Room-temperature magnetoresistance in an all-antiferromagnetic tunnel junction.

Antiferromagnetic spintronics1-16 is a rapidly growing field in condensed-matter physics and information technology with potential applications for high-density and ultrafast information devices. However, the practical application of these devices has been largely limited by small electrical outputs at room temperature. Here we describe a room-temperature exchange-bias effect between a collinear antiferromagnet, MnPt, and a non-collinear antiferromagnet, Mn3Pt, which together are similar to a ferromagnet-antiferromagnet exchange-bias system. We use this exotic effect to build all-antiferromagnetic tunnel junctions with large nonvolatile room-temperature magnetoresistance values that reach a maximum of about 100%. Atomistic spin dynamics simulations reveal that uncompensated localized spins at the interface of MnPt produce the exchange bias. First-principles calculations indicate that the remarkable tunnelling magnetoresistance originates from the spin polarization of Mn3Pt in the momentum space. All-antiferromagnetic tunnel junction devices, with nearly vanishing stray fields and strongly enhanced spin dynamics up to the terahertz level, could be important for next-generation highly integrated and ultrafast memory devices7,9,16.

Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma.

Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as "nuclear activating miRNAs" for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRT‒PCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs.

A conserved mechanism affecting hydride shifting and deprotonation in the synthesis of hopane triterpenes as compositions of wax in oat.

Triterpenoids are biologically active metabolites synthesized from a common linear precursor catalyzed by 2,3-oxidosqualene cyclases (OSCs) to form diverse triterpenoid skeletons. OSCs corresponding to many discovered triterpene alcohols in nature have not been functionally and mechanistically characterized due to the diversity of chemical structures and complexity of the cyclization mechanism. We carried out a genome-wide investigation of OSCs from Avena strigosa and discovered two triterpene synthases, namely, AsHS1 and AsHS2, using a Nicotiana benthamiana expression system. These synthases produce hopenol B and hop-17(21)-en-3ß-ol, which are components of surface wax in oat panicles and sheathes, respectively. We demonstrated that substitutions of two to three amino acid residues in AsHS1 with corresponding residues from AsHS2 allowed it to be completely converted into a hop-17(21)-en-3ß-ol synthase. AsHS2 mutants with a substitution at site 410 could synthesize hopenol B alone or mixed with a side product isomotiol. The combined quantum mechanics and molecular mechanics calculation demonstrated that the side chain size of the residue at site 410 regulated the relative orientations between the hopyl C22 cation and Phe257, leading to a difference in deprotonation positions through providing or not providing cation­π interaction between the aromatic ring of F257 and the carbocation intermediate. A similar mechanism could be applied to a hopenol B synthase from a dicotyledonous plant Aquilegia. This study provided mechanistic insight into triterpenoid synthesis and discovered key amino acid residues acting on hydride transfer and a deprotonation site to differentiate between hopane-type scaffolds in diverse plant species.

Magnetic-Field Response and Giant Electric-Field Modulation of Cu2S.

Cu2S likely plays an important role in the sharp resistivity transition of LK-99. Nevertheless, this immediately arouses an intriguing question of whether the extraordinary room-temperature colossal magnetoresistance in the initial reports, which has been less focused, originates from Cu2S as well. To resolve this issue, we have systematically investigated the electrical transport and magnetotransport properties of near-stoichiometric Cu2S pellets and thin films. Neither Cu2S nor LK-99 containing Cu2S in this study was found to exhibit the remarkable magnetoresistance effect implied by Lee et al. This implies that Cu2S could not account for all of the intriguing transport properties of the initially reported LK-99, and the initially reported LK-99 samples might contain magnetic impurities. Moreover, based on the crystal-structure-sensitive electrical properties of Cu2S, we have constructed a piezoelectric-strain-controlled device and obtained a giant and reversible resistance modulation of 2 orders of magnitude at room temperature, yielding a huge gauge factor of 160,000.

Diverse triterpene skeletons are derived from the expansion and divergent evolution of 2,3-oxidosqualene cyclases in plants.

Triterpenoids are one of the largest groups of secondary metabolites and exhibit diverse structures, which are derived from C30 skeletons that are biosynthesized via the isoprenoid pathway by cyclization of 2,3-oxidosqualene. Triterpenoids have a wide range of biological activities, and are used in functional foods, drugs, and as industrial materials. Due to the low content levels in their native plants and limited feasibility and efficiency of chemical synthesis, heterologous biosynthesis of triterpenoids is the most promising strategy. Herein, we classified 121 triterpene alcohols/ketones according to their conformation and ring numbers, among which 51 skeletons have been experimentally characterized as the products of oxidosqualene cyclases (OSCs). Interestingly, 24 skeletons that have not been reported from nature source were generated by OSCs in heterologous expression. Comprehensive evolutionary analysis of the identified 152 OSCs from 75 species in 25 plant orders show that several pentacyclic triterpene synthases repeatedly originated in multiple plant lineages. Comparative analysis of OSC catalytic reaction revealed that stabilization of intermediate cations, steric hindrance, and conformation of active center amino acid residues are primary factors affecting triterpene formation. Optimization of OSC could be achieved by changing of side-chain orientations of key residues. Recently, methods, such as rationally design of pathways, regulation of metabolic flow, compartmentalization engineering, etc., were introduced in improving chassis for the biosynthesis of triterpenoids. We expect that extensive study of natural variation of large number of OSCs and catalytical mechanism will provide basis for production of high level of triterpenoids by application of synthetic biology strategies.

Altered epitopes enhance macrophage-mediated anti-tumour immunity to low-immunogenic tumour mutations.

Personalized neoantigen therapy has shown long-term and stable efficacy in specific patient populations. However, not all patients have sufficient levels of neoantigens for treatment. Although somatic mutations are commonly found in tumours, a significant portion of these mutations do not trigger an immune response. Patients with low mutation burdens continue to exhibit unresponsiveness to this treatment. We propose a design paradigm for neoantigen vaccines by utilizing the highly immunogenic unnatural amino acid p-nitrophenylalanine (pNO2Phe) for sequence alteration of somatic mutations that failed to generate neoepitopes. This enhances the immunogenicity of the mutations and transforms it into a suitable candidate for immunotherapy. The nitrated altered epitope vaccines designed according to this paradigm is capable of activating circulating CD8+ T cells and inducing immune cross-reactivity against autologous mutated epitopes in different MHC backgrounds (H-2Kb, H-2Kd, and human HLA-A02:01), leading to the elimination of tumour cells carrying the mutation. After immunization with the altered epitopes, tumour growth was significantly inhibited. It is noteworthy that nitrated epitopes induce tumour-infiltrating macrophages to differentiate into the M1 phenotype, surprisingly enhancing the MHC II molecule presenting pathway of macrophages. Nitrated epitope-treated macrophages have the potential to cross-activate CD4+ and CD8+ T cells, which may explain why pNO2Phe can enhance the immunogenicity of epitopes. Meanwhile, the immunosuppressive microenvironment of the tumour is altered due to the activation of macrophages. The nitrated neoantigen vaccine strategy enables the design of vaccines targeting non-immunogenic tumour mutations, expanding the pool of potential peptides for personalized and shared novel antigen therapy. This approach provides treatment opportunities for patients previously ineligible for new antigen vaccine therapy.

A soybean bZIP transcription factor is involved in submergence resistance.

Although the functions of basic leucine zipper (bZIP) family transcription factors in the regulation of various abiotic stresses are beginning to be unveiled, the precise roles of bZIP proteins in plants coping with submergence stress remain unclear. Here we identified a bZIP gene GmbZIP71-4 from soybean, which localized in the nucleus. The GmbZIP71-4 over-expressed tabocco line showed reduced submergence resistance due to the decreased abscisic acid (ABA) content. GO and KEGG pathway analysis based on chromatin immunoprecipitation assay sequencing (ChIP-seq) indicated that the differences expressed genes between submergence treatment and control groups were specially enriched in plant hormone signal transduction items, especially those in response to ABA. Electrophoretic mobility shift assays (EMSA) demonstrated that GmbZIP71-4 bound to the promoter of GmABF2 gene, which is consistent with the ChIP-qPCR results. GmbZIP71-4 function as a negative regulator of soybean in responding to submergence stress through manipulating ABA signaling pathway. This findings will set a solid foundation for the understanding of submergence resistance in plants.

Deep Cracking of Bulky Hydrocarbons into Light Products via Tandem Catalysis over Uniform Interconnected ZSM-5@AlSBA-15 Composites.

Deep cracking of bulky hydrocarbons on zeolite-containing catalysts into light products with high activity, desired selectivity, and long-term stability is demanded but challenging. Herein, the efficient deep cracking of 1,3,5-triisopropylbenzene (TIPB) on intimate ZSM-5@AlSBA-15 composites via tandem catalysis is demonstrated. The rapid aerosol-confined assembly enables the synthesis of the composites composed of a continuous AlSBA-15 matrix decorated with isolated ZSM-5 nanoparticles. The two components at various ZSM-5/AlSBA-15 mass ratios are uniformly mixed with chemically bonded pore walls, interconnected pores, and eliminated external surfaces of nanosized ZSM-5. The typical composite with a ZSM-5/AlSBA-15 mass ratio of 0.25 shows superior performance in TIPB cracking with outstanding activity (≈100% conversion) and deep cracking selectivity (mass of propylene + benzene > 60%) maintained for a long time (> 6 h) under a high TIPB flux (2 mL h-1), far better (several to tens of times higher) than the single-component and physically mixed catalysts and superior to literature results. The high performance is attributed to the cooperative tandem catalytic process, that is, selective and timely pre-cracking of TIPB to isopropylbenzene (IPB) in AlSBA-15 and subsequently timely diffusion and deep cracking of IPB in nanosized ZSM-5.

Upland rice genomic signatures of adaptation to drought resistance and navigation to molecular design breeding.

Upland rice is a distinctive drought-aerobic ecotype of cultivated rice highly resistant to drought stress. However, the genetic and genomic basis for the drought-aerobic adaptation of upland rice remains largely unclear due to the lack of genomic resources. In this study, we identified 25 typical upland rice accessions and assembled a high-quality genome of one of the typical upland rice varieties, IRAT109, comprising 384 Mb with a contig N50 of 19.6 Mb. Phylogenetic analysis revealed upland and lowland rice have distinct ecotype differentiation within the japonica subgroup. Comparative genomic analyses revealed that adaptive differentiation of lowland and upland rice is likely attributable to the natural variation of many genes in promoter regions, formation of specific genes in upland rice, and expansion of gene families. We revealed differentiated gene expression patterns in the leaves and roots of the two ecotypes and found that lignin synthesis mediated by the phenylpropane pathway plays an important role in the adaptive differentiation of upland and lowland rice. We identified 28 selective sweeps that occurred during domestication and validated that the qRT9 gene in selective regions can positively regulate drought resistance in rice. Eighty key genes closely associated with drought resistance were appraised for their appreciable potential in drought resistance breeding. Our study enhances the understanding of the adaptation of upland rice and provides a genome navigation map of drought resistance breeding, which will facilitate the breeding of drought-resistant rice and the "blue revolution" in agriculture.

Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor.

BACKGROUND: BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. METHODS: Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. RESULTS: DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. CONCLUSIONS: The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. TRIAL REGISTRATION: NCT02674152 and NCT02689505.

Functional diversity of oxidosqualene cyclases in genus Oryza.

Triterpene skeletons, catalyzing by 2,3-oxidosqualene cyclases (OSCs), are essential for synthesis of steroids and triterpenoids. In japonica rice cultivars Zhonghua11, a total of 12 OsOSCs have been found. While the catalytic functions of OsOSC1, 3, 4, 9, and 10 remain unclear, the functions of the other OsOSCs have been well studied. In this study, we conducted a comprehensive analysis of 12 OSC genes within genus Oryza with the aid of 63 genomes from cultivated and wild rice. We found that OSC genes are relatively conserved within genus Oryza with a few exceptions. Collinearity analysis further suggested that, throughout the evolutionary history of genus Oryza, the OSC genes have not undergone significant rearrangements or losses. Further functional analysis of 5 uncharacterized OSCs revealed that OsOSC10 was a friedelin synthase, which affected the development of rice grains. Additionally, the reconstructed ancestral sequences of Oryza OSC3 and Oryza OSC9 had lupeol synthase and poaceatapetol synthase activity, respectively. The discovery of friedelin synthase in rice unlocks a new catalytic path and biological function of OsOSC10. The pan-genome analysis of OSCs within genus Oryza gives insights into the evolutionary trajectory and products diversity of Oryza OSCs.

Systemic immune inflammation index with all-cause and cause-specific mortality: a meta-analysis.

IMPORTANCE: Studies have reported an association among systemic immune inflammation index (SII), all-cause and cause-specific mortality, but the results are inconsistent. OBJECTIVE: To comprehensively explore the association between Systemic Immune Inflammation (SII) and the risk of all-cause mortality, cardiovascular disease (CVD), and cancer mortality. EVIDENCE REVIEW: A meta-analysis was conducted by reviewing existing literature. The search encompassed prominent databases including PubMed, Embase, Cochrane, and the Web of Science, with the cutoff date set at March 1, 2024. Furthermore, subgroup analyses and dose-response assessments were undertaken to provide a nuanced exploration of mortality risk factors. FINDINGS: A total of 33 articles were included (427,819 participants). In the study, SII was associated with an increased risk of all-cause mortality (HR = 1.45, 95%CI [1.36,1.54], P < 0.05). SII increased the risk of CVD mortality (HR = 1.44, 95%CI [1.29,1.60], P < 0.05). The Linear independence shows that for every 100 units increase in SII, the risk of all-cause and CVD death increases by 5% and 6%. SII was not associated with a statistically significant risk of cancer death (HR = 1.09, 95%CI [0.96,1.23], P < 0.05). CONCLUSIONS AND RELEVANCE: Meta-analysis showed that SII was associated with all-cause mortality and CVD mortality. More data and basic research are needed to confirm the association.

A regimen based on the combination of trimethoprim/sulfamethoxazole with caspofungin and corticosteroids as a first-line therapy for patients with severe non-HIV-related pneumocystis jirovecii pneumonia: a retrospective study in a tertiary hospital.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening and severe disease in immunocompromised hosts. A synergistic regimen based on the combination of sulfamethoxazole-trimethoprim (SMX-TMP) with caspofungin and glucocorticosteroids (GCSs) may be a potential first-line therapy for PJP. Therefore, it is important to explore the efficacy and safety of this synergistic therapy for treating non-HIV-related PJP patients. METHODS: We retrospectively analysed the data of 38 patients with non-HIV-related PJP at the First Affiliated Hospital of Xi'an Jiaotong University. Patients were divided into two groups: the synergistic therapy group (ST group, n = 20) and the monotherapy group (MT group, n = 18). All patients were from the ICU and were diagnosed with severe PJP. In the ST group, all patients were treated with SMX-TMP (TMP 15-20 mg/kg per day) combined with caspofungin (70 mg as the loading dose and 50 mg/day as the maintenance dose) and a GCS (methylprednisolone 40-80 mg/day). Patients in the MT group were treated only with SMX-TMP (TMP 15-20 mg/kg per day). The clinical response, adverse events and mortality were compared between the two groups. RESULTS: The percentage of patients with a positive clinical response in the ST group was significantly greater than that in the MT group (100.00% vs. 66.70%, P = 0.005). The incidence of adverse events in the MT group was greater than that in the ST group (50.00% vs. 15.00%, P = 0.022). Furthermore, the dose of TMP and duration of fever in the ST group were markedly lower than those in the MT group (15.71 mg/kg/day vs. 18.35 mg/kg/day (P = 0.001) and 7.00 days vs. 11.50 days (P = 0.029), respectively). However, there were no significant differences in all-cause mortality or duration of hospital stay between the MT group and the ST group. CONCLUSIONS: Compared with SMZ/TMP monotherapy, synergistic therapy (SMZ-TMP combined with caspofungin and a GCS) for the treatment of non-HIV-related PJP can increase the clinical response rate, decrease the incidence of adverse events and shorten the duration of fever. These results indicate that synergistic therapy is effective and safe for treating severe non-HIV-related PJP.

Site selection and effects of background towers on urban CO2 estimates: A case study from central downtown Zhengzhou in China.

With China's proposed carbon reduction goals, many carbon monitoring pilot city projects have been launched, involving greenhouse gas (GHG) inverse estimate analysis based on GHG observations. For the evaluation of emissions estimates in a targeted urban area, the contributions of extra-urban fluxes on urban GHG observations must be excluded, especially for core cities within urban agglomerations, which face more severe emission interference from adjacent cities. In this study, we quantified the impact of external emissions on urban carbon dioxide (CO2) mole fraction observations across different seasons in the central downtown area of Zhengzhou, a core city of the Central Plains Urban Agglomeration in China. Results showed that 60% of the CO2 enhancement from the 500-km square area including the city originated outside the core urban area in autumn and winter, predominantly originating from far-field sources (>50 km) in the northeast, west, and northwest of Zhengzhou. To design an optimal monitoring network that accurately accounts for CO2 mole fractions entering the urban domain of interest, three different selection methods (distance, meteorological trajectory, and multiple regression) were used to select background station locations, and the resulting background values were evaluated through the application of observing system simulation experiments, including synthetic flux inverse estimate. Results indicated that the background stations selected by meteorological trajectories more effectively captured CO2 variability, introducing the smallest errors to inverse estimate flux (-8%). This study provides a valuable reference for designing background monitoring stations in dense urban agglomerations, thereby improving the accuracy of high-resolution urban GHG emission inverse estimates.

The diagnosis and treatment of pediatric clinical myocarditis in China: a multicenter retrospective study.

This study aims to examine the clinical characteristics and outcomes of clinical myocarditis in pediatric patients in China. This is a multicenter retrospective study. Children diagnosed with clinical myocarditis from 20 hospitals in China and admitted between January 1, 2015, and December 30, 2021, were enrolled. The clinical myocarditis was diagnosed based on the "Diagnostic Recommendation for Myocarditis in Children (Version 2018)". The clinical data were collected from their medical records. A total of 1210 patients were finally enrolled in this study. Among them, 45.6% had a history of respiratory tract infection. An abnormal electrocardiogram was observed in 74.2% of patients. Echocardiography revealed that 32.3% of patients had a left ventricular ejection fraction of less than 50%. Cardiac MRI was performed in 4.9% of children with clinical myocarditis, of which 61% showed localized or diffuse hypersignal on T2-weighted images. Serum levels of cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), and N-terminal B-type natriuretic peptide (NT-proBNP) were higher in patients with fulminant myocarditis than in patients with myocarditis, making them potential risk factors for fulminant myocarditis. Following active treatment, 12.1% of patients were cured, and 79.1% were discharged with improvement. CONCLUSION: Clinical myocarditis in children often presents with symptoms outside the cardiovascular system. CK-MB, cTnI, and NT-proBNP are important indicators for assessing clinical myocarditis. The electrocardiogram and echocardiogram findings in children with clinical myocarditis exhibit significant variability but lack specificity. Cardiac MRI can be a useful tool for screening clinical myocarditis. Most children with clinical myocarditis have a favorable prognosis. WHAT IS KNOWN: • Pediatric myocarditis presents complex clinical manifestations and exhibits varying degrees of severity. Children with mild myocarditis generally have a favorable prognosis, while a small number of children with critically ill myocarditis experience sudden onset, hemodynamic disorders, and fatal arrhythmias. Therefore, early diagnosis and timely treatment of myocarditis are imperative. WHAT IS NEW: • To the best of our knowledge, this multicenter retrospective study is the largest ever reported in China, aiming to reveal the clinical characteristics and outcomes of pediatric clinical myocarditis in China. We provided an extensive analysis of the clinical characteristics, diagnosis, treatment, prognosis, and factors impacting disease severity in pediatric clinical myocarditis in China, which provides insights into the epidemiological characteristics of pediatric clinical myocarditis.

Glutathione-depleting Liposome Adjuvant for Augmenting the Efficacy of a Glutathione Covalent Inhibitor Oridonin for Acute Myeloid Leukemia Therapy.

BACKGROUND: Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH. METHODS: We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets. RESULTS: We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells. CONCLUSION: The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.

Functional metabolomics characterizes the contribution of farnesoid X receptor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

Consumption of herbal products containing pyrrolizidine alkaloids (PAs) is one of the major causes for hepatic sinusoidal obstruction syndrome (HSOS), a deadly liver disease. However, the crucial metabolic variation and biomarkers which can reflect these changes remain amphibious and thus to result in a lack of effective prevention, diagnosis and treatments against this disease. The aim of the study was to determine the impact of HSOS caused by PA exposure, and to translate metabolomics-derived biomarkers to the mechanism. In present study, cholic acid species (namely, cholic acid, taurine conjugated-cholic acid, and glycine conjugated-cholic acid) were identified as the candidate biomarkers (area under the ROC curve 0.968 [95% CI 0.908-0.994], sensitivity 83.87%, specificity 96.55%) for PA-HSOS using two independent cohorts of patients with PA-HSOS. The increased primary bile acid biosynthesis and decreased liver expression of farnesoid X receptor (FXR, which is known to inhibit bile acid biosynthesis in hepatocytes) were highlighted in PA-HSOS patients. Furtherly, a murine PA-HSOS model induced by senecionine (50 mg/kg, p.o.), a hepatotoxic PA, showed increased biosynthesis of cholic acid species via inhibition of hepatic FXR-SHP singling and treatment with the FXR agonist obeticholic acid restored the cholic acid species to the normal levels and protected mice from senecionine-induced HSOS. This work elucidates that increased levels of cholic acid species can serve as diagnostic biomarkers in PA-HSOS and targeting FXR may represent a therapeutic strategy for treating PA-HSOS in clinics.

Spatial and temporal differentiation and its driving factors of air quality in the economic circle of Shandong Province during 2013-2020.

As the negative repercussions of environmental devastation, such as air quality decline and air pollution, become more apparent, environmental consciousness is growing across the world, forcing nations to take steps to mitigate the damage. China pledged to achieve air quality improvement goal to combat global environment issue, yet the spatial-temporal differentiation and its driving factors of environment-meteorology-economic index for air quality are not fully analysed. To promote regional collaborative control of air pollution and achieve sustainable urban development, spatial and temporal different and its driving factors of air quality in Shandong Province during 2013-2020. Results revealed that concentrations of sulfur dioxide (SO2), nitrogen dioxide (NO2), particulate matter 2.5 (PM2.5), particulate matter 10 (PM10), and carbon monoxide (CO-95per) exhibited decreasing trend (SO2 concentrations decreasing 84 % and CO-95per concentrations decreasing 90 %). Air quality was improved from inland areas to coastal areas. Pollutant indicators of SO2, NO2, PM10, PM2.5, and CO-95per demonstrated significant positive correlation (P < 0.05). Air temperature and precipitation are significantly negatively correlated with concentrations of SO2, NO2, PM10, PM2.5, and CO-95per but significantly positively correlated with ozone (O3-8 h). SO2, NO2, PM2.5, PM10, CO-95per, and proportion of days with heavy pollution are strongly positively correlated with proportion of secondary industry but strongly negatively correlated with proportion of tertiary industry and volume of household waste. Except for O3-8 h, pollutant index of Provincial Capital Economic Circle (PCEC) and Southern Shandong Economic Circle (SSEC) has significant negative correlation (P < 0.05) with regional gross domestic product and investment in environmental protection; however, investment in environmental protection of Eastern Shandong Economic Circle (ESEC) has no significant correlation with air pollution index. There was significant negative correlation between vegetable sowing area and SSEC pollutant index. The relationship between pollution emission and investment in environmental protection has shifted from high pollution-low investment to low pollution-low investment in PCEC, ESEC and SSEC, and the inflection point was in 2020 for PCEC, 2019 for ESEC, and 2020 for SSEC. Those results provide empirical evidence and theoretical support for the improvement of regional air quality, aiming to achieve high-quality development. According to these findings, it has been found that meteorological elements, pollutant emission, socio-economic factors and agricultural data affect air quality. Those results could provide meaningful and significant supporting for synergistic regulation of diverse pollutants.

Letrozole cotreatment progestin-primed ovarian stimulation in women undergoing controlled ovarian stimulation for in vitro fertilization.

AIM: To investigate the impact of letrozole cotreatment progestin-primed ovarian stimulation (PPOS) (Le PPOS) in controlled ovarian stimulation (COS) and the pregnancy outcomes in frozen-thawed embryo transfer cycles. METHODS: This retrospective cohort study included women who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). A total of 2575 cycles were included (1675 in the Le PPOS group and 900 in the PPOS group). The primary outcome was the clinical pregnancy rates. The secondary outcome was the live birth rates. RESULTS: In this study, propensity score matching (PSM) was performed to create a perfect match of 379 patients in each group. After matching, the numbers of oocytes retrieved, mature oocytes, fertilization, and clinical pregnancy rates were more favorable in the Le PPOS group than in the PPOS group (all p < 0.05). The multivariable analysis showed that the clinical pregnancy rate was higher in the Le PPOS than in the PPOS group (odds ratio = 1.46, 95% confidence interval: 1.05-2.04, p = 0.024) after adjusting for potentially confounding factors (age, anti-Müllerian hormone levels, antral follicular count, the type of embryo transferred, number of transferred embryos, body mass index, and follicular stimulating hormone and estradiol levels on starting day). CONCLUSIONS: This retrospective study with a limited sample size suggests that the Le PPOS protocol might be an alternative to the PPOS protocol in women undergoing COS and could lead to better pregnancy outcomes. The results should be confirmed using a formal randomized controlled trial.

Ratiometric electrochemical immunosensor for simultaneous detection of C-myc and Bcl-2 based on multi-role alloy composites.

A ratiometric electrochemical immunosensor is proposed for simultaneous detection of cellular-myelocytomatosis oncoprotein (C-myc) and B-cell lymphoma 2 (Bcl-2) via the potential-resolved strategy. It relied on multi-role co-loaded alloy composites (CLACs) and poly(3,4-ethylenedioxythiophene) (PEDOT)-graphene oxide (GO)-multiwalled carbon nanotubes (MWCNTs) (PGM) modified electrodes. CLACs with good catalytic and enzyme-like properties were synthesized in one step by loading tetramethylbenzidine (TMB) or methylene blue (MB) into Pt-Pd alloy and used as label materials. After immunological reactions, CLACs showed distinguishable dual differential pulse voltammetry signals at - 0.26 V and 0.38 V, corresponding to C-myc and Bcl-2, and the PGM had an electrochemical signal at 1.2 V, which could be used as a reference signal to construct a ratiometric sensor. CLACs had a satisfactory synergistic effect with the PGM, and eventually achieved quadruple signal amplification. Thus, benefiting from multiple magnification and ratiometric self-calibration functions, sensitive detections of C-myc and Bcl-2 were achieved, with detection limits as low as 0.5 and 2.5 pg mL-1, respectively. Additionally, when the designed method was applied to blood samples from lymphoma patients, results consistent with the ELISA kit were obtained. This will open avenues for constructing multiple protein detection sensors.