Structures and Efflux Mechanisms of the AcrAB-TolC Pump.

The global emergence of multidrug resistance (MDR) in gram-negative bacteria has become a matter of worldwide concern. MDR in these pathogens is closely linked to the overexpression of certain efflux pumps, particularly the resistance-nodulation-cell division (RND) efflux pumps. Inhibition of these pumps presents an attractive and promising strategy to combat antibiotic resistance, as the efflux pump inhibitors can effectively restore the potency of existing antibiotics. AcrAB-TolC is one well-studied RND efflux pump, which transports a variety of substrates, therefore providing resistance to a broad spectrum of antibiotics. To develop effective pump inhibitors, a comprehensive understanding of the structural aspect of the AcrAB-TolC efflux pump is imperative. Previous studies on this pump's structure have been limited to individual components or in vitro determination of fully assembled pumps. Recent advancements in cellular cryo-electron tomography (cryo-ET) have provided novel insights into this pump's assembly and functional mechanism within its native cell membrane environment. Here, we present a summary of the structural data regarding the AcrAB-TolC efflux pump, shedding light on its assembly pathway and operational mechanism.

Stabilizing the oxidation state of catalysts for effective electrochemical carbon dioxide conversion.

In the electrocatalytic CO2 reduction reaction (CO2RR), metal catalysts with an oxidation state generally demonstrate more favorable catalytic activity and selectivity than their corresponding metallic counterparts. However, the persistence of oxidative metal sites under reductive potentials is challenging since the transition to metallic states inevitably leads to catalytic degradation. Herein, a thorough review of research on oxidation-state stabilization in the CO2RR is presented, starting from fundamental concepts and highlighting the importance of oxidation state stabilization while revealing the relevance of dynamic oxidation states in product distribution. Subsequently, the functional mechanisms of various oxidation-state protection strategies are explained in detail, and in situ detection techniques are discussed. Finally, the prevailing and prospective challenges associated with oxidation-state protection research are discussed, identifying innovative opportunities for mechanistic insights, technology upgrades, and industrial platforms to enable the commercialization of the CO2RR.

Efficacy and safety of recombinant human thrombopoietin for the treatment of chronic primary immune thrombocytopenia in children and adolescents: A multicentre, randomized, double-blind, placebo-controlled phase III trial.

The efficacy and safety of recombinant human thrombopoietin (rhTPO) in children and adolescent patients with chronic primary immune thrombocytopenia (ITP) remains unclear. A multicentre, randomized, double-blind, placebo-controlled phase III trial was performed. Patients aged 6-17 years, diagnosed with ITP and resistant or relapsed to corticosteroid treatment were included. For the trial, part 1 was exploratory and part 2 was the main analysis, with part 1 determining whether part 2 was stratified by age. Patients in part 1 were treated with rhTPO (the 6- to 11-/12- to 17-year-old groups; 1:1). Patients in part 2 were randomized (3:1) to receive either rhTPO treatment or placebo. Patients received rhTPO or placebo at a dose of 300 U/kg once daily for up to 14 days. A total of 68 patients were included [part 1 (12 patients), part 2 (56 patients)]. The total response rate (TRR) in part 1 was 50.0% (95% CI: 21.09%-78.91%). For part 2, the TRR was 58.5% (95% CI: 42.11%-73.68%) and 13.3% (95% CI: 1.66%-40.46%) in the rhTPO and placebo groups (FAS) respectively. The difference in TRR between the rhTPO group and placebo group was 45.2% (95% CI: 22.33%-68.08%) and 44.6% (95% CI: 21.27%-67.85%) on the FAS and per-protocol set (PPS), respectively, which indicates the superiority of rhTPO treatment.

YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/ß-catenin axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

Heterogeneous-Structured Molybdenum Diboride as a Novel and Promising Anode for Lithium-Ion Batteries.

With the development of electric vehicles, exploiting anode materials with high capacity and fast charging capability is an urgent requirement for lithium-ion batteries (LIBs). Borophene, with the merits of high capacity, high electronic conductivity and fast diffusion kinetics, holds great potential as anode for LIBs. However, it is difficult to fabricate for the intrinsic electron-deficiency of boron atom. Herein, heterogeneous-structured MoB2 (h-MoB2) with amorphous shell and crystalline core, is prepared by solid phase molten salt method. As demonstrated, crystalline core can encapsulate the honeycomb borophene within two adjacent Mo atoms, and amorphous shell can accommodate more lithium ions to strengthen the lithium storage capacity and diffusion kinetics. According to theoretical calculations, the lithium adsorption energy in MoB2 is about -2.7 eV, and the lithium diffusion energy barrier in MoB2 is calculated to be 0.199 eV, guaranteeing the enhanced adsorption capability and fast diffusion kinetic behavior of Li+ ions. As a result, h-MoB2 anode presents high capacity of 798 mAh g-1 at 0.1 A g-1, excellent rate performance of 183 mAh g-1 at 5 A g-1 and long-term cyclic stability for 1200 cycles. This work may inspire ideas for the fabrication of borophene analogs and two-dimensional metal borides.

Inorganic Electrolyte Additive Promoting the Interfacial Stability for Durable Zn-Ion Batteries.

The development of Zn-ion batteries (ZIBs) is always hindered by the ruleless interface reactions between the solid electrode and liquid electrolyte, and seeking appropriate electrolyte additives is considered as a valid approach to stabilize the electrode/electrolyte interphases for high-performance ZIBs. Benefiting from the unique solubility of TiOSO4 in acidic solution, the composite electrolyte of 2 m ZnSO4+30 mm TiOSO4 (ZSO/TSO) is configured and its positive contribution to Zn//Zn cells, Zn//Cu cells, and Zn//NH4V4O10 batteries are comprehensively investigated by electrochemical tests and theoretical calculations. Based on the theoretical calculations, the introduction of TiOSO4 contributes to facilitating the desolvation kinetics of Zn2+ ions and guarantees the stable interface reactions of both zinc anode and NH4V4O10 cathode. As expected, Zn//Zn cells keep long-term cycling behavior for 3750 h under the test condition of 1 mA cm-2-1 mAh cm-2, Zn//Cu cells deliver high Coulombic efficiency of 99.9% for 1000 cycles under the test condition of 5 mA cm-2-1 mAh cm-2, and Zn//NH4V4O10 batteries maintain reversible specific capacity of 193.8 mAh g-1 after 1700 cycles at 5 A g-1 in ZSO/TSO electrolyte. These satisfactory results manifest that TiOSO4 additive holds great potential to improve the performances of ZIBs.

CDSKNNXMBD: a novel clustering framework for large-scale single-cell data based on a stable graph structure.

BACKGROUND: Accurate and efficient cell grouping is essential for analyzing single-cell transcriptome sequencing (scRNA-seq) data. However, the existing clustering techniques often struggle to provide timely and accurate cell type groupings when dealing with datasets with large-scale or imbalanced cell types. Therefore, there is a need for improved methods that can handle the increasing size of scRNA-seq datasets while maintaining high accuracy and efficiency. METHODS: We propose CDSKNNXMBD (Community Detection based on a Stable K-Nearest Neighbor Graph Structure), a novel single-cell clustering framework integrating partition clustering algorithm and community detection algorithm, which achieves accurate and fast cell type grouping by finding a stable graph structure. RESULTS: We evaluated the effectiveness of our approach by analyzing 15 tissues from the human fetal atlas. Compared to existing methods, CDSKNN effectively counteracts the high imbalance in single-cell data, enabling effective clustering. Furthermore, we conducted comparisons across multiple single-cell datasets from different studies and sequencing techniques. CDSKNN is of high applicability and robustness, and capable of balancing the complexities of across diverse types of data. Most importantly, CDSKNN exhibits higher operational efficiency on datasets at the million-cell scale, requiring an average of only 6.33 min for clustering 1.46 million single cells, saving 33.3% to 99% of running time compared to those of existing methods. CONCLUSIONS: The CDSKNN is a flexible, resilient, and promising clustering tool that is particularly suitable for clustering imbalanced data and demonstrates high efficiency on large-scale scRNA-seq datasets.

Strong third-order nonlinearity in amorphous silicon carbide waveguides.

Silicon carbide (SiC) photonic integrated platform has attracted significant research interest for on-chip optical applications, owing to its exceptional optical properties such as a broad transparency window, high refractive index, and strong nonlinearity. Among the various types of SiC, amorphous SiC (a-SiC) has particularly emerged as an accessible choice for forming thin-film SiC-on-insulator (SiCOI) stacks, demonstrating promising capabilities for wafer-scale photonic applications. In this work, we prepare three a-SiCOI samples using the plasma-enhanced chemical vapor deposition, with different refractive indices. We fabricate optical waveguides, conduct four-wave mixing measurements, and characterize the nonlinear refractive index in these samples. Our findings reveal that an increase in the refractive index of a-SiC leads to a corresponding increase in the nonlinear refractive index, which is comparable to that of silicon. Hence, a-SiC offers an approach to develop a SiC platform with a wider bandgap than that of silicon, minimizing two-photon absorption while also providing a higher refractive index and stronger nonlinearity compared to crystalline SiC.

The preoperative scoring system combining neutrophil/lymphocyte ratio and CA19-9 predicts the long-term prognosis of intrahepatic cholangiocarcinoma patients undergoing curative liver resection.

BACKGROUND: This study aims to investigate preoperative prognostic factors available for intrahepatic cholangiocarcinoma (ICC) patients and propose a new preoperative prognostic scoring system for ICC that combines CA19-9 and neutrophil/lymphocyte ratio (NLR). METHODS: In this retrospective analysis, 1728 patients diagnosed with ICC and undergoing curative liver resections were studied. This study employed univariate and multivariate Cox regression to find factors affecting recurrence and overall survival (OS), and furthermore assessed how preoperative models influenced tumor traits and postoperative recurrence. RESULTS: The results of the multivariate Cox regression analysis indicated that two preoperative variables, NLR and Ca19-9, were independent risk factors affecting postoperative recurrence and OS in ICC patients. Based on this data, assigning a score of 0 (NLR ≤ 2.4 and Ca19-9 ≤ 37U/ml) or 1 (NLR > 2.4 and Ca19-9 > 37U/ml) to these two factors, a preoperative prognostic score was derived. According to the scoring model, patients were divided into three groups: 0 points (low-risk group), 1 point (intermediate-risk group), and 2 points (high-risk group). The 5-year recurrence and OS rates for the three groups were 56.6%, 68.2%, 77.8%, and 56.8%, 40.6%, 27.6%, respectively, with all P values < 0.001. Furthermore, high-risk group patients were more prone to early recurrence (early recurrence rates for high-, intermediate-, and low-risk groups were 56.8%, 51.5%, and 37.1%, respectively, P < 0.001) and extrahepatic metastasis (extrahepatic metastasis rates for high-, intermediate-, and low-risk groups were 31.7%, 26.4%, and 15.4%, respectively, P < 0.001). In terms of tumor characteristics, high-risk group patients had larger tumor diameters and were more likely to experience microvascular invasion, lymph node metastasis, and perineural invasion. CONCLUSIONS: The predictive capacity of postoperative recurrence and OS rates in ICC patients is effectively captured by the preoperative scoring system incorporating NLR and CA19-9 levels.

Observation on the Curative Effect of Different Anti-infective Treatment Regimens for Children with Acute Appendicitis.

Objective: To observe the efficacy of different anti-infective treatment regimens on acute appendicitis in children, a retrospective study was conducted by collecting previous cases. Methods: Ninety children with acute appendicitis who received laparoscopic appendectomy from May 2020 to September 2022 were included in this retrospective study. According to the different anti-infective treatment regimens, they were divided into Piperacillin-Tazobactam group, Piperacillin-Tazobactam+Metronidazole group, and Cefminox+Metronidazole group (n=30). Three groups of children received medication treatment before surgery. The postoperative recovery, treatment effect, bacterial clearance, complication rate, pharmacoeconomic evaluation, and adverse reactions were compared. Results: The effective rates in the three groups were 83.33%, 90.00%, and 90.00%, respectively (P > .05). There were no differences in the bacterial clearance, complication incidence, and incidence of pharmaceutical side effects among the three groups (P > .05). The total hospitalization cost, total drug cost, and antimicrobial drug cost in Cefminox + Metronidazole group were lower than those in Piperacillin-Tazobactam group and Piperacillin-Tazobactam + Metronidazole group, respectively (P < .05). The intensity of antibacterial drug use in Piperacillin-Tazobactam group was the lowest, followed by Piperacillin-Tazobactam + Metronidazole group and Cefminox + Metronidazole group (P < .05). Conclusion: The three anti-infective regimens have the same therapeutic effect on acute appendicitis in children. However, the regimen of Cefminox + Metronidazole is the most economical option and can be used as the preferred treatment for acute appendicitis in children. As the preferred treatment for acute appendicitis in children. The Piperacillin-Tazobactam group has the lowest intensity of antibiotic use and can reduce bacterial resistance.

Gold-Catalyzed Diyne-Ene Annulation for the Synthesis of Polysubstituted Benzenes through Formal [3+3] Approach with Amide as the Critical Co-Catalyst.

The one-step synthesis of tetra-substituted benzenes was accomplished via gold-catalyzed diyne-ene annulation. Distinguished from prior modification methods, this novel strategy undergoes formal [3+3] cyclization, producing polysubstituted benzenes with exceptional efficiency. The critical factor enabling this transformation was the introduction of amides, which were reported for the first time in gold catalysis as covalent nucleophilic co-catalysts. This interesting protocol not only offers a new strategy to achieve functional benzenes with high efficiency, but also enlightens potential new reaction pathways within gold-catalyzed alkyne activation processes.

Simultaneous Inhibition of Vanadium Dissolution and Zinc Dendrites by Mineral-Derived Solid-State Electrolyte for High-Performance Zinc Metal Batteries.

Designing solid electrolyte is deemed as an effective approach to suppress the side reaction of zinc anode and active material dissolution of cathodes in liquid electrolytes for zinc metal batteries (ZMBs). Herein, kaolin is comprehensively investigated as raw material to prepare solid electrolyte (KL-Zn) for ZMBs. As demonstrated, KL-Zn electrolyte is an excellent electronic insulator and zinc ionic conductor, which presents wide voltage window of 2.73 V, high ionic conductivity of 5.08 mS cm-1, and high Zn2+ transference number of 0.79. For the Zn//Zn cells, superior cyclic stability lasting for 2200 h can be achieved at 0.2 mA cm-2. For the Zn//NH4V4O10 batteries, stable capacity of 245.8 mAh g-1 can be maintained at 0.2 A g-1 after 200 cycles along with high retention ratio of 81%, manifesting KL-Zn electrolyte contributes to stabilize the crystal structure of NH4V4O10 cathode. These satisfying performances can be attributed to the enlarged interlayer spacing, zinc (de)solvation-free mechanism and fast diffusion kinetics of KL-Zn electrolyte, availably guaranteeing uniform zinc deposition for zinc anode and reversible zinc (de)intercalation for NH4V4O10 cathode. Additionally, this work also verifies the application possibility of KL-Zn electrolyte for Zn//MnO2 batteries and Zn//I2 batteries, suggesting the universality of mineral-based solid electrolyte.

Urolithin A alleviates neuropathic pain and activates mitophagy.

Neuropathic pain (NP) occurs frequently in the general population and has a negative impact on the quality of life. There is no effective therapy available yet owing to the complex pathophysiology of NP. In our previous study, we found that urolithin A (UA), a naturally occurring microflora-derived metabolite, could relieve NP in mice by inhibiting the activation of microglia and release of inflammation factors. Here in this study, we sought to investigate whether mitophagy would be activated when UA alleviated NP in mice. We showed that the autophagy flow was blocked in the spinal dorsal horn of the chronic constriction injury (CCI) mice when the most obvious pain behavior occurs. Intraperitoneal injection of UA markedly activated the mitophagy mediated by PTEN-induced kinase 1/Parkin, promoted mitobiogenesis in both neurons and microglia, and alleviated NP in the CCI mice. In summary, our data suggest that UA alleviates NP in mice and meanwhile induces mitophagy activation, which highlights a therapeutic potential of UA in the treatment of NP.

High-performance silicon carbide polarization beam splitting based on an asymmetric directional couplers for mode conversion.

Polarization manipulation and management are important for 4H-silicon carbide (SiC) integrated photonics, as 4H-SiC has material-based birefringent properties. In this Letter, we propose a low-birefringence polarization beam splitter (PBS) based on asymmetric directional coupler (ADC) mode converters with overall high performances. We numerically and experimentally demonstrate the ADC mode conversion based PBS on a 4H-SiC chip. The experimental results show that the device exhibits high transmittance of -0.6 dB and -1.3 dB for the transverse-electric (TE) and transverse-magnetic (TM) polarized light, respectively, and broad operational bandwidth over 130 nm. The polarization extinction ratio of >25 dB and >17 dB covering the whole C band for the TE and TM polarized light, respectively, and an ultra-large polarization extinction ratio of >32 dB for both polarizations at approximately 1560 nm are achieved.

RIG-I regulates myeloid differentiation by promoting TRIM25-mediated ISGylation.

Retinoic acid-inducible gene I (RIG-I) is up-regulated during granulocytic differentiation of acute promyelocytic leukemia (APL) cells induced by all-trans retinoic acid (ATRA). It has been reported that RIG-I recognizes virus-specific 5'-ppp-double-stranded RNA (dsRNA) and activates the type I interferons signaling pathways in innate immunity. However, the functions of RIG-I in hematopoiesis remain unclear, especially regarding its possible interaction with endogenous RNAs and the associated pathways that could contribute to the cellular differentiation and maturation. Herein, we identified a number of RIG-I-binding endogenous RNAs in APL cells following ATRA treatment, including the tripartite motif-containing protein 25 (TRIM25) messenger RNA (mRNA). TRIM25 encodes the protein known as an E3 ligase for ubiquitin/interferon (IFN)-induced 15-kDa protein (ISG15) that is involved in RIG-I-mediated antiviral signaling. We show that RIG-I could bind TRIM25 mRNA via its helicase domain and C-terminal regulatory domain, enhancing the stability of TRIM25 transcripts. RIG-I could increase the transcriptional expression of TRIM25 by caspase recruitment domain (CARD) domain through an IFN-stimulated response element. In addition, RIG-I activated other key genes in the ISGylation pathway by activating signal transducer and activator of transcription 1 (STAT1), including the modifier ISG15 and several enzymes responsible for the conjugation of ISG15 to protein substrates. RIG-I cooperated with STAT1/2 and interferon regulatory factor 1 (IRF1) to promote the activation of the ISGylation pathway. The integrity of ISGylation in ATRA or RIG-I-induced cell differentiation was essential given that knockdown of TRIM25 or ISG15 resulted in significant inhibition of this process. Our results provide insight into the role of the RIG-I-TRIM25-ISGylation axis in myeloid differentiation.

Gold-Catalyzed Amine Cascade Addition to Diyne-Ene: Enantioselective Synthesis of 1,2-Dihydropyridines.

With the well-documented chemical and biological applications, piperidine and pyridine are among the most important N-heterocycles, and a new synthetic strategy, especially one with an alternative bond-forming design, is of general interest. Using the gold-catalyzed intermolecular condensation of amine and diyne-ene, we report herein the first example of enantioselective 1,2-dihydropyridine synthesis through a formal [3+2+1] fashion (up to 95 % yield, up to 99 % e.e.).

Asymmetric Hydrative Aldol Reaction (HAR) via Vinyl-Gold Promoted Intermolecular Ynamide Addition to Aldehydes.

Herein, we reported an intermolecular asymmetric hydrative aldol reaction through vinyl-gold intermediate under ambient conditions. This tandem alkyne hydration and sequential nucleophilic addition afforded a "base-free" approach to ß-hydroxy amides with high efficiency (up to 95 % yields, >50 examples). Vinyl gold intermediate was applied as reactive nucleophile and Fe(acac)3 was used as the critical co-catalyst to prevent undesired protodeauration, allowing this transformation to proceed under mild conditions with good functional group tolerance and excellent stereoselectivity (>20 : 1 d.r. and up to 99 % ee).

A complete data processing workflow for cryo-ET and subtomogram averaging.

Electron cryotomography is currently the only method capable of visualizing cells in three dimensions at nanometer resolutions. While modern instruments produce massive amounts of tomography data containing extremely rich structural information, data processing is very labor intensive and the results are often limited by the skills of the personnel rather than the data. We present an integrated workflow that covers the entire tomography data processing pipeline, from automated tilt series alignment to subnanometer resolution subtomogram averaging. Resolution enhancement is made possible through the use of per-particle per-tilt contrast transfer function correction and alignment. The workflow greatly reduces human bias, increases throughput and more closely approaches data-limited resolution for subtomogram averaging in both purified macromolecules and cells.

Ultra-compact, efficient and high-polarization-extinction-ratio polarization beam splitters based on photonic anisotropic metamaterials.

Anisotropic metameterials (AM) provide a new avenue for a next-generation silicon platform to design ultra-compact, densely integrated optical components, thus functional devices based on AM are drawing increasing attention recently. Here, we propose a novel efficient polarization beam splitter (PBS) with high polarization extinction ratio based on AM. An ultra-compact coupling region of 2.5 × 14 µm2 is achieved by tailoring the AM structures, which can efficiently suppress the TE mode coupling, and enhance the TM mode coupling in the directional couplers simultaneously. The insertion loss is simulated to be as low as <0.2 dB within a bandwidth of 70 nm for both modes, and the polarization extinction ratio is as high as 46 dB and 33 dB for TE and TM modes, respectively. We also experimentally demonstrate the proposed PBS, with low insertion loss of 1 dB , high extinction ratio of >20 dB and wide operational bandwidth of >80 nm.

Efficient mode converters and filters using asymmetrical directional couplers with subwavelength gratings.

Mode-division multiplexing (MDM) is a promising solution to improve data transmission capacity for future optical interconnect networks. Mode converters and mode filters play a key role in on-chip MDM systems. Here, we propose and experimentally demonstrate a device, enabling mode conversion and filtering simultaneously, which is composed of asymmetrical directional couplers with subwavelength gratings, in a small footprint of 14.7 µm × 1.42 µm. The device can realize optical mode conversion between the first-order transverse electric (TE) mode and the fundamental TE mode, and can also filter the fundamental TE mode efficiently. The conversion efficiency is over 95%, with a broad 1 dB bandwidth over 80 nm and a high mode extinction ratio of >29 dB. As a mode filter, strong mode elimination of >30 dB is achieved.