Discovery of Inhibitors Targeting Protein-Protein Interaction between Bacterial RNA Polymerase and NusG as Novel Antimicrobials.

Bacterial RNA polymerase (RNAP), the core enzyme responsible for bacterial transcription, requires the NusG factor for efficient transcription elongation and termination. As the primary binding site for NusG, the RNAP clamp-helix (CH) domain represents a potential protein-protein interaction (PPI) target for novel antimicrobial agent design and discovery. In this study, we designed a pharmacophore model based on the essential amino acids of the CH for binding to NusG, such as R270, R278, and R281 (Escherichia coli numbering), and identified a hit compound with mild antimicrobial activity. Subsequent rational design and synthesis of this hit compound led to improved antimicrobial activity against Streptococcus pneumoniae, with the minimum inhibitory concentration (MIC) reduced from 128 to 1 µg/mL. Additional characterization of the antimicrobial activity, inhibitory activity against RNAP-NusG interaction, and cell-based transcription and fluorescent assays of the optimized compounds demonstrated their potential for further lead optimization.

Using MXene as a Chemically Induced Initiator to Construct High-Performance Cathodes for Aqueous Zinc-Ion Batteries.

MXene usually exhibits weak pseudo-capacitance behavior in aqueous zinc-ion batteries, which cannot provide sufficient reversible capacity, resulting in the decline of overall capacity when used as the cathode materials. Taking inspiration from polymer electrolyte engineering, we have conceptualized an in situ induced growth strategy based on MXene materials. Herein, 5.25 % MXene was introduced into the nucleation and growth process of vanadium oxide (HVO), providing the heterogeneous nucleation site and serving as an initiator to regulate the morphology and structural of vanadium oxide (T-HVO). The resulted materials can significantly improve the capacity and rate performance of zinc-ion batteries. The growth mechanism of T-HVO was demonstrated by both characterizations and DFT simulations, and the improved performance was systematically investigated through a series of in situ experiments related to dynamic analysis steps. Finally, the evaluation and comparison of various defect introduction strategies revealed the efficient, safety, and high production output characteristics of the in situ induced growth strategy. This work proposes the concept of in situ induced growth strategy and discloses the induced chemical mechanism of MXene materials, which will aid the understanding, development, and application of cathode in aqueous zinc-ion batteries.

2D Memory Selectors with Giant Nonlinearity Enabled by Van der Waals Heterostructures.

The integration of one-selector-one-resistor crossbar arrays requires the selectors featured with high nonlinearity and bipolarity to prevent leakage currents and any crosstalk among distinct cells. However, a selector with sufficient nonlinearity especially in the frame of device miniaturization remains scarce, restricting the advance of high-density storage devices. Herein, a high-performance memory selector is reported by constructing a graphene/hBN/WSe2 heterostructure. Within the temperature range of 300-80 K, the nonlinearity of this selector varies from ≈103 - ≈104 under forward bias, and increases from ≈300 - ≈105 under reverse bias, the highest reported nonlinearity among 2D selectors. This improvement is ascribed to direct tunneling at low bias and Fowler-Nordheim tunneling at high bias. The tunneling current versus voltage curves exhibit excellent bipolarity behavior because of the comparable hole and electron tunneling barriers, and the charge transport polarity can be effectively tuned from N-type or P-type to bipolar by simply changing source-drain bias. In addition, the conceptual memory selector exhibits no sign of deterioration after 70 000 switching cycles, paving the way for assembling 2D selectors into modern memory devices.

Self-condensation-assisted chemical vapour deposition growth of atomically two-dimensional MOF single-crystals.

Two-dimensional metal-organic frameworks (MOFs) have a wide variety of applications in molecular separation and other emerging technologies, including atomically thin electronics. However, due to the inherent fragility and strong interlayer interactions, high-quality MOF crystals of atomic thickness, especially isolated MOF crystal monolayers, have not been easy to prepare. Here, we report the self-condensation-assisted chemical vapour deposition growth of atomically thin MOF single-crystals, yielding monolayer single-crystals of poly[Fe(benzimidazole)2] up to 62 µm in grain sizes. By using transmission electron microscopy and high-resolution atomic force microscopy, high crystallinity and atomic-scale single-crystal structure are verified in the atomically MOF flakes. Moreover, integrating such MOFs with MoS2 to construct ultrathin van der Waals heterostructures is achieved by direct growth of atomically MOF single-crystals onto monolayer MoS2, and enables a highly selective ammonia sensing. These demonstrations signify the great potential of the method in facilitating the development of the fabrication and application of atomically thin MOF crystals.

Study on the Performance of a Surface with Coupled Wettability Difference and Convex-Stripe Array for Improved Air Layer Stability.

The existence of an air layer reduces friction drag on superhydrophobic surfaces. Therefore, improving the air layer stability of superhydrophobic surfaces holds immense significance in reducing both energy consumption and environmental pollution caused by friction drag. Based on the properties of mathematical discretization and the contact angle hysteresis generated by the wettability difference, a surface coupled with a wettability difference treatment and a convex-stripe array is developed by laser engraving and fluorine modification, and its performance in improving the air layer stability is experimentally studied in a von Kármán swirling flow field. The results show that the destabilization of the air layer is mainly caused by the Kelvin-Helmholtz instability, which is triggered by the density difference between gas and liquid, as well as the tangential velocity difference between gas and liquid. When the air layer is relatively thin, tangential wave destabilization occurs, whereas for larger thicknesses, the destabilization mode is coupled wave destabilization. The maximum Reynolds number that keeps the air layer fully covering the surface of the rotating disk (with drag reduction performance) during the disk rotation process is defined as the critical Reynolds number (Rec), which is 1.62 × 105 for the uniform superhydrophobic surface and 3.24 × 105 for the superhydrophobic surface with a convex stripe on the outermost ring (SCSSP). Individual treatments of wettability difference and a convex-stripe array on the SCSSP further improve the air layer stability, but Rec remains at 3.24 × 105. Finally, the coupling of the wettability difference treatment with a convex-stripe array significantly improves the air layer stability, resulting in an increase of Rec to 4.05 × 105, and the drag reduction rate stably maintained around 30%.

Graphene binding on black phosphorus enables high on/off ratios and mobility.

Graphene is one of the most promising candidates for integrated circuits due to its robustness against short-channel effects, inherent high carrier mobility and desired gapless nature for Ohmic contact, but it is difficult to achieve satisfactory on/off ratios even at the expense of its carrier mobility, limiting its device applications. Here, we present a strategy to realize high back-gate switching ratios in a graphene monolayer with well-maintained high mobility by forming a vertical heterostructure with a black phosphorus multi-layer. By local current annealing, strain is introduced within an established area of the graphene, which forms a reflective interface with the rest of the strain-free area and thus generates a robust off-state via local current depletion. Applying a positive back-gate voltage to the heterostructure can keep the black phosphorus insulating, while a negative back-gate voltage changes the black phosphorus to be conductive because of hole accumulation. Then, a parallel channel is activated within the strain-free graphene area by edge-contacted electrodes, thereby largely inheriting the intrinsic carrier mobility of graphene in the on-state. As a result, the device can provide an on/off voltage ratio of >103 as well as a mobility of ∼8000 cm2 V-1 s-1 at room temperature, meeting the low-power criterion suggested by the International Roadmap for Devices and Systems.

Esterase-Labile Quaternium Lipidoid Enabling Improved mRNA-LNP Stability and Spleen-Selective mRNA Transfection.

Ionizable cationic lipids are recognized as an essential component of lipid nanoparticles (LNPs) for messenger RNA (mRNA) delivery but can be confounded by low lipoplex stability with mRNA during storage and in vivo delivery. Herein, the rational design and combinatorial synthesis of esterase-triggered decationizable quaternium lipid-like molecules (lipidoids) are reported to develop new LNPs with high delivery efficiency and improved storage stability. This top lipidoid carries positive charges at the physiological condition but promptly acquires negative charges in the presence of esterase, thus permitting stable mRNA encapsulation during storage and in vivo delivery while balancing efficient mRNA release in the cytosol. An optimal LNP formulation is then identified through orthogonal optimization, which enables efficacious mRNA transfection selectively in the spleen following intravenous administration. LNP-mediated delivery of ovalbumin (OVA)-encoding mRNA induces efficient antigen expression in antigen-presenting cells and elicits robust antigen-specific immune responses against OVA-transduced tumors. The work demonstrates the potential of decationizable quaternium lipidoids for spleen-selective RNA transfection and cancer immunotherapy.

Sedation with a 1:1 mixture of etomidate and propofol for gastroscopy in hypertensive elderly patients.

We hypothesized that the combined use of etomidate and propofol for endoscopic sedation in elderly hypertensive patients could reduce adverse reactions while providing ideal sedation. To validate our hypothesis, we conducted a prospective, randomized, controlled, double-blinded study. A total of 360 elderly hypertensive patients scheduled for gastroscopy at our hospital were enrolled in the study, of whom 328 completed the trial. The patients were randomly assigned to one of three groups: the propofol group (group P), the etomidate group (group E), or the propofol-etomidate combination group (mixed at a ratio of 1:1, group PE). We collected and analyzed the cardiopulmonary effects and side effects in each group. Regardless of the sedation drug used, the systolic blood pressure, mean blood pressure, and heart rate of involved patients were significantly affected. Oxygen desaturation and injection pain were more common in group P compared to groups E (33.6% vs. 14.8%, 31.8% vs. 2.7%, both P < 0.01) and group PE (33.6% vs. 13.6%, 31.8% vs. 6.4%, both P < 0.01). The incidence of myoclonus in the PE group was lower than that in the E group (10.9% vs. 61.2%, P < 0.01). Our results indeed demonstrated that the combined use of etomidate and propofol appeared to maintain cardiopulmonary stability with minimal side effects in older hypertensive patients scheduled for gastroscopy, which further implied that this sedation strategy could be a safe and pain-free option for managing patients undergoing gastroscopy, particularly those at a higher risk of adverse cardiovascular events.

Peritoneal Gene Transfection of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand for Tumor Surveillance and Prophylaxis.

Peritoneal metastasis is very common in gastrointestinal, reproductive, and genitourinary tract cancers in late stages or postsurgery, causing poor prognosis, so effective and nontoxic prophylactic strategies against peritoneal metastasis are highly imperative. Herein, we demonstrate the first gene transfection as a nontoxic prophylaxis preventing peritoneal metastasis or operative metastatic dissemination. Lipopolyplexes of TNF-related-apoptosis-inducing-ligand (TRAIL) transfected peritonea and macrophages to express TRAIL for over 15 days. The expressed TRAIL selectively induced tumor cell apoptosis while exempting normal tissue, providing long-term tumor surveillance. Therefore, tumor cells inoculated in the pretransfected peritoneal cavity quickly underwent apoptosis and, thus, barely formed tumor nodules, significantly prolonging the mouse survival time compared with chemotherapy prophylaxis. Furthermore, lipopolyplex transfection showed no sign of toxicity. Therefore, this peritoneal TRAIL-transfection is an effective and safe prophylaxis, preventing peritoneal metastasis.

Redox-Responsive Lipidic Prodrug Nano-Delivery System Improves Antitumor Effect of Curcumin Derivative C210.

The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives.

Osteoporosis remission via an anti-inflammaging effect by icariin activated autophagy.

The pace of bone formation slows down with aging, which leads to the development of osteoporosis. In addition to senescent bone marrow mesenchymal stem cells (S-BMSCs), senescent macrophages (S-MΦs) present in the bone marrow produce numerous inflammatory cytokines that contribute to the inflammaged microenvironment and are involved in the development of osteoporosis. Although autophagy activation has shown a significant anti-aging effect, its influence on inflammaging and its role in osteoporosis treatment remain unclear. Traditional Chinese herbal medicine contains bioactive components that exhibit remarkable advantages in bone regeneration. We have demonstrated that icariin (ICA), a bioactive component of traditional Chinese herbal medicine, activates autophagy, exerts a significant anti-inflammaging effect on S-MΦs, and rejuvenates osteogenesis of S-BMSCs, thereby alleviating bone loss in osteoporotic mice. The transcriptomic analysis further reveals that the TNF-α signaling pathway, which is significantly associated with the level of autophagy, regulates this effect. Moreover, the expression of senescence-associated secretory phenotype (SASP) is significantly reduced after ICA treatment. In summary, our findings suggest that bioactive components/materials targeting autophagy can effectively modulate the inflammaging of S-MΦs, offering an innovative treatment strategy for osteoporosis remission and various age-related comorbidities.

The Interaction of 2D Materials With Circularly Polarized Light.

2D materials (2DMs), due to spin-valley locking degree of freedom, exhibit strongly bound exciton and chiral optical selection rules and become promising material candidates for optoelectronic and spin/valleytronic devices. Over the last decade, the manifesting of 2D materials by circularly polarized lights expedites tremendous fascinating phenomena, such as valley/exciton Hall effect, Moiré exciton, optical Stark effect, circular dichroism, circularly polarized photoluminescence, and spintronic property. In this review, recent advance in the interaction of circularly polarized light with 2D materials covering from graphene, black phosphorous, transition metal dichalcogenides, van der Waals heterostructures as well as small proportion of quasi-2D perovskites and topological materials, is overviewed. The confronted challenges and theoretical and experimental opportunities are also discussed, attempting to accelerate the prosperity of chiral light-2DMs interactions.

Surface acoustic wave induced phenomena in two-dimensional materials.

Surface acoustic wave (SAW)-matter interaction provides a fascinating key for inducing and manipulating novel phenomena and functionalities in two-dimensional (2D) materials. The dynamic strain field and piezo-electric field associated with propagating SAWs determine the coherent manipulation and transduction between 2D excitons and phonons. Over the past decade, many intriguing acoustic-induced effects, including the acousto-electric effect, acousto-galvanic effect, acoustic Stark effect, acoustic Hall effect and acoustic exciton transport, have been reported experimentally. However, many more phenomena, such as the valley acousto-electric effect, valley acousto-electric Hall effect and acoustic spin Hall effect, were only theoretically proposed, the experimental verification of which are yet to be achieved. In this minireview, we attempt to overview the recent breakthrough of SAW-induced phenomena covering acoustic charge transport, acoustic exciton transport and modulation, and coherent acoustic phonons. Perspectives on the opportunities of the proposed SAW-induced phenomena, as well as open experimental challenges, are also discussed, attempting to offer some guidelines for experimentalists and theorists to explore the desired exotic properties and boost practical applications of 2D materials.

[Key technology of brain-computer interaction based on speech imagery].

Speech expression is an important high-level cognitive behavior of human beings. The realization of this behavior is closely related to human brain activity. Both true speech expression and speech imagination can activate part of the same brain area. Therefore, speech imagery becomes a new paradigm of brain-computer interaction. Brain-computer interface (BCI) based on speech imagery has the advantages of spontaneous generation, no training, and friendliness to subjects, so it has attracted the attention of many scholars. However, this interactive technology is not mature in the design of experimental paradigms and the choice of imagination materials, and there are many issues that need to be discussed urgently. Therefore, in response to these problems, this article first expounds the neural mechanism of speech imagery. Then, by reviewing the previous BCI research of speech imagery, the mainstream methods and core technologies of experimental paradigm, imagination materials, data processing and so on are systematically analyzed. Finally, the key problems and main challenges that restrict the development of this type of BCI are discussed. And the future development and application perspective of the speech imaginary BCI system are prospected.

Hydrovoltaic technology: from mechanism to applications.

Water is a colossal reservoir of clean energy as it adsorbs thirty-five percent of solar energy reaching the Earth's surface. More than half of the adsorbed energy turns into latent heat for water evaporation, driving the water cycle of the Earth.1 Yet, only very limited energy in the water cycle is harvested by current industrial technologies. The past decade has witnessed the emergence of hydrovoltaic technology, which generates electricity from nanomaterials by direct interaction with water and enables energy harvesting from the water cycle such as from rain, waves, flows, moisture and natural evaporation. Years of efforts have been committed to improve the conversion efficiency of hydrovoltaic devices through chemical synthesis of advanced nanomaterials and innovative design of device structures. Further development of this field, however, still requires in-depth understanding of hydrovoltaic mechanisms and boosting of the electrical outputs for wider applications. Here, we present a tutorial review of different mechanisms of generating electricity from droplets, flows, natural evaporation and ambient moisture by analyzing basic interactions at various water-material interfaces. Key aspects in raising the output power of hydrovoltaic devices are then discussed in terms of material synthesis, structural design, and device optimization. We also provide an outlook on the potential applications of this technology ranging from sensors, power suppliers to multifunctional systems as well as on the scientific and technological challenges in transforming its potential into practical utility. The prospects of this emerging field are considered for future endeavor.

Coupling Red-to-blue Upconversion Organic Microcrystals with Cd0.5 Zn0.5 S for Efficient and Durable Photocatalytic Hydrogen Production.

For semiconductor photocatalysts with excellent performance in solar H2 production, broadening the utilization of solar irradiation is highly necessary to further improve the solar conversion efficiency. Herein, we combined a Cd0.5 Zn0.5 S photocatalyst with DPA/PdTPTBP microcrystals capable of red-to-blue photon upconversion, realizing substantial performance enhancement and an apparent quantum yield of 0.16% for H2 production driven by sub-bandgap photons (600∼650 nm). Meanwhile, this system could smoothly work with H2 production rate of 1.40 mmol g-1 h-1 for as long as 40 hours under 200 mW/cm2 irradiation with only 3% attenuation of photocatalytic activity. Moreover, the O2 -barrier property of DPA/PdTPTBP microcrystals assures that photocatalytic H2 production remains effective in the presence of 10% O2 by volume, which offers an opportunity for the photocatalytic application in O2 -enriched environments. The combination of O2 -resistant upconversion microcrystals and semiconductor catalysts is the most successful solution for the construction of TTA-UC-based photocatalytic H2 production system so far. The present study provides a clear guideline for designing new TTA-UC-based photocatalytic systems.

Mucus Penetrating and Cell-Binding Polyzwitterionic Micelles as Potent Oral Nanomedicine for Cancer Drug Delivery.

Orally administrable anticancer nanomedicines are highly desirable due to their easy and repeatable administration, but are not yet feasible because the current nanomedicine cannot simultaneously overcome the strong mucus and villi barriers and thus have very low bioavailability (BA). Herein, this work presents the first polymeric micelle capable of fast mucus permeation and villi absorption and delivering paclitaxel (PTX) efficiently to tumors with therapeutic efficacy even better than intravenously administered polyethylene glycol based counterpart or free PTX. Poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), a water-soluble polyzwitterion, is highly nonfouling to proteins and other biomacromolecules such as mucin but can weakly bind to phospholipids. Therefore, the micelle of its block copolymer with poly(ε-caprolactone) (OPDEA-PCL) can efficiently permeate through the viscous mucus and bind to villi, which triggers transcytosis-mediated transepithelial transport into blood circulation for tumor accumulation. The orally administered micelles deliver PTX to tumors, efficiently inhibiting the growth of HepG2 and patient-derived hepatocellular carcinoma xenografts and triple-negative breast tumors. These results demonstrate that OPDEA-based micelles may serve as an efficient oral nanomedicine for delivering other small molecules or even large molecules.

Metal-free alkylation of quinoxalinones with aryl alkyl ketones.

The first metal-free method for alkylation of quinoxalinones using cheap and stable aryl alkyl ketones as nucleophilic alkylation reagents is reported. This strategy greatly broadens the application channels of aryl alkyl ketones through carbon-carbon bond activation. In addition, the protocol has the advantages of simple operation, broad substrate scope, and good functional group tolerance.

Longitudinal resting-state functional connectivity and regional brain atrophy-based biomarkers of preclinical cognitive impairment in healthy old adults.

BACKGROUND: Intervention against age-related neurodegenerative diseases may be difficult once extensive structural and functional deteriorations have already occurred in the brain. AIM: Investigating 6-year longitudinal changes and implications of regional brain atrophy and functional connectivity in the triple-network model as biomarkers of preclinical cognitive impairment in healthy aging. METHODS: We acquired longitudinal cognitive scores and magnetic resonance imaging (MRI) data from 74 healthy old adults. Resting-state functional MRI (rs-fMRI) analysis was conducted using FSL6.0.1 to examine functional connectivity changes and regional brain morphometries were quantified using FreeSurfer5.3. Finally, we cross-validated and compared two support vector machine (SVM) regression models to predict future 6-year cognition score from the baseline regional brain atrophy and resting-state functional connectivity (rs-FC) measures. RESULTS: After a 6-year follow-up, our results (P < 0.05-corrected) indicated significant connectivity reduction within all the three brain networks, significant differences in regional brain volumes and cortical thickness. We also observed significant improvement in episodic memory and significant decline in executive functions. Finally, comparing the two models, we observed that regional brain atrophy predictors were more efficient in approximating future 6-year cognitive scores (R = 0.756, P < 0.0001) than rs-FC predictors (R = 0.6, P < 0.0001). CONCLUSION: This study used longitudinal data to keep subject variability low and to increase the validity of the results. We demonstrated significant changes in structural and functional MRI over 6 years. Our findings present a potential neuroimaging-based biomarker to detect cognitive impairment and prevent risks of neurodegenerative diseases in healthy old adults.

Microstructural properties of major white matter tracts in constant exotropia before and after strabismus surgery.

AIMS: The purpose of this study was to explore the microstructural properties of the major white matter (WM) tracts in constant exotropia (XT) before and after strabismus surgery, and further investigate the association between microstructural alterations and the ocular dominance (OD). METHODS: We collected diffusion tensor imaging data of patients with XT before (n=19) and after (n=15) strabismus surgery and 20 healthy controls and evaluated OD and stereopsis. The probabilistic streamline tractography of the 24 major WM tracts was reconstructed by using the automated fibre quantification package. Fractional anisotropy and mean diffusivity (MD) along each tract were estimated, and their differences between the groups were examined. Furthermore, we evaluated the relationship between OD and the absolute value of altered microstructural parameters. RESULTS: While all postoperative XT patients restored normal stereopsis, most of their OD remained aberrant (9 out of 11). Compared with that of preoperation, the MD of postoperative patients decreased significantly along left anterior thalamic radiation (ATR), left arcuate fasciculus (AF), left corticospinal tract (CST), left cingulum cingulate (CGC) and left inferior fronto-occipital fasciculus. Moreover, OD was negatively correlated with the absolute value of MD changes in left ATR, left AF, left CST and left CGC. CONCLUSION: Microstructural alterations after surgery in the visuospatial network tracts may contribute to the stereopsis restoration. Additionally, the results of the correlation analysis may signify that the balanced binocular input may be more conducive for the restoration and improvement of binocular visual function, including stereopsis. Thus, restoring normal ocular balance after surgical correction may be necessary to achieve more substantial improvements.