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In this work, the coordination chemistry of the uranyl ion(\begin{document}${\mathrm{UO}}_2^{2+} $\end{document}) with N, N-dimethyl-diglycolamic acid(HDMDGA, HLI) and N, N-diethyl-diglycolamic acid(HDEDGA, HLII) has been systematically studied through thermodynamic and structural analysis, by means of both potentiometric and spectroscopic titration, as well as Raman spectroscopy and X-ray diffractometry. The protonation constants of L−(L=LI, LII) and the stability constants of the uranyl complexes were determined by potentiometric and spectroscopic titrations in 1.0 mol/L NaClO4, with the molar absorption spectra of all species deconvoluted in the process of the latter titration. Besides, the standard Raman spectra of various complexes were confirmed by Raman spectroscopic titration. Furthermore, the single crystal of compound \begin{document}${\mathrm{UO}}_2{\mathrm{L}}^{{\mathrm{II}}}_2 $\end{document} was obtained by slow evaporation of aqueous solution containing uranyl ion and LII ligands at room temperature. X-ray diffraction analysis shows a monoclinic crystal system in P21/c space group, with lattice parameters: a=15.5096(6) Å（1 Å=0.1 nm）, b=7.7934(3) Å, c=11.3732(4) Å, α=90°, β=97.388(4)°, γ=90° and Z=2. Although both ligands show a similar structure and protonation constant, the different values of stability constant in aqueous solution and the different bond length of U-O in two complexes indicate the distinct coordination ability for two ligands with \begin{document}${\mathrm{UO}}_2^{2+} $\end{document}, where HDEDGA performs better. Like the crystal structure of \begin{document}$ {\mathrm{UO}}_2{\mathrm{L}}^{{\mathrm{I}}}_2$\end{document}, the ligand LII in the \begin{document}${\mathrm{UO}}_2{\mathrm{L}}^{{\mathrm{II}}}_2 $\end{document} complex coordinates with \begin{document}${\mathrm{UO}}_2^{2+} $\end{document} in a tridentate manner, with three oxygen atoms(amide oxygen, ether oxygen and carboxylic acid oxygen) coordinating with the linear \begin{document}${\mathrm{UO}}_2^{2+} $\end{document} at the equatorial plane. In addition, the diffuse reflectance spectra of the \begin{document}${\mathrm{UO}}_2{\mathrm{L}}^{{\mathrm{II}}}_2 $\end{document} crystal show characteristics significantly different from the absorption spectra of the corresponding complex in the aqueous solution. Meanwhile, the Raman shift of the characteristic peak of uranyl ion between hydrated uranyl ion and the 1∶1 complex(U∶ LII) is significantly larger than that between 1∶1 and 1∶2. Therefore, it is speculated that the structure of the 1∶2 complex in aqueous solution is supposed to be different from that in the solid crystal.

Abstract The processes h c → γP (P = η′, η, π 0) are studied with a sample of (27.12 ± 0.14) × 108 ψ(3686) events collected by the BESIII detector at the BEPCII collider. The decay h c → γη is observed for the first time with the significance of 9.0 σ, and the branching fraction is determined to be (3.77 ± 0.55 ± 0.13 ± 0.26) × 10 −4, while B $$ \mathcal{B} $$ (h c → γη′) is measured to be (1.40 ± 0.11 ± 0.04 ± 0.10) × 10 −3, where the first uncertainties are statistical, the second systematic, and the third from the branching fraction of ψ(3686) → π 0 h c . The combination of these results allows for a precise determination of R h c = B h c → γη B h c → γ η ′ , $$ {R}_{h_c}=\frac{\mathcal{B}\left({h}_c\to {\pi}^0\gamma \eta \right)}{\mathcal{B}\left({h}_c\to {\pi}^0\gamma {\eta}^{\prime}\right)}, $$ which is calculated to be (27.0 ± 4.4 ± 1.0)%. The results are valuable for gaining a deeper understanding of η − η′ mixing, and its manifestation within quantum chromodynamics. No significant signal is found for the decay h c → γπ 0, and an upper limit is placed on its branching fraction of B $$ \mathcal{B} $$ (h c → γπ 0) < 5.0 × 10 −5, at the 90% confidence level.

Abstract Quantitative structure–property relationships have been extensively studied in the field of predicting retention times in liquid chromatography (LC). However, making transferable predictions is inherently complex because retention times are influenced by both the structure of the molecule and the chromatographic method used. Despite decades of development and numerous published machine learning models, the practical application of predicting small molecule retention time remains limited. The resulting models are typically limited to specific chromatographic conditions and the molecules used in their training and evaluation. Here, we have developed a comprehensive dataset comprising over 10,000 experimental retention times. These times were derived from 30 different reversed-phase liquid chromatography methods and pertain to a collection of 343 small molecules representing a wide range of chemical structures. These chromatographic methods encompass common LC setups for studying the retention behavior of small molecules. They offer a wide range of examples for modeling retention time with different LC setups.

Abstract How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.

Abstract Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.

Abstract Colorectal cancer (CRC) ranks as the third most prevalent cancer globally. It’s recognized that the molecular subtype of CRC, characterized by mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), plays a critical role in determining appropriate treatment strategies. This review examines the current molecular classifications, focusing on dMMR/MSI-H CRC and its subtypes: Lynch syndrome (LS), Lynch-like syndrome (LLS), and sporadic cases. Despite advances in understanding of these genetic backgrounds, clinical trials have not conclusively differentiated the efficacy of immune checkpoint inhibitors among these subgroups. Therefore, while this review details the molecular characteristics and their general implications for treatment and prognosis, it also highlights the limitations and the need for more refined clinical studies to ascertain tailored therapeutic strategies for each subtype. Furthermore, this review summarizes completed and ongoing clinical studies, emphasizing the importance of developing treatments aligned more closely with molecular profiles. By discussing these aspects, the review seeks to provide a comprehensive analysis of oncological characteristics, presenting a detailed understanding of their implications for treatment and prognosis in dMMR/MSI-H CRC.

Abstract Background Difficult-to-treat Rheumatoid arthritis (D2T RA) is primarily characterised by failure of at least two different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drug (DMARDs) with evidence of active/progressive disease. While a variety of drugs have been used in previous studies to treat D2T RA, there has been no systematic summary of these drugs. This study conducted a systematic review of randomized controlled trials aimed at analyzing the efficacy and safety of individual therapeutic agents for the treatment of D2T RA and recommending the optimal therapeutic dose. Methods The English databases were searched for studies on the treatment of D2T RA published between the date of the database’s establishment and March, 2024. This study uses R 3.1.2 for data analysis, and the rjags package runs JAGS 3.4.0.20. The study fitted a stochastic effects Bayesian network meta-analysis for each outcome measure. Result A total of 42 studies were included in this study. Compared with placebo, the improvement of Disease Activity Score of 28 Joints (DAS28) score is ranked from high to low as tocilizumab, baricitinib and opinercept. The improvement of American College of Rheumatology 50 response (ACR50) score in patients with drug use was ranked from good to poor as follows: olokizumab, tocilizumab, adalimumab, baricitinib, and upadacitinib, and 8 mg/4w tocilizumab demonstrated the best efficacy. Notably, rituximab is generally the safest drug. Janus kinase (JAK) inhibitors and T cell costimulation modulators are effective in D2T RA refractory to biologic DMARDs, while JAK inhibitors and interleukin-6 (IL-6) inhibitors show effectiveness in D2T RA refractory to csDMARDs. Conclusion Tocilizumab and rituximab have better efficacy and safety in the treatment of D2T RA, and the 8 mg/4w dose of tocilizumab may be the first choice for achieving disease remission.

Abstract Background The aim of this research is to prospectively investigate the diagnostic performance of intravoxel incoherent motion (IVIM) using the integrated slice-specific dynamic shimming (iShim) technique in staging primary esophageal squamous cell carcinoma (ESCC) and predicting presence of lymph node metastases from ESCC. Methods Sixty-three patients with ESCC were prospectively enrolled from April 2016 to April 2019. MR and IVIM using iShim technique (b = 0, 25, 50, 75, 100, 200, 400, 600, 800 s/mm2) were performed on 3.0T MRI system before operation. Primary tumour apparent diffusion coefficient (ADC) and IVIM parameters, including true diffusion coefficient (D), pseudodiffusion coefficient (D*), pseudodiffusion fraction (f) were measured by two independent radiologists. The differences in D, D*, f and ADC values of different T and N stages were assessed. Intraclass correlation coefficients (ICCs) were calculated to evaluate the interobserver agreement between two readers. The diagnostic performances of D, D*, f and ADC values in primary tumour staging and prediction of lymph node metastasis of ESCC were determined using receiver operating characteristic (ROC) curve analysis. Results The inter-observer consensus was excellent for IVIM parameters and ADC (D: ICC = 0.922; D*: ICC = 0.892; f: ICC = 0.948; ADC: ICC = 0.958). The ADC, D, D* and f values of group T1 + T2 were significantly higher than those of group T3 + T4a [ADC: (2.55 ± 0.43) ×10− 3 mm2/s vs. (2.27 ± 0.40) ×10− 3 mm2/s, t = 2.670, P = 0.010; D: (1.82 ± 0.39) ×10− 3 mm2/s vs. (1.53 ± 0.33) ×10− 3 mm2/s, t = 3.189, P = 0.002; D*: 46.45 (30.30,55.53) ×10− 3 mm2/s vs. 32.30 (18.60,40.95) ×10− 3 mm2/s, z=-2.408, P = 0.016; f: 0.45 ± 0.12 vs. 0.37 ± 0.12, t = 2.538, P = 0.014]. The ADC, D and f values of the lymph nodes-positive (N+) group were significantly lower than those of lymph nodes-negative (N0) group [ADC: (2.10 ± 0.33) ×10− 3 mm2/s vs. (2.55 ± 0.40) ×10− 3 mm2/s, t=-4.564, P

Abstract Background Ulcerative colitis (UC) is a chronic intestinal inflammation, resulting in a global healthcare challenge with no real specific medicine. Natural medicines are recognized as a potential clinical alternative therapy, but their applications are limited by poor solubility and low bioavailability. Results In this work, inspired by the natural medicines of ancient China, novel functional carbon dots derived from Magnetite and Medicated Leaven (MML-CDs) were synthesized by hydrothermal method, and confirmed their ultrasmall nano-size (3.2 ± 0.6 nm) and Fe doped surface structure, thereby with excellent gastrointestinal stability, remarkable capabilities in eliminating ROS, and highly biocompatibility. With no external stimuli, the oral administration of MML-CDs demonstrated obvious alleviation to UC. Further experiments pointed that MML-CDs could improve hemostasis capability, suppress inflammation reactions and oxidative stress, and up-regulate the expression of tight junction proteins. Furthermore, MML-CDs also showed well regulation in the dysbiosis of intestinal flora. Conclusion Overall, above evidence reveals that green-synthesized MML-CDs can significantly alleviate intestinal bleeding, inhibit colon inflammation, and repair colonic barrier damage, further regulating intestinal flora and intestinal inflammation microenvironment. Our findings provide an efficient oral administration of MML-CDs as a novel therapy strategy for ulcerative colitis. Graphical Abstract

Abstract Despite advancements in chemotherapy and the availability of novel therapies, the outcome of adult patients with B-cell acute lymphoblastic leukemia (B-ALL) remains unsatisfactory. Therefore, it is necessary to understand the molecular mechanisms underlying the progression of B-ALL. Brahma-related gene 1 (BRG1) is a poor prognostic factor for multiple cancers. Here, the expression of BRG1 was found to be higher in patients with B-ALL, irrespective of the molecular subtype, than in healthy individuals, and its overexpression was associated with a poor prognosis. Upregulation of BRG1 accelerated cell cycle progression into the S phase, resulting in increased cell proliferation, whereas its downregulation facilitated the apoptosis of B-ALL cells. Mechanistically, BRG1 occupies the transcriptional activation site of PPP2R1A, thereby inhibiting its expression and activating the PI3K/AKT signaling pathway to regulate the proto-oncogenes c-Myc and BCL-2. Consistently, silencing of BRG1 and administration of PFI-3 (a specific inhibitor targeting BRG1) significantly inhibited the progression of leukemia and effectively prolonged survival in cell-derived xenograft mouse models of B-ALL. Altogether, this study demonstrates that BRG1-induced overactivation of the PPP2R1A/PI3K/AKT signaling pathway plays an important role in promoting the progression of B-ALL. Therefore, targeting BRG1 represents a promising strategy for the treatment of B-ALL in adults.

Abstract Background Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. Methods The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. Results APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. Conclusions APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.

Abstract Based on our previous findings that salicylic acid and jasmonic acid increased Nostoc flagelliforme polysaccharide yield by regulating intracellular nitric oxide (NO) levels, the mechanism through which NO affects polysaccharide biosynthesis in Nostoc flagelliforme was explored from the perspective of S-nitrosylation (SNO). The addition of NO donor and scavenger showed that intracellular NO had a significant positive effect on the polysaccharide yield of N. flagelliforme. To explore the mechanism, we investigated the relationship between NO levels and the activity of several key enzymes involved in polysaccharide biosynthesis, including fructose 1,6-bisphosphate aldolase (FBA), glucokinase (GK), glucose 6-phosphate dehydrogenase (G6PDH), mitochondrial isocitrate dehydrogenase (ICDH), and UDP-glucose dehydrogenase (UGDH). The enzymatic activities of G6PDH, ICDH, and UGDH were shown to be significantly correlated with the shifts in intracellular NO levels. For further validation, G6PDH, ICDH, and UGDH were heterologously expressed in Escherichia coli and purified via Ni+-NAT affinity chromatography, and subjected to a biotin switch assay and western blot analysis, which revealed that UGDH and G6PDH were susceptible to SNO. Furthermore, mass spectrometry analysis of proteins treated with S-nitrosoglutathione (GSNO) identified the SNO modification sites for UGDH and G6PDH as cysteine 423 and cysteine 249, respectively. These findings suggest that NO modulates polysaccharide biosynthesis in N. flagelliforme through SNO of UGDH and G6PDH. This reveals a potential mechanism through which NO promotes polysaccharide synthesis in N. flagelliforme, while also providing a new strategy for improving the industrial production of polysaccharides.

Abstract Background Schizophrenia is a pervasive and severe mental disorder characterized by significant disability and high rates of recurrence. The persistently high rates of readmission after discharge present a serious challenge and source of stress in treating this population. Early identification of this risk is critical for implementing targeted interventions. The present study aimed to develop an easy-to-use predictive instrument for identifying the risk of readmission within 1-year post-discharge among schizophrenia patients in China. Methods A prediction model, based on static factors, was developed using data from 247 schizophrenia inpatients admitted to the Mental Health Center in Wuxi, China, from July 1 to December 31, 2020. For internal validation, an additional 106 patients were included. Multivariate Cox regression was applied to identify independent predictors and to create a nomogram for predicting the likelihood of readmission within 1-year post-discharge. The model’s performance in terms of discrimination and calibration was evaluated using bootstrapping with 1000 resamples. Results Multivariate cox regression demonstrated that involuntary admission (adjusted hazard ratio [aHR] 4.35, 95% confidence interval [CI] 2.13–8.86), repeat admissions (aHR 3.49, 95% CI 2.08–5.85), the prescription of antipsychotic polypharmacy (aHR 2.16, 95% CI 1.34–3.48), and a course of disease ≥ 20 years (aHR 1.80, 95% CI 1.04–3.12) were independent predictors for the readmission of schizophrenia patients within 1-year post-discharge. The area under the curve (AUC) and concordance index (C-index) of the nomogram constructed from these four factors were 0.820 and 0.780 in the training set, and 0.846 and 0.796 for the validation set, respectively. Furthermore, the calibration curves of the nomogram for both the training and validation sets closely approximated the ideal diagonal line. Additionally, decision curve analyses (DCAs) demonstrated a significantly better net benefit with this model. Conclusions A nomogram, developed using pre-discharge static factors, was designed to predict the likelihood of readmission within 1-year post-discharge for patients with schizophrenia. This tool may offer clinicians an accurate and effective way for the timely prediction and early management of psychiatric readmissions.

The classification and identification of species in Populus has remained a formidable challenge due to widespread interspecies hybridization. The complete chloroplast genome of Populus maximowiczii was obtained by Illumina high-throughput sequencing technology, with a typical quadripartite structure and 37.0% GC content. The chloroplast genome of P. maximowiczii was 156,892 in length, including a large single-copy region (LSC: 84,988 bp), a small single-copy region (SSC: 16,630 bp), and a pair of inverted repeats (IRs: each 27,637 bp in length). A total of 131 genes were annotated, including 86 protein-coding genes, 37 tRNAs, and 8 rRNAs. The phylogenetic analysis indicated that 43 species belonging to Populus were classified into monophyly, with P. cathayana being the closest relatives to P. maximowiczii. In conclusion, this study provides valuable insights into understanding the phylogeny of Populus.

Abstract Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8+ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach.

Abstract Fiddler crabs, as coastal ecosystem engineers, play a crucial role in enhancing biodiversity and accelerating the flow of material and energy. Here we show how widespread crab burrows modify the carbon sequestration capacity of different habitats across a large climatic gradient. The process of crab burrowing results in the reallocation of sediment organic carbon and humus. Crab burrows can increase more greenhouse gases emissions compared to the sediment matrix (CO2: by 17–30%; CH4: by 49–141%). Straightforward calculations indicate that these increased emissions could offset 35–134% of sediment carbon burial in these two ecosystems. This research highlights the complex interactions between crab burrows, habitat type, and climate which reveal a potential lower carbon sink function of blue carbon ecosystems than previously expected without considering crab burrows.

Abstract Golden buckwheat, also called Fagopyrum dibotrys (D. Don) H. Hara, is a plant of the genus Buckwheat in the buckwheat family. The aim of this study was to screen the bioactive ingredients of golden buckwheat extract and investigate the protective effect on acute lung injury (ALI). The ethyl acetate extract (EAE) was identified as the active fraction in LPS‐induced RAW264.7 cells, with gallic acid, proanthocyanidin B2, and epicatechin at 0.0563%, 0.3707%, and 0.3868%, respectively. At the same time, 20 compounds (mainly flavonoids and organic acids) were identified by UPLC‐Q‐Exactive Orbitrap‐HRMS in EAE. Furthermore, the EAE reduced lung histopathology scores in mice with ALI, decreased the dry‐to‐wet weight ratio of lung tissue, and significantly inhibited the concentrations of IL‐1β, TNFα, and IL‐6 in bronchoalveolar lavage fluid (BALF). It also reduced the number of leukocytes, decreased the activity of MPO in lung tissue, and inhibited the levels of TLR4/NLRP3 pathway mRNA and protein in lung tissue. Our study indicated that golden buckwheat as a source of functional food prevents or treats associated lung diseases by modulating the activation of the TLR4/NLRP3 signaling pathway.

Abstract Bacterial testicular inflammation is one of the important causes of male infertility. Using plant-derived compounds to overcome the side effects of antibiotics is an alternative treatment strategy for many diseases. Schizandrin B (SchB) is a bioactive compound of herbal medicine Schisandra chinensis which has multiple pharmacological effects. However its effect and the mechanism against testicular inflammation are unknown. Here we tackled these questions using models of lipopolysaccharide (LPS)-induced mice and -Sertoli cells (SCs). Histologically, SchB ameliorated the LPS-induced damages of the seminiferous epithelium and blood-testicular barrier, and reduced the production of pro-inflammatory mediators in mouse testes. Furthermore, SchB decreased the levels of pro-inflammatory mediators and inhibited the nuclear factor kB (NF-κB) and MAPK (especially JNK) signaling pathway phosphorylation in LPS-induced mSCs. The bioinformatics analysis based on receptor prediction and the molecular docking was further conducted. We targeted androgen receptor (AR) and illustrated that AR might bind with SchB in its function. Further experiments indicate that the AR expression was upregulated by LPS stimulation, while SchB treatment reversed this phenomenon; similarly, the expression of the JNK-related proteins and apoptotic-related protein were also reversed after AR activator treatment. Together, SchB mitigates LPS-induced inflammation and apoptosis by inhibiting the AR-JNK pathway.

Abstract The trade-off between electrostrain and strain hysteresis for piezo/ferroelectric materials largely restrains the development of high precision actuators and remains unresolved over the past few decades. Here, a simple composition of (Bi0.5Na0.5)1-x/100Sr x/100TiO3 in the ergodic relaxor state is collaboratively designed through the segregated domain structure with the ferroelectric core, local polarization heterogeneity, and defect engineering. The ferroelectric core can act as a seed to facilitate the field-induced nonpolar-to-polar transition. Together with the internal bias field caused by defect dipoles and adjusted through electric field cycling and heat treatment technology, a giant unipolar strain of 1.03% is achieved in the x = 30 ceramic with a low hysteresis of 27%, while the electric-field-independent large-signal piezoelectric strain coefficient of ~1000 pm/V and ultralow hysteresis of

Abstract Background Gemmatimonadota bacteria are widely distributed in nature, but their metabolic potential and ecological roles in marine environments are poorly understood. Results Here, we obtained 495 metagenome-assembled genomes (MAGs), and associated viruses, from coastal to deep-sea sediments around the world. We used this expanded genomic catalog to compare the protein composition and update the phylogeny of these bacteria. The marine Gemmatimonadota are phylogenetically different from those previously reported from terrestrial environments. Functional analyses of these genomes revealed these marine genotypes are capable of degradation of complex organic carbon, denitrification, sulfate reduction, and oxidizing sulfide and sulfite. Interestingly, there is widespread genetic potential for secondary metabolite biosynthesis across Gemmatimonadota, which may represent an unexplored source of novel natural products. Furthermore, viruses associated with Gemmatimonadota have the potential to “hijack” and manipulate host metabolism, including the assembly of the lipopolysaccharide in their hosts. Conclusions This expanded genomic diversity advances our understanding of these globally distributed bacteria across a variety of ecosystems and reveals genetic distinctions between those in terrestrial and marine communities. Video Abstract

Abstract Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.

Abstract Background Accumulating evidence suggests that cardiovascular diseases and breast cancer share a number of common risk factors, however, evidence on the association between cardiovascular health (CVH) and breast cancer is limited. The present study aimed to assess the association of CVH, defined by Life’s Essential 8 (LE8) and genetic risk with breast cancer incidence and mortality among premenopausal and postmenopausal women. Methods We used data from the UK Biobank and conducted the multivariate Cox proportional-hazards models to examine associations of LE8 score and genetic risk with breast cancer incidence and mortality. Date on LE8 score was collected between 2006 and 2010 and composed of eight components, including behavioral metrics (diet, tobacco or nicotine exposure, physical activity, and sleep health), and biological metrics (body mass index, blood lipids, blood glucose, and blood pressure). The polygenic risk score (PRS) was calculated as the sum of effect sizes of individual genetic variants multiplied by the allele dosage. Results A total of 150,566 premenopausal and postmenopausal women were included. Compared to postmenopausal women with low LE8 score, those with high LE8 score were associated with 22% lower risk of breast cancer incidence (HR: 0.78, 95% CI: 0.70–0.87) and 43% lower risk of breast cancer mortality (HR: 0.57, 95% CI: 0.36–0.90). By contrast, we did not observe the significant association among premenopausal women. Further analyses stratified by PRS categories showed that high LE8 score was associated with 28% and 71% decreased risk of breast cancer incidence (HR: 0.72, 95% CI: 0.60–0.87) and mortality (HR: 0.29, 95% CI: 0.10–0.83) compared to low LE8 score among high genetic risk groups, but no significant associations were found among low genetic risk groups. Furthermore, compared with postmenopausal women with high LE8 score and low genetic risk, those with low LE8 score and high genetic risk were associated with increased risk of breast cancer incidence (HR: 6.26, 95% CI: 4.43–8.84). Conclusions The present study suggests that better CVH is a protective factor for both breast cancer incidence and mortality among postmenopausal women. Moreover, the risk of developing breast cancer caused by high genetic susceptibility could be largely offset by better CVH.

Objective: To improve the taste of sea buckthorn juice and remove the bitter substance isorhamnetin glycoside. Methods: Fermentation of sea buckthorn juice with Lactiplantibacillus plantarum to study the growth curves of probiotics, the changes of various indexes such as total phenolic content and antioxidant activity during the fermentation process, as well as the changes of isorhamnetin glycosides and isorhamnetin content. Results: The sea buckthorn juice fermented by Lactiplantibacillus plantarum 67-25-2 fermentation had its bitter flavour improved and the sensory analysis score reached 85, and the total free phenol content and antioxidant activity of the juice were increased, reaching maximum at 62 h, in which the total phenol content was increased to 598.9 mg GAE/L, and the scavenging rate of the ABTS+ free radicals and the DPPH free radicals were reached 67.5% and 61.8%, respectively. Pearson correlation analysis revealed that total phenol content and isorhamnetin content were significantly positively correlated with DPPH radical scavenging and ABTS+ radical scavenging (P

Polygonatum sibiricum, a plant homologous to both medicine and food, is of significant importance. Its primary active components include polysaccharides, saponin, flavonoids, polyphenols, and alkaloids. These constituents are known for their roles in enhancing immune function, combating fatigue, providing anti-oxidative benefits, reducing blood sugar, and offering anti-inflammatory effects. Consequently, P. sibiricum presents wide-ranging prospects in health food and pharmaceutical research and development. This paper provides a comprehensive summary of research advancements in the polysaccharides, flavonoids, saponins, and solomonseal rhizome extract of P. sibiricum, particularly in metabolic regulation. It delves into the mechanisms by which the main active substances of P. sibiricum influence glucose and lipid metabolism. Simultaneously, the paper analyzes current patents and the state of industrial development related to P. sibiricum, aiming to provide a reference for future research and development of metabolic regulation functional products based on this plant.

Water is the important medium of the tea infusions, which plays a crucial role in the development of tea quality. Tooma sinensis (TS) fermented tea was brewed with tap water, mineral water and purified water. The physicochemical indexes, biochemical components, antioxidant activity and flavor compounds of three types tea infusions were analyzed using ultraviolet spectrophotometer, electronic tongue and gas chromatography-mass spectrometry (GC-MS) to elucidate the influence of different brewing water on the quality of TS fermented tea infusions. The results demonstrated that the quality and antioxidant activity of TS fermented tea infusions were significant influenced by different brewing water (P

Objective: This study aimed to investigate the protective effect and mechanism of yeast extract and curcumin-yeast extract on acute alcoholic liver injury in mice. Methods: The mouse model of acute alcoholic liver injury was established, and the mice were administered with yeast extract and curcumin-yeast extract. Changes in ALT, AST, T-GSH, GSH-Px, and MDA levels were observed in the serum and liver tissue, respectively. Pathological sections of liver tissue were examined to observe the damage. The intestinal flora of mice was analyzed. Results: Compared with the model group, both yeast extract and curcumin-yeast extract reduced the levels of ALT, AST, MDA, TC, and TG, increased the activities of GSH-Px and T-GSH, and alleviated fatty infiltration and inflammatory infiltration of hepatocytes. Curcumin-yeast extract effectively restored the abundance of Acinetobacter, Prevotella, and Ruminococcus, which had been altered by alcohol. The restorative effect was superior to that of the yeast extract group. Conclusion: Yeast extract and curcumin-yeast extract showed significant protective effects against acute alcoholic liver injury in mice. This mechanism may be associated with the regulation of oxidative stress, lipid metabolism, and intestinal flora.

Objective Compared to Mimas pigeons, Shiqi pigeons exhibit greater tolerance to coarse feeding because of their abundant gut microbiota. Here, to investigate the potential of utilizing intestinal flora derived from Shiqi pigeons, the intestinal flora and body indices of Mimas squabs were evaluated after fecal microbiota transplantation (FMT) from donors. Methods A total of 90 one-day-old squabs were randomly divided into the control group (CON), the low-concentration group (LC) and the high-concentration group (HC): gavaged with 200 μL of bacterial solution at concentrations of 0, 0.1, and 0.2 g/15 mL, respectively. Results The results suggested that FMT improved the body weight of Mimas squabs in the HC and LC groups (p

Myocardial ischemia is a serious threat to human health, and vascular dysfunction is its main cause. Buxu Tongyu (BXTY) Granule is an effective traditional Chinese medicine (TCM) for treating myocardial ischemia. However, the underlying mechanism of BXTY is still unclear. In this study, we demonstrate that BXTY ameliorates myocardial ischemia by activating the soluble guanylate cyclase (sGC)–3′,5′-cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) signaling pathway in vascular smooth muscle cells (VSMCs) to dilate the arteries. BXTY was given by gavage for ten consecutive days before establishing an animal model of acute myocardial ischemia in mice via the intraperitoneal injection of pituitrin. The results showed that BXTY alleviated the symptoms of myocardial ischemia induced by pituitrin in mice, including electrocardiogram abnormalities and changes in plasma enzymes. In addition, BXTY dilated pre-constricted blood vessels and inhibited the vasoconstriction of the superior mesenteric artery in a dose-dependent but endothelial-independent manner. These effects were eliminated by pre-incubating vascular rings with the sGC inhibitors NS 2028 or ODQ, or with the PKG inhibitor KT 5823. Moreover, BXTY increased the protein expression of sGC-β1 and the intracellular second messenger cGMP level in mouse aortic vascular smooth muscle cells (MOVAs). NS 2028 or ODQ reversed these effects of BXTY. The expression level of the cGMP downstream effector protein PKG-1 increased after treating MOVAs with BXTY. NS 2028, ODQ, or KT 5823 also reversed this effect of BXTY. In conclusion, BXTY can improve the symptoms of acute myocardial ischemia in mice, and activating the sGC–cGMP–PKG pathway in VSMCs to induce vasodilation is its key pharmacodynamic mechanism.

Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

Abstract High myopia can lead to pathologic myopia and visual impairment, whereas its causes are unclear. We retrospectively researched high myopia cases from patient records to investigate the association between axial elongation and myopic maculopathy. Sixty-four eyes were examined in patients who visited the department between July 2017 and June 2018, had an axial length of 26 mm or more, underwent fundus photography, and had their axial length measured twice or more. The average axial length was 28.29 ± 1.69 mm (mean ± standard deviation). The average age was 58.3 ± 14.4 years old. Myopic maculopathy was categorized as mild (grades 0 and 1) and severe (grades 2, 3, and 4). The severe group had longer axial lengths than the mild group (P

In order to explore the forming mechanism of direct energy deposition of magnesium-lithium alloy wire with high lithium content, this study introduces a novel approach utilizing Cold Metal Transfer Wire Arc Additive Manufacturing (CMT-WAAM) to successfully fabricate thin-walled structures of LA103Z Mg–Li alloy. A comprehensive comparison was conducted to evaluate the microstructure and mechanical properties of different regions on CMT-WAAM samples, in addition to cast and rolled samples. The microstructure of CMT-WAAM samples is mainly composed of β-Li phase and fine needle shaped α-Mg phase, exhibiting a notable divergence from the microstructure observed in cast and rolled samples. It is noteworthy that the mechanical properties along the deposition direction exhibited significant variability in CMT-WAAM samples, but no significant anisotropy is discerned in the mechanical properties along the deposition and scanning directions. The discrepancies in mechanical properties across different regions are predominantly attributed to variations in grain size, and the size and proportion of the α-Mg phase and secondary phases, which are related to the low heat input and high cooling rate of the CMT-WAAM process. The mean tensile strength of CMT-WAAM samples is 159.5 MPa, marking a respective increase of 30.7% and 13.9% compared to cast and rolled samples. These findings underscore the outstanding strength of CMT-WAAM samples compared to conventionally formed samples. This study provides novel insights into additive manufacturing of dual-phase Mg–Li alloys for large-scale complex structures.

Abstract Background Logsplitter Injury is a type of high-energy ankle fracture dislocation. The mechanism of injury has not been described in detail. A detailed understanding of the radiological features and pathological changes can further guide treatment. Methods Between April 2009 and December 2018, a retrospective analysis was conducted on 62 patients with Logsplitter injury. The study analysed the characteristics of fibular injury, tibial injury, syndesmosis injury, medial injury and lateral ligament injury on preoperative X-ray and CT scans. The incidence of the different injury types was summarised. The correlation between Logsplitter injuries and the mechanisms causing them were analysed using the Lauge-Hansen classification of ankle fractures. Results The study provides data on the types of fractures observed. Of the total fractures, 98.4% were open fractures. The fibula injuries were classified as no fracture (1.6%), transverse or short oblique fractures (61.3%), butterfly fragments (25.8%), and comminuted fractures (11.3%). The tibial injuries included compression of lateral articular surfaces (38.7%) and posterior compressions (6.5%). Medial injuries, including medial malleolar fractures, accounted for 87.1%, and deltoid ligament rupture accounted for 12.9%. The study found that injuries to the syndesmosis consisted of simple ligament ruptures (11.3%), Tillaux fractures (8.1%), Volkmann fractures (43.5%), and Tillaux and Volkmann fractures (37.1%). In 12.9% of cases, there was a complete rupture of the lateral collateral ligament. Based on the Lauge-Hansen classification, 87.1% of injuries were pronation-abduction injuries, while 8.1% were pronation and external rotation injuries, and 1.6% were supination external rotation injuries. Furthermore, 3.2% of cases could not be classified. Conclusion The pathoanatomic characteristics of Logsplitter injury are diverse, with some cases accompanied by collateral ligament injury. It is important to note that these evaluations are objective and based on current results. The most common injury mechanism is vertical violence combined with abduction, although in some cases, it may be a vertical combined external-rotation injury. Level of evidence (4) case series. Trial registration This study has been approved by the ethical research committee of the Honghui Hospital of Xi’an Jiaotong University, under the code: 202,003,002.

Abstract Using e + e − collision data collected with the BESIII detector at the BEPCII collider at center-of-mass energies between 3.510 and 4.914 GeV, corresponding to an integrated luminosity of 25 fb −1, we measure the Born cross sections for the process e + e − → K − Ξ ¯ + Λ / Σ 0 $$ {e}^{+}{e}^{-}\to {K}^{-}{\overline{\Xi}}^{+}\Lambda /{\Sigma}^0 $$ at thirty-five energy points with a partial-reconstruction strategy. By fitting the dressed cross sections of e + e − → K − Ξ ¯ + Λ / Σ 0 $$ {e}^{+}{e}^{-}\to {K}^{-}{\overline{\Xi}}^{+}\Lambda /{\Sigma}^0 $$ , evidence for ψ 4160 → K − Ξ ¯ + Λ $$ \psi (4160)\to {K}^{-}{\overline{\Xi}}^{+}\Lambda $$ is found for the first time with a significance of 4.4σ, including systematic uncertainties. No evidence for other possible resonances is found. In addition, the products of electronic partial width and branching fraction for all assumed resonances decaying into K − Ξ ¯ + Λ / Σ 0 $$ {K}^{-}{\overline{\Xi}}^{+}\Lambda /{\Sigma}^0 $$ are determined.

Abstract Corn silage can usually improve the growth performance and the meat quality of ruminants, and subsequently increase the economic benefits of farming. However, little is known about the effects of corn silage on donkeys. This experiment investigated the effects of corn silage on the weight gain, gut microbiota and metabolites of Dezhou donkeys. A total of 24 Dezhou donkeys, sourced from the same farm and exhibiting similar age and average body weight, were utilized in this experiment. The donkeys were allocated into two groups: a control group receiving a basic diet and a test group receiving a basic diet supplemented with 30% corn silage. Each group comprised 12 donkeys, evenly distributed by sex (6 males and 6 females). The experiment lasted for 100 days. Results showed that dietary supplementation with corn silage significantly (P

Abstract High areal capacity and low-temperature ability are critical for lithium-ion batteries (LIBs). However, the practical operation is seriously impeded by the sluggish rates of mass and charge transfer. Herein, the active electronic states of TiNb2O7 material is modulated by dopant and O-vacancies for enhanced low-temperature dynamics. Femtosecond laser-based transient absorption spectroscopy is employed to depict carrier dynamics of TiNb2O7, which verifies the localized structure polarization accounting for reduced transport overpotential, facilitated electron/ion transport, and improved Li+ adsorption. At high-mass loading of 10 mg cm−2 and −30 °C, TNO-x @N microflowers exhibit stable cycling performance with 92.9% capacity retention over 250 cycles at 1 C (1.0-3.0 V, 1 C = 250 mA g−1). Even at −40 °C, a competitive areal capacity of 1.32 mAh cm−2 can be achieved. Such a fundamental understanding of the intrinsic structure-function put forward a rational viewpoint for designing high-areal-capacity batteries in cold regions.

Abstract This study aimed to determine the relationships between prenatal PM2.5 exposure and childhood growth trajectories during the first 6 years of life. A total of 47,625 pairs of mothers and children were recruited from a prospective birth cohort conducted between 2011 and 2013 in Wuhan, China, and followed for 6 years. We used the group-based trajectory models to classify the population into three trajectory groups: slow growth (n = 13,671, 28.7%), normal growth (n = 29,736, 62.4%), and rapid growth (n = 4218, 8.9%). Multinomial logistic regression models were used to determine the associations of prenatal PM2.5 exposure and childhood growth trajectories. Compared to normal growth trajectory, increased PM2.5 exposure in trimester 1, trimester 2 and the entire pregnancy showed significant associations with an increased risk of the slow growth trajectory but reduced the risk for the rapid growth trajectory, significant association of prenatal PM2.5 exposure with rapid growth trajectory was only observed in the trimester 3. Stratified analyses displayed relatively stronger associations among those mothers with maternal age over 35 years, pre-pregnancy BMI ≥ 25 kg/m2, and previous delivery experience. Prenatal exposure to PM2.5, particularly during the midpoint period of pregnancy, was more likely to have a slow growth trajectory and a lower risk of rapid growth trajectory. Maternal age, pre-pregnancy BMI, and previous delivery experience might modify these associations.

Objective To explore the influencing factors of spontaneous bacterial peritonitis and the predictive value of multiple inflammatory indicators in elderly alcoholic liver cirrhosis patients. Methods A total of 276 patients with alcoholic cirrhosis hospitalized in Beijing Friendship Hospital, Capital Medical University from January 2020 to June 2023 were selected for retrospective analysis. Seventy-two elderly patients with alcoholic cirrhosis who had spontaneous bacterial peritonitis at admission were included in the observation group, and 204 elderly patients with alcoholic cirrhosis who did not have SBP were included in the control group. The clinical data of patients in the two groups were collected by an electronic medical record system at admission. Multivariate logistic regression model was used to analyze the correlation between inflammatory factors and spontaneous bacterial peritonitis. ROC curve was used to evaluate the diagnostic efficacy of inflammatory factors for spontaneous bacterial peritonitis. Results Univariate analysis showed that the proportion of combined diabetes, hepatic encephalopathy, and upper gastrointestinal bleeding in the observation group was higher than that in the control group, prothrombin time was longer than that in the control group, neutrolphil to lymphocyte ratio(NLR) and C-reactive protein to albumin ratio(CAR) were higher than those in the control group, and lymphocyte to monocyte ratio(LMR) was lower than that in the control group, and the differences were statistically significant (P

Abstract With a sample of (10087 ± 44) × 106 J/ψ events accumulated with the BESIII detector, we analyze the decays η′ → π + π − l + l − (l = e, μ) via the process J/ψ → γη′. The branching fractions are measured to be B $$ \mathcal{B} $$ (η′ → π + π − e + e − ) = (2.45 ± 0.02(stat.) ± 0.08(syst.)) × 10 −3 and B $$ \mathcal{B} $$ (η′ → π + π − μ + μ − ) = (2.16 ± 0.12(stat.) ± 0.06(syst.)) × 10 −5, and the ratio is B η ′ → π + π − e + e − B η ′ → π + π − μ + μ − = 113.4 ± 0.9 stat . ± 3.7 syst . $$ \frac{\mathcal{B}\left({\eta}^{\prime}\to {\pi}^{+}{\pi}^{-}{e}^{+}{e}^{-}\right)}{\mathcal{B}\left({\eta}^{\prime}\to {\pi}^{+}{\pi}^{-}{\mu}^{+}{\mu}^{-}\right)}=113.4\pm 0.9\left(\textrm{stat}.\right)\pm 3.7\left(\textrm{syst}.\right) $$ . In addition, by combining the η′ → π + π − e + e − and η′ → π + π − μ + μ − decays, the slope parameter of the electromagnetic transition form factor is measured to be b η′ = 1.30 ± 0.19 (GeV/c 2) −2, which is consistent with previous measurements from BESIII and theoretical predictions from the VMD model. The asymmetry in the angle between the π + π − and l + l − decay planes, which has the potential to reveal the CP-violation originating from an unconventional electric dipole transition, is also investigated. The asymmetry parameters are determined to be A CP η ′ → π + π − e + e − = − 0.21 ± 0.73 stat . ± 0.01 syst . % $$ {\mathcal{A}}_{CP}\left({\eta}^{\prime}\to {\pi}^{+}{\pi}^{-}{e}^{+}{e}^{-}\right)=\left(-0.21\pm 0.73\left(\textrm{stat}.\right)\pm 0.01\left(\textrm{syst}.\right)\right)\% $$ and A CP η ′ → π + π − μ + μ − = 0.62 ± 4.71 stat . ± 0.08 syst . % $$ {\mathcal{A}}_{CP}\left({\eta}^{\prime}\to {\pi}^{+}{\pi}^{-}{\mu}^{+}{\mu}^{-}\right)=\left(0.62\pm 4.71\left(\textrm{stat}.\right)\pm 0.08\left(\textrm{syst}.\right)\right)\% $$ , implying that no evidence of CP-violation is observed at the present statistics. Finally, an axion-like particle is searched for via the decay η′ → π + π − a, a → e + e − , and upper limits of the branching fractions are presented for the mass assumptions of the axion-like particle in the range of 0 − 500 MeV/c 2.

Abstract Background Atherogenic index of plasma (AIP) has been reported as a critical predictor on the risks and clinical outcomes of cardiovascular diseases (CVDs), and we aimed to explore the potential predictive value of cumulative AIP on major adverse cardiac events (MACE), stroke, myocardial infarction (MI) and cardiovascular mortality. Methods A large-scale community-based prospective cohort was established from December 2011 to April 2012 and followed up in May to July 2014. The endpoint outcomes were obtained before December 31, 2021. AIP was calculated as the logarithmically transformed ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-c) and cumulative AIP was the average value of AIP in 2012 and 2014. Results An overall of 3820 participants (36.1% male) with mean (SD) age of 59.1 (8.7) years, were enrolled. Within a median follow-up of 7.5 years, a total of 371 (9.7%) participants were documented with MACE, 293 (7.7%) participants developed stroke, 68 (1.8%) suffered from MI and 65 (1.7%) experienced cardiovascular mortality. Multivariable Cox regression analysis revealed significant associations between cumulative AIP and the risk of MACE, stroke and MI. Regarding MACE, individuals with one higher unit of cumulative AIP were associated with 75% increment on the incidence of going through MACE in fully adjusted model, while categorizing participants into four groups, individuals in the highest cumulative AIP quartile were significantly associated with increased incidence of MACE (HR = 1.76, 95%CI: 1.27–2.44, p

Abstract High-purity ethylene production from CO2 electroreduction (CO2RR) is a coveted, yet arduous feat because the product stream comprises a blend of unreacted CO2, H2, and other off-target CO2 reduction products. Here we present an indirect reduction strategy for CO2-to-ethylene conversion, one that employs 2-bromoethanol (Br-EO) as a mediator. Br-EO is initially generated from CO2RR and subsequently undergoes reduction to ethylene without the need for energy-intensive separation steps. The optimized AC-Ag/C catalyst with Cl incorporation reduces the energy barrier of the debromination step during Br-EO reduction, and accelerates the mass-transfer process, delivering a 4-fold decrease of the relaxation time constant. Resultantly, AC-Ag/C achieved a FEethylene of over 95.0 ± 0.36% at a low potential of −0.08 V versus reversible hydrogen electrode (RHE) in an H-type cell with 0.5 M KCl electrolyte, alongside a near 100% selectivity within the range of −0.38 to −0.58 V versus RHE. Through this indirect strategy, the average ethylene purity within 6-hour electrolysis was 98.00 ± 1.45 wt%, at −0.48 V (vs RHE) from the neutralized electrolyte after CO2 reduction over the Cu/Cu2O catalyst in a flow-cell.

Abstract Trace NO2 detection is essential for the production and life, where the sensing strategy is appropriate for rapid detection but lacks molecular specificity. This investigation proposes a sensing mechanism dominated by surface-scattering to achieve the molecularly-specific detection. Two-dimensional Bi2O2Se is firstly fabricated into a Schottky-junction-based gas-sensor. Applied with an alternating excitation, the sensor simultaneously outputs multiple response signals (i.e., resistance, reactance, and the impedance angle). Their response times are shorter than 200 s at room temperature. In NO2 sensing, these responses present the detection limit in ppt range and the sensitivity is up to 16.8 %·ppb−1. This NO2 sensitivity presents orders of magnitude higher than those of the common gases within the exhaled breath. The impedance angle is involved in the principle component analysis together with the other two sensing signals. Twelve kinds of typical gases containing NO2 are acquired with molecular characteristics. The change in dipole moment of the target molecule adsorbed is demonstrated to correlate with the impedance angle via surface scattering. The proposed mechanism is confirmed to output ultra-sensitive sensing responses with the molecular characteristic.

Abstract Human iPSC-derived cardiomyocytes (hiPSC-CMs) have proven invaluable for cardiac disease modeling and regeneration. Challenges with quality, inter-batch consistency, cryopreservation and scale remain, reducing experimental reproducibility and clinical translation. Here, we report a robust stirred suspension cardiac differentiation protocol, and we perform extensive morphological and functional characterization of the resulting bioreactor-differentiated iPSC-CMs (bCMs). Across multiple different iPSC lines, the protocol produces 1.2E6/mL bCMs with ~94% purity. bCMs have high viability after cryo-recovery (>90%) and predominantly ventricular identity. Compared to standard monolayer-differentiated CMs, bCMs are more reproducible across batches and have more mature functional properties. The protocol also works with magnetically stirred spinner flasks, which are more economical and scalable than bioreactors. Minor protocol modifications generate cardiac organoids fully in suspension culture. These reproducible, scalable, and resource-efficient approaches to generate iPSC-CMs and organoids will expand their applications, and our benchmark data will enable comparison to cells produced by other cardiac differentiation protocols.

Abstract Background The combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon. Methods Constructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels. Results The abscopal effect was further amplified in the “cold” tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response. Conclusions Bi was used as an artificially implanted anaerobic target to cause a transient “infection” at the tumor, causing the tumor to become locally inflamed and “hot”, and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.

Abstract Peripheral arterial diseases (PAD) have been reported to be the leading cause for limb amputations, and the current therapeutic strategies including antiplatelet medication or intervene surgery are reported to not clinically benefit the patients with high-grade PAD. To this respect, revascularization based on angiogenetic vascular endothelial growth factor (VEGF) gene therapy was attempted for the potential treatment of critical PAD. Aiming for transcellular delivery of VEGF-encoding plasmid DNA (pDNA), we proposed to elaborate intriguing virus-like DNA condensates, wherein the supercoiled rigid micrometer-scaled plasmid DNA (pDNA) could be regulated in an orderly fashion into well-defined nano-toroids by following a self-spooling process with the aid of cationic block copolymer poly(ethylene glycol)-polylysine at an extraordinary ionic strength (NaCl: 600 mM). Moreover, reversible disulfide crosslinking was proposed between the polylysine segments with the aim of stabilizing these intriguing toroidal condensates. Pertaining to the critical hindlimb ischemia, our proposed toroidal VEGF-encoding pDNA condensates demonstrated high levels of VEGF expression at the dosage sites, which consequently contributed to the neo-vasculature (the particularly abundant formation of micro-vessels in the injected hindlimb), preventing the hindlimb ischemia from causing necrosis at the extremities. Moreover, excellent safety profiles have been demonstrated by our proposed toroidal condensates, as opposed to the apparent immunogenicity of the naked pDNA. Hence, our proposed virus-like DNA condensates herald potentials as gene therapy platform in persistent expressions of the therapeutic proteins, and might consequently be highlighted in the management of a variety of intractable diseases.

Abstract Triple negative breast cancer (TNBC) has the characteristics of low immune cell infiltration, high expression of tumor programmed death ligand 1 (PD-L1), and abundant cancer stem cells. Systemic toxicity of traditional chemotherapy drugs due to poor drug selectivity, and chemotherapy failure due to tumor drug resistance and other problems, so it is particularly important to find new cancer treatment strategies for TNBC with limited treatment options. Both the anti-tumor natural drugs curcumin and ginsenoside Rg3 can exert anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells, reducing PD-L1 expression, and reducing cancer stem cells. However, they have the disadvantages of poor water solubility, low bioavailability, and weak anti-tumor effect of single agents. We used vinyl ether bonds to link curcumin (Cur) with N-O type zwitterionic polymers and at the same time encapsulated ginsenoside Rg3 to obtain hyperbranched zwitterionic drug-loaded micelles OPDEA-PGED-5HA@Cur@Rg3 (PPH@CR) with pH response. In vitro cell experiments and in vivo animal experiments have proved that PPH@CR could not only promote the maturation of dendritic cells (DCs) and increase the CD4+ T cells and CD8+ T cells by inducing ICD in tumor cells but also reduce the expression of PD-L1 in tumor tissues, and reduce cancer stem cells and showed better anti-tumor effects and good biological safety compared with free double drugs, which is a promising cancer treatment strategy.

Given the large hysteresis in the material outlet temperature of the heating furnace, a differential evolution algorithm with adaptive adjustment factors (AAFDE)-radial basis function (RBF)-proportional integral derivative (PID)-PI cascade is proposed. First, we introduce an adaptive mutation factor into the differential evolution (DE) algorithm and define the individual merit coefficient to incorporate a self-adaptive crossover probability factor. Second, the initial parameters of RBF are optimized by the AFFDE algorithm, and RBF neural network model is established. Then, we obtain gradient information by RBF online identification. Finally, we perform online adjustments to the three parameters of PID based on the gradient information. The three parameters are applied to the adjustment of the main controller, while the sub-controller employs PI control. Experimental results show that the anti-disturbance performance of the AFFDE-RBF-PID-PI cascade control outperforms the improved differential evolution (IDE)-RBF-PID-PI cascade control, generalized opposition-based differential evolution (GODE)-RBF-PID-PI cascade control, and MCOBDE-RBF-PID-PI cascade control respectively by 16%, 11%, and 7%, with the response speed improving by 18%, 12%, and 9%, and the stability improving by 19%, 13%, and 8%. These results show that AFFDE-RBF-PID-PI cascade control exhibits enhanced anti-disturbance performance, faster response speed, improved stability, and superior control effect.

Abstract We measured the Born cross sections for the process e + e − → ωη′ at 22 center-of-mass energies from 2.000 to 3.080 GeV with the BESIII detector at the BEPCII collider. We observed a resonant structure with a statistical significance of 9.6σ. A Breit-Wigner fit determines its mass to be M R = (2153 ± 30 ± 31) MeV/c 2 and its width to be Γ R = (167 ± 77 ± 7) MeV, where the first uncertainties are statistical and the second are systematic.

Abstract High-grade serous ovarian cancer (HGSOC) is an aggressive disease known to develop resistance to chemotherapy. We investigated the prognostic significance of tumor cell states and potential mechanisms underlying chemotherapy resistance in HGSOC. Transcriptome deconvolution was performed to address cellular heterogeneity. Kaplan–Meier survival curves were plotted to illustrate the outcomes of patients with varying cellular abundances. The association between gene expression and chemotherapy response was tested. After adjusting for surgery status and grading, several cell states exhibited a significant correlation with patient survival. Cell states can organize into carcinoma ecotypes (CE). CE9 and CE10 were proinflammatory, characterized by higher immunoreactivity, and were associated with favorable survival outcomes. Ratios of cell states and ecotypes had better prognostic abilities than a single cell state or ecotype. A total of 1265 differentially expressed genes were identified between samples with high and low levels of C9 or CE10. These genes were partitioned into three co-expressed modules, which were associated with tumor cells and immune cells. Pogz was identified to be linked with immune cell genes and the chemotherapy response of paclitaxel. Collectively, the survival of HGSOC patients is correlated with specific cell states and ecotypes.

Abstract Background Long-term natural and artificial selection has resulted in many genetic footprints within the genomes of pig breeds across distinct agroecological zones. Nevertheless, the mechanisms by which these signatures contribute to phenotypic diversity and facilitate environmental adaptation remain unclear. Results Here, we leveraged whole-genome sequencing data from 82 individuals from 6 domestic pig breeds originating in tropical, high-altitude, and frigid regions. Population genetic analysis suggested that habitat isolation significantly shaped the genetic diversity and contributed to population stratification in local Chinese pig breeds. Analysis of selection signals revealed regions under selection for adaptation in tropical (55.5 Mb), high-altitude (43.6 Mb), and frigid (17.72 Mb) regions. The potential functions of the selective sweep regions were linked to certain complex traits that might play critical roles in different geographic environments, including fat coverage in frigid environments and blood indicators in tropical and high-altitude environments. Candidate genes under selection were significantly enriched in biological pathways involved in environmental adaptation. These pathways included blood circulation, protein degradation, and inflammation for adaptation to tropical environments; heart and lung development, hypoxia response, and DNA damage repair for high-altitude adaptation; and thermogenesis, cold-induced vasodilation (CIVD), and the cell cycle for adaptation to frigid environments. By examining the chromatin state of the selection signatures, we identified the lung and ileum as two candidate functional tissues for environmental adaptation. Finally, we identified a mutation (chr1: G246,175,129A) in the cis-regulatory region of ABCA1 as a plausible promising variant for adaptation to tropical environments. Conclusions In this study, we conducted a genome-wide exploration of the genetic mechanisms underlying the adaptability of local Chinese pig breeds to tropical, high-altitude, and frigid environments. Our findings shed light on the prominent role of cis-regulatory elements in environmental adaptation in pigs and may serve as a valuable biological model of human plateau-related disorders and cardiovascular diseases.

Abstract Background Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent–offspring trios and proband only analysis. Methods We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation. Results Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications. Conclusion CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities.