Promote electroreduction of CO2 via catalyst valence state manipulation by surface-capping ligand.

Electrochemical CO2 reduction provides a potential means for synthesizing value-added chemicals over the near equilibrium potential regime, i.e., formate production on Pd-based catalysts. However, the activity of Pd catalysts has been largely plagued by the potential-depended deactivation pathways (e.g., [Formula: see text]-PdH to [Formula: see text]-PdH phase transition, CO poisoning), limiting the formate production to a narrow potential window of 0 V to -0.25 V vs. reversible hydrogen electrode (RHE). Herein, we discovered that the Pd surface capped with polyvinylpyrrolidone (PVP) ligand exhibits effective resistance to the potential-depended deactivations and can catalyze formate production at a much extended potential window (beyond -0.7 V vs. RHE) with significantly improved activity (~14-times enhancement at -0.4 V vs. RHE) compared to that of the pristine Pd surface. Combined results from physical and electrochemical characterizations, kinetic analysis, and first-principle simulations suggest that the PVP capping ligand can effectively stabilize the high-valence-state Pd species (Pdδ+) resulted from the catalyst synthesis and pretreatments, and these Pdδ+ species are responsible for the inhibited phase transition from [Formula: see text]-PdH to [Formula: see text]-PdH, and the suppression of CO and H2 formation. The present study confers a desired catalyst design principle, introducing positive charges into Pd-based electrocatalyst to enable efficient and stable CO2 to formate conversion.

Newcastle disease virus induces clathrin-mediated endocytosis to establish infection through the activation of PI3K/AKT signaling pathway by VEGFR2.

The phosphatidyl-inositol 3-kinase/serine-threonine kinase (PI3K/ AKT) signaling pathway constitutes a classical phosphorylation cascade that integrates tyrosine, lipid, and serine acid-threonine phosphorylation, affecting cell function. The pathway is vulnerable to viral infection. Newcastle disease virus (NDV) poses a significant threat to the global poultry industry; however, its mechanism of early viral cell invasion and pathogenesis remain unclear. Previous in vivo and in vitro studies have shown that NDV infection activates PI3K/AKT signaling; however, it remains unclear whether NDV establishes infection through endocytosis regulated by this pathway. This study aimed to examine whether different genotypes of NDV strains could activate the PI3K/AKT signaling pathway within 2 h of in vitro infection. This activation, which relies on PI3K phosphorylation, remains unaffected by the phosphorylation-phosphatase and tensin homolog/phosphatase and tensin homolog (p-PTEN/PTEN) signaling pathway. Moreover, inhibition of PI3K activity impedes NDV replication. Additionally, interfering with the PI3K regulatory subunit p85 has no significant effect on NDV replication. Conversely, the tyrosine kinase activity upstream of PI3K can influence AKT activation and viral replication, particularly through vascular endothelial growth factor receptor 2 (VEGFR2). Additionally, NDV F protein primarily mediates PI3K and AKT phosphorylation to activate the PI3K/AKT signaling pathway. NDV F and VEGFR2 proteins, along with the PI3K p85α subunit, interact and co-localize at the cell membrane. NDV-induced PI3K/AKT signaling pathway activation impacts clathrin-mediated endocytosis, with VEGFR2 playing a pivotal role. In conclusion, this study shows that NDV infection is established early through F protein binding to VEGFR2, activating the PI3K/AKT signaling pathway and inducing clathrin-mediated endocytosis, supporting infection prevention and control measures. IMPORTANCE: Newcastle disease virus (NDV) is a threat to the global poultry industry; however, the mechanisms of NDV infection remain unclear. NDV affects the phosphatidyl-inositol 3-kinase/serine-threonine kinase (PI3K/ AKT) signaling pathway, requiring endocytosis for successful infection. Based on previous studies, we identified a close correlation between NDV infection and replication and the PI3K/AKT signaling pathway activity. This study examined the molecular mechanisms through which NDV activates the PI3K/AKT signaling pathway to regulate endocytosis and facilitate infection. This study showed that early-stage in vitro NDV infection activated the PI3K/AKT signaling pathway, enhancing clathrin-mediated endocytosis, crucial for infection onset. Notably, this process involves the interaction between NDV F protein and the vascular endothelial growth factor receptor 2 tyrosine kinase, leading to the subsequent binding and phosphorylation of the PI3K p85α regulatory subunit. This activation primes PI3K, initiating a cascade that promotes clathrin-mediated endocytosis. Our findings elucidate how NDV capitalizes on the PI3K/AKT signaling pathway to establish infection through endocytosis.

Climatic and biotic factors influencing regional declines and recovery of tropical forest biomass from the 2015/16 El Niño.

The 2015/16 El Niño brought severe drought and record-breaking temperatures in the tropics. Here, using satellite-based L-band microwave vegetation optical depth, we mapped changes of above-ground biomass (AGB) during the drought and in subsequent years up to 2019. Over more than 60% of drought-affected intact forests, AGB reduced during the drought, except in the wettest part of the central Amazon, where it declined 1 y later. By the end of 2019, only 40% of AGB reduced intact forests had fully recovered to the predrought level. Using random-forest models, we found that the magnitude of AGB losses during the drought was mainly associated with regionally distinct patterns of soil water deficits and soil clay content. For the AGB recovery, we found strong influences of AGB losses during the drought and of [Formula: see text]. [Formula: see text] is a parameter related to canopy structure and is defined as the ratio of two relative height (RH) metrics of Geoscience Laser Altimeter System (GLAS) waveform data-RH25 (25% energy return height) and RH100 (100% energy return height; i.e., top canopy height). A high [Formula: see text] may reflect forests with a tall understory, thick and closed canopy, and/or without degradation. Such forests with a high [Formula: see text] ([Formula: see text] ≥ 0.3) appear to have a stronger capacity to recover than low-[Formula: see text] ones. Our results highlight the importance of forest structure when predicting the consequences of future drought stress in the tropics.

Thrombocytopenia in SFTS due to platelets with altered function undergoing cell death pathways.

BACKGROUND: Thrombocytopenia is the major clinical feature associated with the severity of SFTS, but the mechanism by which it occurs remains unclear. METHODS: RNA transcriptome analyses were performed on platelets purified from SFTS patients and SFTSV-infected mice. The functions of differentially expressed genes (DEGs) in the platelets were characterized. ELISA, flow cytometry, and qRT-PCR were used to measure the levels of platelet activation, SFTSV infection in platelets, formation of neutrophil extracellular traps (NETs), transcription of DEGs and percent of platelets undergoing cell death. RESULTS: Enhanced neutrophil activation and interferon (IFN) signaling involved in the viral life cycle were common platelet responses in SFTS, which may consume increasing numbers of platelets. Other functional changes may be associated with different outcomes of SFTS. SFTSV infection led to platelet destruction by pyroptosis, apoptosis, necroptosis, and autophagy. In contrast to SFTS patients, platelets in SFTSV-infected mice mainly play a role in adaptive immunity, and platelet death was not as severe as in humans. CONCLUSIONS: The altered functions of platelets, such as mediating leukocyte activation and undergoing cell death, contribute to thrombocytopenia in SFTS patients. The different mechanisms of thrombocytopenia in mice, suggest that platelet functions should be considered in experimental animal models.

Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial.

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Omicron breakthrough infections after triple-dose inactivated COVID-19 vaccination: A comprehensive analysis of antibody and T-cell responses.

This study longitudinally evaluated the immune response in individuals over a year after receiving three doses of an inactivated SARS-CoV-2 vaccine, focusing on reactions to Omicron breakthrough infections. From 63 blood samples of 37 subjects, results showed that the third booster enhanced the antibody response against Alpha, Beta, and Delta VOCs but was less effective against Omicron. Although antibody titres decreased post-vaccination, SARS-CoV-2-specific T-cell responses, both CD4+ and CD8+, remained stable. Omicron breakthrough infections significantly improved neutralization against various VOCs, including Omicron. However, the boost in antibodies against WT, Alpha, Beta, and Delta variants was more pronounced. Regarding T cells, breakthrough infection predominantly boosted the CD8+ T-cell response, and the intensity of the spike protein-specific T-cell response was roughly comparable between WT and Omicron BA.5.

The Association Between Elevated Myocardial Injury-Related Biomarker (TnI) and Increased Mortality in Patients With Severe Fever With Thrombocytopenia Syndrome.

OBJECTIVES: The objective of this study was to investigate the dynamic profiles of myocardial injury biomarkers and their association with mortality in patients with severe fever with thrombocytopenia syndrome (SFTS). DESIGN: A retrospective cohort study. SETTINGS: Union Hospital in Wuhan, China. PATIENTS: A total of 580 patients with SFTS, observed between May 2014 and December 2021, were included in the final analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 580 patients with SFTS were enrolled in the study, comprised of 469 survivors and 111 nonsurvivors, with a 21-day fatality rate of 19.1%. The elevation of troponin I (TnI) was observed in 61.6% patients (357/580) with SFTS upon admission, and 68.4% patients (397/580) developed an abnormal TnI level during hospitalization. Multivariate logistic regression identified age, viral load, platelet count, creatinine level, and TnI level as potential risk factors for mortality in patients with SFTS. The results of restricted cubic splines revealed that when the TnI level (baseline TnI: 1.55 [lg (ng/L+1)], peak value: TnI 1.90 [lg (ng/L+1)]) exceeded a certain threshold, the predicted mortality of patients with SFTS increased alongside the rise in TnI levels. Mortality rate surpassed 40% among patients with SFTS with TnI greater than or equal to 10 times the upper limit of normal at admission (43.8%) or during hospitalization (41.7%). Older age, a history of cardiovascular disease, and higher d -dimer levels were potential risk factors for elevated TnI levels in patients with SFTS. CONCLUSIONS: Elevated TnI levels were prevalent among patients with SFTS and were strongly associated with an increased risk of mortality.

Exosomal miR-361-3p promotes the viability of breast cancer cells by targeting ETV7 and BATF2 to upregulate the PAI-1/ERK pathway.

BACKGROUND: Malignant progression is the major cause of poor prognosis in breast cancer (BC) patients. Plasma exosomal miRNAs have been reported to be involved in tumor progression, but their roles in BC remain unclear. METHODS: We performed plasma exosomal miRNA sequencing on 45 individuals, including healthy controls and nonmetastatic and metastatic BC patients. We examined the correlation between miRNA expression in tumor tissues and plasma exosomes in BC patients by qRT‒PCR. The effects of exosomal miR-361-3p on BC cells were determined by CellTiter-Glo, migration and wound healing assays. The target genes of miR-361-3p and downstream pathways were explored by dual-luciferase reporter assay, RNA knockdown, rescue experiments, and western blotting. We utilized murine xenograft model to further assess the impact of plasma exosomal miR-361-3p on the malignant progression of BC. RESULTS: We found that the expression level of plasma exosomal miR-361-3p gradually increased with malignant progression in BC patients, and the expression of miR-361-3p in plasma exosomes and BC tissues was positively correlated. Consistently, exosomal miR-361-3p enhanced the migration and proliferation of two BC cell lines, MDA-MB-231 and SK-BR-3. Furthermore, our data showed that miR-361-3p inhibited two novel target genes, ETV7 and BATF2, to activate the PAI-1/ERK pathway, leading to increased BC cell viability. Finally, the consistency of the in vivo experimental results supported that elevated plasma exosomal miR-361-3p promote the malignant progression of BC. CONCLUSIONS: We found for the first time that plasma exosomal miR-361-3p was associated with malignant progression in BC patients. Mechanistically, exosomal miR-361-3p can enhance the migration and proliferation of BC cells by targeting the ETV7 and BATF2/PAI-1/ERK pathways. Our data suggest that plasma exosomal miR-361-3p has the potential to serve as a biomarker for predicting malignant progression in BC patients.

Construction of a tumor mutational burden-derived LncRNA prognostic computational framework associated with therapy sensitivity in skin cutaneous melanoma.

BACKGROUND: Skin cutaneous melanoma (SKCM) poses a significant public health challenge due to its aggressive nature and limited treatment options. To address this, the study introduces the Tumor Mutational Burden-Derived Immune lncRNA Prognostic Index (TILPI) as a potential prognostic tool for SKCM. METHODS: TILPI was developed using a combination of gene set variation analysis, differential expression analysis, and COX regression analysis. Additionally, functional experiments were conducted to validate the findings, focusing on the effects of STARD4-AS1 knockdown on SKCM tumor cell behavior. These experiments encompassed assessments of tumor cell proliferation, gene and protein expression, migration, invasion, and in vivo tumor growth. RESULTS: The results demonstrated that knockdown of STARD4-AS1 led to a significant reduction in tumor cell proliferation and impaired migration and invasion abilities. Moreover, it resulted in the downregulation of ADCY4, PRKACA, and SOX10 gene expression, as well as decreased protein expression of ADCY4, PRKACA, and SOX10. In vivo experiments further confirmed the efficacy of STARD4-AS1 knockdown in reducing tumor growth. CONCLUSIONS: This study elucidates the mechanistic role of STARD4-AS1 and its downstream targets in SKCM progression, highlighting the importance of the ADCY4/PRKACA/SOX10 pathway. The integration of computational analysis with experimental validation enhances the understanding of TILPI and its clinical implications. Overall, the findings underscore the potential of novel computational frameworks like TILPI in predicting and managing SKCM, particularly through targeting the ADCY4/PRKACA/SOX10 pathway.

Research on the tilt-to-length coupling noise suppression method inside the gravitational wave detection telescope.

As an integral component of the laser interferometry measurement system, the tilt-to-length (TTL) coupling noise inside the telescope stands out as a critical noise factor that requires meticulous consideration. In the TianQin project, the non-geometric TTL-coupled noise inside the telescope should be less than 0.22 pm/Hz1/2. Additionally, the wavefront aberration RMS at the small pupil of the telescope needs to be better than 0.0065 λ. These requirements set for the telescope are exceptionally stringent. To address this challenge, this study aims to relax the wavefront aberration requirements by mitigating non-geometric TTL coupling noise, while ensuring the non-geometric TTL coupling noise remains below 0.22 pm/Hz1/2. By controlling the coupling aberration proportion, the wavefront aberration RMS at the small pupil of the telescope can be relaxed to 0.014 λ. Alternatively, optimizing the Gaussian beam waist radius can relax the wavefront aberration RMS to 0.016 λ. By simultaneously utilizing two optimization methods, the wavefront aberration at the small pupil of the telescope can be reduced to 0.033 λ, resulting in an impressive success rate of 91.15% in meeting the noise requirements.

A leaf age-dependent light use efficiency model for remote sensing the gross primary productivity seasonality over pantropical evergreen broadleaved forests.

Tropical and subtropical evergreen broadleaved forests (TEFs) contribute more than one-third of terrestrial gross primary productivity (GPP). However, the continental-scale leaf phenology-photosynthesis nexus over TEFs is still poorly understood to date. This knowledge gap hinders most light use efficiency (LUE) models from accurately simulating the GPP seasonality in TEFs. Leaf age is the crucial plant trait to link the dynamics of leaf phenology with GPP seasonality. Thus, here we incorporated the seasonal leaf area index of different leaf age cohorts into a widely used LUE model (i.e., EC-LUE) and proposed a novel leaf age-dependent LUE model (denoted as LA-LUE model). At the site level, the LA-LUE model (average R2 = .59, average root-mean-square error [RMSE] = 1.23 gC m-2 day-1) performs better than the EC-LUE model in simulating the GPP seasonality across the nine TEFs sites (average R2 = .18; average RMSE = 1.87 gC m-2 day-1). At the continental scale, the monthly GPP estimates from the LA-LUE model are consistent with FLUXCOM GPP data (R2 = .80; average RMSE = 1.74 gC m-2 day-1), and satellite-based GPP data retrieved from the global Orbiting Carbon Observatory-2 (OCO-2) based solar-induced chlorophyll fluorescence (SIF) product (GOSIF) (R2 = .64; average RMSE = 1.90 gC m-2 day-1) and the reconstructed TROPOspheric Monitoring Instrument SIF dataset using machine learning algorithms (RTSIF) (R2 = .78; average RMSE = 1.88 gC m-2 day-1). Typically, the estimated monthly GPP not only successfully represents the unimodal GPP seasonality near the Tropics of Cancer and Capricorn, but also captures well the bimodal GPP seasonality near the Equator. Overall, this study for the first time integrates the leaf age information into the satellite-based LUE model and provides a feasible implementation for mapping the continental-scale GPP seasonality over the entire TEFs.

Dominant role of the non-forest woody vegetation in the post 2015/16 El Niño tropical carbon recovery.

The extreme dry and hot 2015/16 El Niño episode caused large losses in tropical live aboveground carbon (AGC) stocks. Followed by climatic conditions conducive to high vegetation productivity since 2016, tropical AGC are expected to recover from large losses during the El Niño episode; however, the recovery rate and its spatial distribution remain unknown. Here, we used low-frequency microwave satellite data to track AGC changes, and showed that tropical AGC stocks returned to pre-El Niño levels by the end of 2020, resulting in an AGC sink of 0.18 0.14 0.26 $$ {0.18}_{0.14}^{0.26} $$ Pg C year-1 during 2014-2020. This sink was dominated by strong AGC increases ( 0.61 0.49 0.84 $$ {0.61}_{0.49}^{0.84} $$ Pg C year-1) in non-forest woody vegetation during 2016-2020, compensating the forest AGC losses attributed to the El Niño event, forest loss, and degradation. Our findings highlight that non-forest woody vegetation is an increasingly important contributor to interannual to decadal variability in the global carbon cycle.

Refractory pure red cell aplasia associated with T-cell large granular lymphocyte leukemia treated by ruxolitinib.

Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by normocytic normochromic anemia with severe reticulocytopenia and absence of erythroid precursors in the bone marrow. For refractory PRCA patients, the low response rate and high toxicity of alternative therapies pose a great challenge. T-cell large granular lymphocyte (T-LGL) leukemia is one of the most common conditions in secondary PRCA and also the most difficult form to manage with an inferior treatment response to other secondary PRCA forms. T-LGL leukemia exhibits sustained activation of the intracellular JAK-STAT signaling pathway. We herein report a case of PRCA associated with T-LGL leukemia that had been refractory to multiple lines of therapies and was successfully treated by ruxolitinib. The patient achieved complete remission and tolerated ruxolitinib well without occurrence of neutropenia or thrombocytopenia. This preliminary finding favors ruxolitinib as a potential salvage therapy for refractory PRCA associated with T-LGL leukemia.

Venetoclax plus dose-adjusted R-EPOCH (VR-DA-EPOCH) or G-EPOCH bridging to subsequent cellular therapy for the patients with transformed lymphoma a single center clinical experience.

Indolent lymphoma, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL), can undergo histological transformation into an aggressive subtype, typically diffuse large B-cell lymphoma (DLBCL). The prognosis of transformed lymphoma is poor. In this study, we reported the efficacy and toxicity of a combination of venetoclax, dose-adjusted rituximab or obinutuzumab, etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide (VR-DA-EPOCH or VG-DA-EPOCH) in 11 patients with biopsy-proven histology transformation into DLBCL, including 8 patients with RT and 3 with transformed FL (tFL). The study was conducted between October 2019 and March 2023 at our single center. The median age of participants at enrolment was 53 years. Six patients (85.7%, 6/7) achieved complete remission (CR) at the end of treatment. The best overall response rate (ORR) and CR rate were both 72.7%, respectively. Two patients received autologous hemopoietic stem cell transplant (ASCT) while two patients received ASCT concurrently with CAR-T therapy for consolidation. With a median follow-up of 13.5 (range, 2.4-29.8) months after enrollment, the median event-free survival, progression-free survival, and overall survival were 9.4, 11.5, and 17.5 months, respectively. Hematologic toxicities of grade ≥3 consisted of neutropenia (90.9%, 10/11), thrombocytopenia (63.6%, 7/11), and febrile neutropenia (54.5%, 6/11). In conclusion, VR-DA-EPOCH or VG-DA-EPOCH was a promising strategy to achieve an early remission, bridging to cellular therapy within this population.

Base-Promoted Nucleophilic Phosphorylation of Benzyl Fluorides via C(sp3)-F Cleavage.

Herein, a transition-metal-free phosphorylation of benzyl fluorides with P(O)-H compounds is disclosed. In the presence of tBuOK, various benzyl fluorides react with P(O)-H compounds to produce the corresponding benzyl phosphine oxides, phosphinates, and phosphonates in good to high yields. This base-promoted phosphorylation reaction offers a facile and general strategy for the construction of a C(sp3)-P bond.

Elongin B promotes breast cancer progression by ubiquitinating tumor suppressor p14/ARF.

Elongin B (ELOB), a pivotal element in the ELOB/c-Cullin2/5-SOCS-box E3 ubiquitin-protein ligase complex, plays a significant role in catalyzing the ubiquitination and subsequent degradation of a broad spectrum of target proteins. Notably, it is documented to facilitate these processes. However, the regulatory role of ELOB in breast cancer remains ambiguous. In this study, through bio-informatic analysis of The Cancer Genome Atlas and Fudan University Shanghai Cancer Center database, we demonstrated that ELOB was over-expressed in breast cancer tissues and was related to unfavorable prognosis. Additionally, pathway enrichment analysis illustrated that high expression of ELOB was associated with multiple cancer promoting pathways, like cell cycle, DNA replication, proteasome and PI3K - Akt signaling pathway, indicating ELOB as a potential anticancer target. Then, we confirmed that both in vivo and in vitro, the proliferation of breast cancer cells could be significantly suppressed by the down-regulation of ELOB. Mechanically, immunoprecipitation and in vivo ubiquitination assays prompted that, as the core element of Cullin2-RBX1-ELOB E3 ligase (CRL2) complex, ELOB regulated the ubiquitination and the subsequent degradation of oncoprotein p14/ARF. Moreover, the anticancer efficacy of erasing ELOB could be rescued by simultaneous knockdown of p14/ARF. Finally, through analyzing breast cancer tissue microarrays and western blot of patient samples, we demonstrated that the expression of ELOB in tumor tissues was elevated in compared to adjacent normal tissues. In conclusion, ELOB is identified to be a promising innovative target for the drug development of breast cancer by promoting the ubiquitination and degradation of oncoprotein p14/ARF.

The difference of addictive behavior of freebase nicotine and nicotine salts in mice base on an aerosol self-administration model.

INTRODUCTION: The distinctions in the biological impacts of distinct forms of nicotine have become a prominent subject of current research. However, relatively little research has been done on the addictive effects of different forms of nicotine. METHODS: The aerosol self-administration device was briefly characterized by determining aerosol concentration, particle size, and distributional diffusion of the aerosol. And the aerosol self-administration model was constructed at 1, 5, and 10 mg/mL of nicotine to select the appropriate nicotine concentration. Subsequently, the model was used to explore the differences in aerosol self-administration behavior of freebase nicotine and nicotine salts and the behavioral differences after withdrawal. RESULTS: We successfully constructed mouse aerosol self-administration models at 1, 5, and 10 mg/mL nicotine concentrations. In the study of the difference in addictive behaviors between freebase nicotine and nicotine salts, mice with freebase nicotine and different nicotine salts showed varying degrees of drug-seeking behavior, with nicotine benzoate showing the strongest reinforcement. During the withdrawal phase, nicotine salts mice showed more robust anxiety-like behaviors. CONCLUSIONS: These results confirm the successful development and stability of the nicotine aerosol self-administration model. Furthermore, they demonstrated that nicotine salts enhance drug-seeking behavior to a greater extent than freebase nicotine, with nicotine benzoate exhibiting the most significant effects. IMPLICATIONS: In this study, an aerosol self-administered model of mice was constructed, which can be used not only for comparing the effects of freebase nicotine and nicotine salts on the behavior, but also for other addictive drugs, such as fentanyl and cannabis. In addition, this study shows that nicotine salts may be more addictive compared to freebase nicotine, which is a reference for the future use of nicotine salts in tobacco products such as e-cigarettes.

Injectable ultrasound-powered bone-adhesive nanocomposite hydrogel for electrically accelerated irregular bone defect healing.

The treatment of critical-size bone defects with irregular shapes remains a major challenge in the field of orthopedics. Bone implants with adaptability to complex morphological bone defects, bone-adhesive properties, and potent osteogenic capacity are necessary. Here, a shape-adaptive, highly bone-adhesive, and ultrasound-powered injectable nanocomposite hydrogel is developed via dynamic covalent crosslinking of amine-modified piezoelectric nanoparticles and biopolymer hydrogel networks for electrically accelerated bone healing. Depending on the inorganic-organic interaction between the amino-modified piezoelectric nanoparticles and the bio-adhesive hydrogel network, the bone adhesive strength of the prepared hydrogel exhibited an approximately 3-fold increase. In response to ultrasound radiation, the nanocomposite hydrogel could generate a controllable electrical output (-41.16 to 61.82 mV) to enhance the osteogenic effect in vitro and in vivo significantly. Rat critical-size calvarial defect repair validates accelerated bone healing. In addition, bioinformatics analysis reveals that the ultrasound-responsive nanocomposite hydrogel enhanced the osteogenic differentiation of bone mesenchymal stem cells by increasing calcium ion influx and up-regulating the PI3K/AKT and MEK/ERK signaling pathways. Overall, the present work reveals a novel wireless ultrasound-powered bone-adhesive nanocomposite hydrogel that broadens the therapeutic horizons for irregular bone defects.

M2 microglia-derived exosome-loaded electroconductive hydrogel for enhancing neurological recovery after spinal cord injury.

Electroconductive hydrogels offer a promising avenue for enhancing the repair efficacy of spinal cord injuries (SCI) by restoring disrupted electrical signals along the spinal cord's conduction pathway. Nonetheless, the application of hydrogels composed of diverse electroconductive materials has demonstrated limited capacity to mitigate the post-SCI inflammatory response. Recent research has indicated that the transplantation of M2 microglia effectively fosters SCI recovery by attenuating the excessive inflammatory response. Exosomes (Exos), small vesicles discharged by cells carrying similar biological functions to their originating cells, present a compelling alternative to cellular transplantation. This investigation endeavors to exploit M2 microglia-derived exosomes (M2-Exos) successfully isolated and reversibly bonded to electroconductive hydrogels through hydrogen bonding for synergistic promotion of SCI repair to synergistically enhance SCI repair. In vitro experiments substantiated the significant capacity of M2-Exos-laden electroconductive hydrogels to stimulate the growth of neural stem cells and axons in the dorsal root ganglion and modulate microglial M2 polarization. Furthermore, M2-Exos demonstrated a remarkable ability to mitigate the initial inflammatory reaction within the injury site. When combined with the electroconductive hydrogel, M2-Exos worked synergistically to expedite neuronal and axonal regeneration, substantially enhancing the functional recovery of rats afflicted with SCI. These findings underscore the potential of M2-Exos as a valuable reparative factor, amplifying the efficacy of electroconductive hydrogels in their capacity to foster SCI rehabilitation.

Optimized design of a gravitational wave telescope system based on pupil aberration.

The telescope is vital for accurate gravitational wave detection in the TianQin project. It must meet criteria like a geometric tilt-to-length (TTL) coupling noise c o e f f i c i e n t≤0.02√2n m/µr a d and wavefront R M S≤λ/30. Analyzing the pupil aberration's impact on geometric TTL noise, we devised an optimization method using the chief ray spot diagram's standard deviation. Implementing this in Zemax with a ZPL macro, we designed an optical system meeting TianQin's requirements. The system has a maximum geometric TTL noise coefficient of 0.0250 nm/µrad over the science FOV and a wavefront RMS of 0.0111λ, confirming the method's feasibility.