient and stable electrocatalysts for the bifunctional oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) is vital to developing renewable energy technologies. However, due to the substantial and intricate design space associated with these bifunctional OER/ORR electrocatalysts, their development presents a formidable challenge, resulting in their cost-prohibitive nature in both experimental and computational studies. Herein, using the defect physics method, we systematically investigate the formation energies and bifunctional overpotential (ηBi) of 4d-transition-metal (4d-TM, 4d-TM = Zr, Nb, Mo, Ru, Rh, Pd, and Ag)-doped monolayer supercell g-C3N4 (4d-TM@C54N72) based on the density functional theory (DFT) calculations. Under N-rich and C-rich conditions, we find that the formation energies of RhN@C54N71 (Rh occupation N) and PdN@C54N71 (Pd occupation N) are smaller than that of other 4d-TMN@C54N71 (4d-TM occupation N site); for the 4d-TMint@C54N72 (4d-TM interstitial site occupation), the lowest-formation energy defects are Pdint@C54N72. These results indicate that they have better stabilities. Interestingly, for these formation energy lower systems, Pd0int@C54N72 (ηBi = 1.00 V) and Rh1+N@C54N71 (ηBi = 0.73 V) have ultralow overpotential and can be great candidates for bifunctional OER/ORR electrocatalysts. We find the reason is that adjusting the charge states of 4d-TM@C54N72 can tune the interaction strength between the oxygenated intermediates and the 4d-TM@C54N72, which plays a crucial role in the activity of reactions. Additionally, the data obtained through machine learning (ML) application suggest that the electronegativity (Nm) and bond length of 4d-TM and coordination atoms (dTM-OOH) are primary descriptors characterizing the OER and ORR activities, respectively. The charged defect tuning of the bifunctional OER/ORR activity for 4d-TM@C54N72 would enable electrocatalytic performance optimization and the development of potential electrocatalysts for renewable energy applications.

Suppressed Lattice Thermal Conductivity in Haeckelite Compounds for High-Performance Thermoelectric Applications.

Traditional semiconductors are known to exhibit excellent electrical properties but oversized lattice thermal conductivities, thus limiting their thermoelectric performance. Herein, we have discovered a low-energy allotrope of those traditional semiconductors. Compared with the wurtzite structure, the lattice thermal conductivity is reduced by more than five times in the haeckelite structure. This is attributed to the softening of acoustic phonon modes and concurrently enhanced anharmonicity in the haeckelite structure. Benefiting from the suppressed lattice thermal conductivity while retaining the excellent electrical properties of wurtzite structure, haeckelite compounds have been proven to be a novel category of high-performance thermoelectric materials. As an excellent representative, haeckelite CdTe exhibits a peak figure of merit approaching 1.3 at n-type doping and high temperature, which experiences a 3-fold improvement compared with its wurtzite counterpart. This work provides an alternative pathway of engineering the lattice thermal conductivities of traditional semiconductors toward superior thermoelectric properties.

Mechanistic prediction and validation of Brevilin A Therapeutic effects in Lung Cancer.

BACKGROUND: Traditional Chinese medicine (TCM) has been found widespread application in neoplasm treatment, yielding promising therapeutic candidates. Previous studies have revealed the anti-cancer properties of Brevilin A, a naturally occurring sesquiterpene lactone derived from Centipeda minima (L.) A.Br. (C. minima), a TCM herb, specifically against lung cancer. However, the underlying mechanisms of its effects remain elusive. This study employs network pharmacology and experimental analyses to unravel the molecular mechanisms of Brevilin A in lung cancer. METHODS: The Batman-TCM, Swiss Target Prediction, Pharmmapper, SuperPred, and BindingDB databases were screened to identify Brevilin A targets. Lung cancer-related targets were sourced from GEO, Genecards, OMIM, TTD, and Drugbank databases. Utilizing Cytoscape software, a protein-protein interaction (PPI) network was established. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene set enrichment analysis (GSEA), and gene-pathway correlation analysis were conducted using R software. To validate network pharmacology results, molecular docking, molecular dynamics simulations, and in vitro experiments were performed. RESULTS: We identified 599 Brevilin A-associated targets and 3864 lung cancer-related targets, with 155 overlapping genes considered as candidate targets for Brevilin A against lung cancer. The PPI network highlighted STAT3, TNF, HIF1A, PTEN, ESR1, and MTOR as potential therapeutic targets. GO and KEGG analyses revealed 2893 enriched GO terms and 157 enriched KEGG pathways, including the PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. GSEA demonstrated a close association between hub genes and lung cancer. Gene-pathway correlation analysis indicated significant associations between hub genes and the cellular response to hypoxia pathway. Molecular docking and dynamics simulations confirmed Brevilin A's interaction with PTEN and HIF1A, respectively. In vitro experiments demonstrated Brevilin A-induced dose- and time-dependent cell death in A549 cells. Notably, Brevilin A treatment significantly reduced HIF-1α mRNA expression while increasing PTEN mRNA levels. CONCLUSIONS: This study demonstrates that Brevilin A exerts anti-cancer effects in treating lung cancer through a multi-target and multi-pathway manner, with the HIF pathway potentially being involved. These results lay a theoretical foundation for the prospective clinical application of Brevilin A.