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Information on the distribution of vernalization genes and their association with growth habit is crucial to understanding the adaptability of wheat (Triticum aestivum L.) cultivars to different environments. In this study, 278 Chinese wheat cultivars were characterized with molecular markers for the vernalization genes Vrn-A1, -B1, -D1, and -B3 Heading time was evaluated in a greenhouse under long days without vernalizaton. The dominant Vrn-D1 allele showed the highest frequency in the Chinese wheat cultivars (37.8%), followed by the dominant Vrn-A1, -B1, and -B3 alleles. Ninety-two winter cultivars carried recessive alleles of all four vernalization loci, whereas 172 spring genotypes contained at least one dominant Vrn allele. All cultivars released in the North China Plain Winter Wheat Zone were winter type. Winter (53.0%), spring (36.1%), and early-heading (10.9%) cultivars were grown in the Yellow and Huai River Valley Winter Zone. Most of the spring genotypes from this zone carried only the dominant Vrn-D1 allele, which was also predominant (64.1%) in the Middle and Lower Yangtze Valley Winter Zone and Southwestern Winter Wheat Zone. In three spring-sown wheat zones, all cultivars were early-heading spring types that frequently possessed the strongest dominant Vrn-A1a allele and combinations with other dominant Vrn gene(s). The Vrn-D1 allele is associated with the latest heading time, Vrn-A1 the earliest, and Vrn-B1 intermediate values. The information is important for breeding programs in countries interested in using Chinese wheats.

Cervical cancer, CC, is one of the malignant cancers in women worldwide. Many studies about the genesis and progression of CC have been done at genomic, transcriptional, translational, and epigenetic levels. However, much less is done at post-translational modification (PTM) level. We first used pan-PTM antibodies to compare the pan PTM levels between clinical normal cervical tissues and CC tissues; we then sent the selected samples for label-free identification of acetylation sites. Next, we employed WT or K119A mutant PARP1-EGFP-STREPII plasmid transfection in Hela cells and examined various indexes including colony formation, wound healing, ROS generation, early apoptosis, and immunofluorescence and quantification of proliferation markers (Ki67, PCNA, and p-P53). Last, we examined the levels of multiple important kinases regulating cervical cancer progression. We found that pan-acetylation was the most downregulated in clinical CC samples, whereas the acetylation of PARP1, Poly(ADP-ribose) polymerase-1, was upregulated at K119. Next, we showed that PARP1-WT overexpression significantly suppressed the proliferation and progression in CC cell line Hela, while K119A overexpression didn't show any impact. Finally, PARP1-WT overexpression significantly decreased p-ERK1/2 while didn't affect the phosphorylation levels of other important kinases such as AKT, MTOR, and RPS6. This study discovered a new type of PTM of PARP1 in CC, and showed that PARP1 acetylation at K119 is essential in regulating the proliferation and progression of CC through ERK1/2. Further studies are required to investigate how PARP1 acetylation impact its function., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: S100β is a biomarker of astroglial damage, the level of which is significantly increased following brain injury. However, the characteristics of S100β and its association with prognosis in patients with acute ischemic stroke following intravenous thrombolysis (IVT) remain unclear., Methods: Patients in this multicenter prospective cohort study were prospectively and consecutively recruited from 16 centers. Serum S100β levels were measured 24 h after IVT. National Institutes of Health Stroke Scale (NIHSS) and hemorrhagic transformation (HT) were measured simultaneously. NIHSS at 7 days after stroke, final infarct volume, and modified Rankin Scale (mRS) scores at 90 days were also collected. An mRS score ≥ 2 at 90 days was defined as an unfavorable outcome., Results: A total of 1072 patients were included in the analysis. The highest S100β levels (> 0.20 ng/mL) correlated independently with HT and higher NIHSS at 24 h, higher NIHSS at 7 days, larger final infarct volume, and unfavorable outcome at 3 months. The patients were divided into two groups based on dominant and non-dominant stroke hemispheres. The highest S100β level was similarly associated with the infarct volume in patients with stroke in either hemisphere (dominant: β 36.853, 95% confidence interval (CI) 22.659-51.048, P < 0.001; non-dominant: β 23.645, 95% CI 10.774-36.516, P = 0.007). However, serum S100β levels at 24 h were more strongly associated with NIHSS scores at 24 h and 3-month unfavorable outcome in patients with dominant hemisphere stroke (NIHSS: β 3.470, 95% CI 2.392-4.548, P < 0.001; 3-month outcome: odds ratio (OR) 5.436, 95% CI 2.936-10.064, P < 0.001) than in those with non-dominant hemisphere stroke (NIHSS: β 0.326, 95% CI  - 0.735-1.387, P = 0.547; 3-month outcome: OR 0.882, 95% CI 0.538-1.445, P = 0.619). The association of S100β levels and HT was not significant in either stroke lateralization group., Conclusions: Serum S100β levels 24 h after IVT were independently associated with HT, infarct volume, and prognosis in patients with IVT, which suggests the application value of serum S100β in judging the degree of disease and predicting prognosis., (© 2024. The Author(s).)

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic tumor microenvironment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks the activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibits pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy., (© 2024 Wiley‐VCH GmbH.)

Guided by the conceptual frameworks of social withdrawal (Rubin, K. H., & Chronis-Tuscano, A. (2021). Perspectives on social withdrawal in childhood: Past, present, and prospects. Child Development Perspectives, 15(3), 160-167.) and emotion socialization (Eisenberg, N., Cumberland, A., & Spinrad, T. L. (1998). Parental socialization of emotion. Psychological Inquiry, 9, 241-273.; Morris, (A) S., Criss, M. M., Silk, J. S., & Houltberg, (B) J. (2017). The impact of parenting on emotion regulation during childhood and adolescence. Child Development Perspectives, 11(4), 233-238.), the current study examined multifaceted relations among temperamental shyness, peer competence, and loneliness and focused on the role of socializing and expressing positive emotion in middle childhood. Participants included 1,364 families, among whom mothers reported children's temperament when children were 4.5 years old. Mothers and alternative caregivers (usually fathers) independently rated family expressiveness when children were 8-9 years old. Mothers rated their children's peer competence, and children's positive affect with peers were observed when children were ages 8-9 and 10-11. Children self-rated their loneliness levels at ages 10-11. A path model revealed a moderated mediation effect, such that family positive expressiveness moderated the sequential mediation pathway from child temperamental shyness through child peer competence at ages 8-9 and positive affect with peers at ages 10-11 to loneliness at ages 10-11. This sequential mediation was significant only under low but not high levels of family positive expressiveness. Findings support the importance of socializing positive emotion in the context of temperamental shyness and have implications for family-based intervention strategies aimed at children exhibiting high temperamental shyness., (© 2024. The Author(s).)

The microbial terroir is an indispensable part of the terroir panorama, and can improve wine quality with special characteristics. In this study, eight autochthonous yeasts ( Saccharomyces cerevisiae ), selected in Huailai country, China, were trailed in small-scale and pilot fermentations for both white (Riesling and Sémillon) and red (Cabernet Sauvignon and Syrah) wines and evaluated by GC-MS analysis and the rate-all-that-apply (RATA) method. Compared to commercial yeast strains, the indigenous yeasts were able to produce higher concentrations of ethyl esters and fatty acid ethyl esters, and higher alcohol, resulting in higher odor activity values of fruity, floral attributes. Marked varietal effects were observed in the pilot fermentation, but yeast strains exerted a noticeable impact in modulating wine aroma and sensory profile. Overall, indigenous yeast could produce more preferred aroma compounds and sensory characteristics for both white and red wines, demonstrating the potential for improving wine quality and regional characteristics.

Whether the dynamic development of peripheral inflammation aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis (IVT), remains unclear and warrants further study. In this study, total of 1034 patients with acute ischemic stroke who underwent IVT were enrolled. Serum leukocyte variation (whether increase from baseline to 24 h after IVT), National Institutes of Health Stroke Scale (NIHSS), infarct volume, early neurologic deterioration (END), the unfavorable outcome at 3-month (modified Rankin Scale [mRS] score ≥3) and mortality were recorded. Serum brain injury biomarkers, including Glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), S100 β , neuron-specific enolase (NSE), were measured to reflect the extent of brain injury. We found that patients with increased serum leukocytes had elevated brain injury biomarkers (GFAP, UCH-L1, and S100 β ), larger infarct volume, higher 24 h NIHSS, higher proportion of END, unfavorable outcome and mortality. Furthermore, an increase in serum leukocytes was independently associated with infarct volume, 24 h NIHSS, END, and unfavorable outcome at 3 months, and serum UCH-L1, S100 β , and NSE levels. These results suggest that an increase in serum leukocytes indicates severe brain injury and may be used to predict the outcome of patients with ischemic stroke who undergo IVT., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Delirium is a significant health concern in acute stroke patients. We aim to systematically summarize existing evidence to conduct a meta-analysis to quantify the occurrence and risk factors for delirium after acute stroke., Method: PubMed, EMBASE and MEDLINE were searched from inception to Feb. 2023 for prospective observational studies that reported the incidence or prevalence of post-stroke delirium and/or evaluated potential risk factors. The search strategy was created using controlled vocabulary terms and text words for stroke and delirium. We performed a meta-analysis of the estimates for occurrence and risk factors using random-effects models. Meta-regression and subgroup meta-analyses were conducted to explore the sources of heterogeneity. Study quality and quality of evidence were assessed using the customized Newcastle-Ottawa Scale and GRADE, respectively., Results: Forty-nine studies that enrolled 12383 patients were included. The pooled occurrence rate of post-stroke delirium was 24.4 % (95 %CI, 20.4 %-28.9 %, I 2 =96.2 %). The pooled occurrence of hyperactive, hypoactive, and mixed delirium was 8.5 %, 5.7 % and 5.0 %, respectively. Study location, delirium assessment method and stroke type independently affected the heterogeneity of the pooled estimate of delirium. Statistically significant risk factors were older age, low education level, cigarette smoking, alcohol drinking, atrial fibrillation, lower ADL level, higher pre-stroke mRS score, premorbid cognitive impairment or dementia, aphasia, total anterior circulation impairment, higher National Institute of Health Stroke Scale score and infection., Conclusions: Delirium affected 1 in 4 acute stroke patients, although reported rates may depend on assessment method and stroke type. Timely prevention, recognition and intervention require prioritizing patients with dominant risk factors., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon secretion to promote hepatic amino acid catabolism. Interruption of glucagon signaling disrupts the liver-α cells axis leading to hyperaminoacidemia, which triggers a compensatory rise in glucagon secretion and α cell hyperplasia. The mechanisms of hyperaminoacidemia-induced α cell hyperplasia remain incompletely understood. Using a mouse α cell line and in vivo studies in zebrafish and mice, we found that hyperaminoacidemia-induced α cell hyperplasia requires ErbB3 signaling. In addition to mechanistic target of rapamycin complex 1, another ErbB3 downstream effector signal transducer and activator of transcription 3 also plays a role in α cell hyperplasia. Mechanistically, ErbB3 may partner with ErbB2 to stimulate cyclin D2 and suppress p27 via mechanistic target of rapamycin complex 1 and signal transducer and activator of transcription 3. Our study identifies ErbB3 as a new regulator for hyperaminoacidemia-induced α cell proliferation and a critical component of the liver-α cells axis that regulates aminoacidemia., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα's tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G 2 /M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G 2 /M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: This study comprehensively investigates the association between the expression of nicotinamide N-methyltransferase (NNMT) and clinical outcomes of urothelial bladder cancer (UBC), as well as the molecular mechanisms by which NNMT in cancer-associated fibroblast (CAF) modulates tumor progression and immunotherapy resistance in UBC., Methods: Single-cell transcriptomic analyses, immunohistochemical and immunofluorescence assays were performed on bladder cancer samples to validate the relationship between NNMT expression and clinical outcomes. A series of experiments, including chromatin immunoprecipitation assay, liquid chromatography tandem mass spectrometry assay, and CRISPR‒Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9) knockout, together with in vivo models, have been established to determine the molecular functions of NNMT in CAFs in UBC., Results: We demonstrated that elevated expression of the nicotinamide adenine dinucleotide (NAD + ) metabolism enzyme NNMT in CAFs (NNMT + CAFs) was significantly associated with non-response to programmed death-ligand 1 (PD-L1) blockade immunotherapy in patients with UBC and predicted the unfavorable prognosis of UBC in two independent large cohorts. Targeting NNMT using the inhibitor 5-Amino-1-methylquinolinium iodide significantly reduced tumor growth and enhanced the apoptotic effects of the anti-PD-L1 antibody in UBC mouse models. Mechanistically, NNMT + CAFs recruit tumor-associated macrophages via epigenetic reprogramming of serum amyloid A (SAA) to drive tumor cell proliferation and confer resistance to programmed death-1/PD-L1 blockade immunotherapy., Conclusions: NNMT + CAFs were significantly associated with non-response to PD-L1 blockade immunotherapy in patients with UBC. Elevated NNMT, specifically in CAFs, upregulates SAA expression and enhances the recruitment and differentiation of macrophages in the tumor microenvironment, thereby directly or indirectly promoting tumor progression and conferring resistance to immunotherapies in bladder cancer., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy., (© 2024. The Author(s).)

Panax notoginseng is a highly valued perennial medicinal herb in China and is widely used in clinical treatments. The main purpose of this study was to elucidate the changes in the composition of P. notoginseng saponins (PNSs), which are the main bioactive substances, triggered by arbuscular mycorrhizal fungi (AMF) via ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS). A total of 202 putative terpenoid metabolites were detected, of which 150 triterpene glycosides were identified, accounting for 74.26% of the total. Correlation analysis, principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) of the metabolites revealed that the samples treated with AMF (group Ce) could be clearly separated from the CK samples. In total, 49 differential terpene metabolites were identified between the Ce and CK groups, of which 38 and 11 metabolites were upregulated and downregulated, respectively, and most of the upregulated differentially abundant metabolites were mainly triterpene glycosides. The relative abundances of the two major notoginsenosides (MNs), ginsenosides Rd and Re, and 13 rare notoginsenosides (RNs), significantly increased. The differential saponins, especially RNs, were more easily clustered into one branch and had a high positive correlation. It could be concluded that the biosynthesis and accumulation of some RNs share the same pathways as those triggered by AMF. This study provides a new way to obtain more notoginsenoside resources, particularly RNs, and sheds new light on the scientization and rationalization of the use of AMF agents in the ecological planting of medicinal plants.

Background: PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer., Methods: We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing., Findings: Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis., Interpretation: Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach., Funding: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Sixteen alkaloid compounds were isolated from the dried rhizomes of P. zanlanscianense , including a pair of new enantiomers ( R / S )-7'-ethoxy- trans -p-couma-royltyramine ( 1a / 1b ) and 14 known compounds (2-14) isolated from this plant for the first time. The structures of new compounds were identified by IR, NMR and MS spectroscopic analysis, and their absolute configurations were determined by comparison of the experimental and calculated ECD data.

Introduction: Hepatocellular carcinoma (HCC), which is closely associated with chronicinflammation, is the most common liver cancer and primarily involves dysregulated immune responses in the precancerous microenvironment. Currently, most studies have been limited to HCC incidence. However, the immunopathogenic mechanisms underlying precancerous lesions remain unknown. Methods: We obtained single-cell sequencing data (GSE136103) from two nonalcoholic fatty liver disease (NAFLD) cirrhosis samples and five healthy samples. Using pseudo-time analysis, we systematically identified five different T-cell differentiation states. Ten machine-learning algorithms were used in 81 combinations to integrate the frameworks and establish the best T-cell differentiation-related prognostic signature in a multi-cohort bulk transcriptome analysis. Results: LDHA was considered a core gene, and the results were validated using multiple external datasets. In addition, we validated LDHA expression using immunohistochemistry and flow cytometry. Conclusion: LDHA is a crucial marker gene in T cells for the progression of NAFLD cirrhosis to HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Ye, Ning, Zhang, Lv, Li and Wang.)

Objective: To prepare interleukin-1β-targeted nanoantibodies and observe their effects on apoptosis in hypoxic cardiomyocyte of mice. Methods: Using DNA recombination technology, the pET-16b and pHEN1 expression vectors were used to construct the prokaryotic expression plasmids of interleukin-1β-targeted nanobodies (pET-16b-4G6M-VHH, pET-16b-5BVP-VHH, pET-16b-5MVZ-VHH, pHEN1-4G6M-VHH, pHEN1-5BVP-VHH and pHEN1-5MVZ-VHH, where VHH is a variable domain of heavy chain antibody, 4G6M-VHH, 5BVP-VHH, 5MVZ-VHH were three interleukin-1β-targeted nanoantibodies respectively). The constructed plasmids were transferred into Escherichia coli Rosetta2 (DE3) for induction of expression and nickel column purification, respectively. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting were employed to identify the expression product and purified product, and the enzyme-linked immune sorbent assay (ELISA) was performed to determine their affinity. The cardiomyocyte hypoxia model was used with the highest affinity IL-1β-targeted nanobody (pHEN1-5MVZ-VHH), and cell survival and apoptosis rates were detected (the experiment was divided into normal control group, hypoxia model group, blank plasmid group and 12.5, 25.0, 50.0 μg/ml pHEN1-5MVZ-VHH treatment groups). Results: SDS-PAGE and Western blotting results showed that the anti-interleukin-1β (IL-1β) nanobodies with a relative molecular mass of about 15 000 were successfully obtained. Likewise, ELISA results found that the nanobodies expressed in pHEN1 vector group had higher affinity for IL-1β antigen compared with pET-16b vector group (4G6M-VHH group: 3.20±0.03 vs 1.20±0.03, P <0.001; 5BVP-VHH group: 3.18±0.06 vs 1.21±0.02, P <0.001; 5MVZ-VHH group: 3.38±0.05 vs 1.62±0.04, P <0.001). Additionally, the results of cell survival assay and apoptosis assay detected that compared with the hypoxia model group, HL-1 cell activity was significantly increased in the 25.0 μg/ml and 50.0 μg/ml pHEN1-5MVZ-VHH treatment groups [(75.55±2.23)% vs (46.90±2.51)%, P <0.001; (74.36±1.96)% vs (46.90±2.51)%, P <0.001], and apoptosis rate was significantly reduced [(6.83±0.27)% vs (10.24±0.76)%, P <0.001; (6.68±0.38)% vs (10.24±0.76)%, P <0.001]. Conclusions: 4G6M-VHH, 5BVP-VHH, and 5MVZ-VHH are expressed by both pET-16b and pHEN1 expression vectors and the nanobodies produced by the pHEN1 vector display enhanced antigen affinity. Furthermore, in hypoxic cardiomyocytes, pHEN1-5MVZ-VHH treatment reduces cell apoptosis.

In this study, a benzoselenadiazole- and pyridine-bifunctionalized hydrogen-bonded arylamide foldamer was synthesized. A co-crystallization experiment with 1,4-diiodotetrafluorobenzene showed that a new type of supramolecular double helices, which were induced by three orthogonal interactions, namely, three-center hydrogen bonding (O⋯H⋯O), I⋯N halogen bonding and Se⋯N chalcogen bonding, have been constructed in the solid state. This work presents a novel instance of multiple non-covalent interactions that work together to construct supramolecular architectures.

The dysfunction of matriptase, a membrane-anchored protease, is highly related to the progression of skin and breast cancers. Epidermal growth factor (EGF)-induced matriptase activation and cancer invasion are known but with obscure mechanisms. Here, we demonstrate a vesicular-trafficking-mediated interplay between matriptase and EGF signaling in cancer promotion. We found that EGF induces matriptase to undergo endocytosis together with the EGF receptor, followed by acid-induced activation in endosomes. Activated matriptase is then secreted extracellularly on exosomes to catalyze hepatocyte growth factor precursor (pro-HGF) cleavage, resulting in autocrine HGF/c-Met signaling. Matriptase-induced HGF/c-Met signaling represents the second signal wave of EGF, which promotes cancer cell scattering, migration, and invasion. These findings demonstrate a role of vesicular trafficking in efficient activation and secretion of membrane matriptase and a reciprocal regulation of matriptase and EGF signaling in cancer promotion, providing insights into the physiological functions of vesicular trafficking and the molecular pathological mechanisms of skin and breast cancers., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Panax notoginseng is a highly valued perennial medicinal herb plant in Yunnan Province, China, and the taproots are the main medicinal parts that are rich in active substances of P. notoginseng saponins. The main purpose of this study is to uncover the physiological and molecular mechanism of Panax notoginseng saponin accumulation triggered by methyl jasmonate (MeJA) under arbuscular mycorrhizal fungi (AMF) by determining physiological indices, high-throughput sequencing and correlation analysis. Physiological results showed that the biomass and saponin contents of P. notoginseng , the concentrations of jasmonic acids (JAs) and the key enzyme activities involved in notoginsenoside biosynthesis significantly increased under AMF or MeJA, but the interactive treatment of AMF and MeJA weakened the effect of AMF, suggesting that a high concentration of endogenous JA have inhibitory effect. Transcriptome sequencing results indicated that differential expressed genes (DEGs) involved in notoginsenoside and JA biosynthesis were significantly enriched in response to AMF induction, e.g., upregulated genes of diphosphocytidyl-2-C-methyl-d-erythritol kinases ( ISPEs ), cytochrome P450 monooxygenases ( CYP450s ) &#95; and glycosyltransferases ( GTs ), while treatments AMF-MeJA and salicylhydroxamic acid (SHAM) decreased the abundance of these DEGs. Interestingly, a high correlation presented between any two of saponin contents, key enzyme activities and expression levels of DEGs. Taken together, the inoculation of AMF can improve the growth and saponin accumulation of P. notoginseng by strengthening the activities of key enzymes and the expression levels of encoding genes, in which the JA regulatory pathway is a key link. This study provides references for implementing ecological planting of P. notoginseng , improving saponin accumulation and illustrating the biosynthesis mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dai, Zhang, Bi, Chen, Long, Wu, Cao and He.)

Background: High rates of postoperative infection persist after different surgical procedures, encompassing surgical site infections (SSIs), remote infections, sepsis, and septic shock. Our aim was to assess presepsin's diagnostic accuracy for postoperative infections in patients across surgical procedures., Method: We conducted a comprehensive search in seven databases, extracting data independently. Using STATA 14.0, we calculated pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and Under the receiver operator curve and 95 ​% confidence interval (AUC, 95 ​% CI) as primary outcomes, with secondary outcomes involving sensitivity and specificity in subgroup analyses., Results: This meta-analysis of 14 studies (1891 cases) evaluated presepsin's diagnostic value for postoperative infectious complications. Results include sensitivity of 77 ​% (70-83), specificity of 81 ​% (71-88), DOR of 14 (8-26), AUC of 84 (80-87), PLR of 4 (3-6), and NLR of 0.28 (0.21-0.38). Presepsin exhibits promise as a diagnostic tool for postoperative infections., Conclusion: In summary, compared to conventional markers like C-reactive protein (CRP) and procalcitonin (PCT), presepsin demonstrated superior sensitivity and specificity for detecting postoperative infectious complications across various surgical procedures., Competing Interests: Declaration of competing interest The authors declare no financial interests or potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Since the discovery of classical chiral oxazoline ferrocene ligands in 1995, they have become pivotal in transition metal-catalyzed asymmetric transformations. Over the past decade, a notable evolution has been observed with the emergence of siloxane-substituted oxazoline ferrocenes, demonstrating significant potential as chiral ligands and catalysts. These compounds have consistently delivered exceptional results in diverse and mechanistically distinct transformations, surpassing the capabilities of classical oxazoline ferrocene ligands. This review meticulously delineates the research progress on siloxane-substituted oxazoline ferrocene compounds. It encompasses the synthesis of crucial precursors and desired products, highlights their achievements in asymmetric catalysis reactions, and delves into the exploration of the derivatization of these compounds, emphasizing the introduction of ionophilic groups and their impact on the recovery of transition metal catalysts. In addition to presenting the current state of knowledge, this review propels future research directions by identifying potential topics for further investigation concerning the siloxane-tagged derivatives. These derivatives are poised to be promising candidates for the next generation of highly efficient ligands and catalysts., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could appear to have influenced the work reported in this paper.

Co-loading doxorubicin (DOX) and Schizandrin A (SchA) long-circulating liposome (SchA-DOX-Lip) have been confirmed to have good antitumor activity in vitro . However, in vivo pharmacodynamics, targeting, safety, and mechanism of action of SchA-DOX-Lip still need to be further verified. We investigated the tumor inhibition effect, targeting, safety evaluation, and regulation of tumor apoptosis-related proteins of the SchA-DOX-Lip. MTT assay was used to investigate the inhibitory effect of SchA-DOX-Lip on CBRH7919 cells. The drug uptake of CBRH7919 cells was observed by inverted fluorescence microscope. The tumor-bearing nude mice models of CBRH7919 were established, and the anti-tumor effect of SchA-DOX-Lip in vivo was evaluated by tumor biological observation, H&E staining, and TUNEL staining. The distribution and targeting of SchA-DOX-Lip in nude mice models were investigated by small animal imaging and tissue distribution experiment of CBRH7919. The biosafety of SchA-DOX-Lip was evaluated by blood routine parameters, biochemical indexes, and H&E staining. The expression of tumor-associated apoptotic proteins (Bcl-2, Bax, and Caspase-3) was detected by immunohistochemistry anvd western blotting. The results showed that SchA-DOX-Lip had cytotoxicity to CBRH7919 cells which effectively inhibited the proliferation of CBRH7919 cells, improved the uptake of drugs by CBRH7919 cells and the targeting effect of drugs on tumor site. H&E staining and biochemical detection results showed that SchA-DOX-Lip had high biosafety and did not cause serious damage to normal tissues. Western-blotting and TUNEL staining results showed that SchA-DOX-Lip could improve the regulatory effect of drugs on tumor apoptosis proteins. It was demonstrated that SchA-DOX-Lip had high safety and strong tumor inhibition effects, providing a new method for the clinical treatment of hepatocellular carcinoma (HCC).

Background: Post-operative infection remains a major cause of morbidity and mortality in adults early after liver transplantation (LT). Procalcitonin (PCT) may be a good test method for early diagnosis of post-operative infection and determining its severity. This study was performed to assess the diagnostic accuracy of PCT as a biomarker for infection after LT. Patients and Methods: A meta-analysis and systematic review was conducted for studies reporting diagnostic performance of PCT for infection in adults after LT. Observational studies were evaluated for their reporting of diagnostic accuracy, relevance, and quality. Results: Ten eligible studies assessing 730 patients were included in this meta-analysis and systematic review summarizing the diagnostic value of PCT for post-operative infection in adult liver transplantation. Pooled sensitivity and specificity with corresponding 95% confidence interval were 69% (95% confidence interval [CI], 54-81; heterogeneity I 2  = 82.4%) and 88% (95% CI, 82-92; I 2  = 52.7%), respectively. The diagnostic odd ratio (DOR) was 16 (95% CI, 10-25; I 2  = 76.4%). The summary receiver operator characteristic (SROC) of PCT for post-operative infection was 0.88. There was a wide range of variability in the cutoff values, ranging from 0.22 to 42.80 ng/mL. Heterogeneity was reduced by excluding studies that focused on pediatric LT recipients. Conclusions: Procalcitonin is a moderately accurate diagnostic marker for post-operative infection in adult LT. Additionally, the diagnostic performance can be improved by combining it with other inflammatory biomarkers. This article provides the research direction for post-operative infection control.

Non-enzymatic browning occurs widely in both white and red wines, and it has a huge impact on the color evolution and aging potential. Previous studies have proved that phenolic compounds, especially those with catechol groups, are the most important substrates involved in browning reactions of wine. This review focus on the current knowledge of non-enzymatic browning in wine resulting from monomeric flavan-3-ols. First, some relevant aspects of monomeric flavan-3-ols are introduced, including their structures, origins, chemical reactivities, as well as potential impacts on the organoleptic properties of wine. Second, the mechanism for non-enzymatic browning induced by monomeric flavan-3-ols is discussed, with an emphasis on the formation of yellow xanthylium derivatives, followed by their spectral properties and effects on the color change of wine. Finally, attentions are also be given to the factors that influence non-enzymatic browning, such as metal ions, light exposure, additives in winemaking, etc., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Stable isotope technique is important for understanding the structure and function of soil food web, which is considered as a belowground black box. We reviewed typical application cases of stable isotope techniques in the research of soil food webs, including to determine food sources and feeding preferences of soil fauna by using isotopes, and to analyze the trophic structure of soil food webs through isotope fractionation effects during the process of feeding and nutrient sequestration by soil fauna. Additionally, stable isotope techniques could reveal the role of soil biota at different trophic levels within soil food web in ecosystem matter and energy flow, which favored to carry out accurate and efficient research on the contribution of soil food webs to soil carbon and nitrogen cycling process and the corresponding influence mechanism. We further put forward the limitations of current stable isotope techniques and the future development directions.

Background: The maturation of microRNAs (miRNAs) successively undergoes Drosha, Dicer, and Argonaute -mediated processing, however, the intricate regulations of the individual miRNA maturation are largely unknown. Retinoid x receptor alpha (RXRα) belongs to nuclear receptors that regulate gene transcription by binding to DNA elements, however, whether RXRα binds to miRNAs to exert physiological functions is not known., Results: In this work, we found that RXRα directly binds to the precursor of miR-103 (pre-miR-103a-2) via its DNA-binding domain with a preferred binding sequence of AGGUCA. The binding of RXRα inhibits the processing of miR-103 maturation from pre-miR-103a-2. Mechanistically, RXRα prevents the nuclear export of pre-miR-103a-2 for further processing by inhibiting the association of exportin-5 with pre-miR-103a-2. Pathophysiologically, the negative effect of RXRα on miR-103 maturation correlates to the positive effects of RXRα on the expression of Dicer, a target of miR-103, and on the inhibition of breast cancer., Conclusions: Our findings unravel an unexpected role of transcription factor RXRα in specific miRNA maturation at post-transcriptional level through pre-miRNA binding, and present a mechanistic insight regarding RXRα role in breast cancer progression., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The transcription factor Fli-1, a member of the ETS family of transcription factors, is implicated in the pathogenesis of lupus disease. Reduced Fli-1 expression in lupus mice leads to decreased renal Cxcl10 mRNA levels and renal infiltrating CXCR3+ T cells that parallels reduced renal inflammatory cell infiltration and renal damage. Inflammatory chemokine CXCL10 is critical for attracting inflammatory cells expressing the chemokine receptor CXCR3. The CXCL10/CXCR3 axis plays a role in the pathogenesis of various inflammatory diseases including lupus. Our data here demonstrate that renal CXCL10 protein levels are significantly lower in Fli-1 heterozygous MRL/ lpr mice compared to wild-type MRL/ lpr mice. Knockdown of Fli-1 significantly reduced CXCL10 secretion in mouse and human endothelial cells, and human mesangial cells, upon LPS or TNFα stimulation. The Fli-1 inhibitor, Camptothecin, significantly reduced CXCL10 production in human monocyte cells upon interferon stimulation. Four putative Ets binding sites in the Cxcl10 promoter showed significant enrichment for FLI-1; however, FLI-1 did not directly drive transcription from the human or mouse promoters, suggesting FLI-1 may regulate CXCL10 expression indirectly. Our results also suggest that the DNA binding domain of FLI-1 is necessary for regulation of human hCXCR3 promotor activity in human T cells and interactions with co-activators. Together, these results support a role for FLI-1 in modulating the CXCL10-CXCR3 axis by directly or indirectly regulating the expression of both genes to impact lupus disease development. Signaling pathways or drugs that reduce FLI-1 expression may offer novel approaches to lupus treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Richard, Caldwell, Sundararaj, Sato, Nowling and Zhang.)

Non-obstract azoospermia (NOA) is a serious male infertility disease. At present, testicular sperm extraction (micro-TESE) is performed in combination with intracytoplasmic sperm injection (ICSI) technology, NOA patients can have their own consanguine offspring. However, due to the invasiveness and uncertainty of micro-TESE surgery, it is difficult for patients to accept it. Therefore, finding an accurate method to predict the possibility of micro-TESE successful sperm retrival would be beneficial to azoospermia patients. Many genes are transcribed and expressed during spermatogenesis, and molecular assays have irreplaceable sensitivity and specificity in predicting the success sperm retrivel of micro-TESE. This article reviews the methods to predict the success sperm retrivel of micro-TESE including mRNA, non-coding RNA (piRNA, microRNA, cirRNA, tFRNAs) and some protein so far, to provide certain reference value for clinical and subsequent research.

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host&apos;s antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.

The main purpose of this study was to reveal the nutritional value and antioxidant activity of 34 edible flowers that grew in Yunnan Province, China, through a comprehensive assessment of their nutritional composition and antioxidant indices. The results showed that sample A3 of Asteraceae flowers had the highest total flavonoid content, with a value of 8.53%, and the maximum contents of vitamin C and reducing sugars were from Rosaceae sample R1 and Gentianaceae sample G3, with values of 143.80 mg/100 g and 7.82%, respectively. Samples R2 and R3 of Rosaceae were the top two flowers in terms of comprehensive nutritional quality. In addition, the antioxidant capacity of Rosaceae samples was evidently better than that of three others, in which Sample R1 had the maximum values in hydroxyl radical ( · OH) scavenging and superoxide anion radical ( · O 2 - ) scavenging rates, and samples R2 and R3 showed a high total antioxidant capacity and 2,2-diphenyl-1-pyridylhydrazine (DPPH) scavenging rate, respectively. Taken together, there were significant differences in the nutrient contents and antioxidant properties of these 34 flowers, and the comprehensive quality of Rosaceae samples was generally better than the other three families. This study provides references for 34 edible flowers to be used as dietary supplements and important sources of natural antioxidants., Competing Interests: The authors declare that they have no competing interest.

Astringency is one of the most important organoleptic characteristics of red wines, and its intensity evaluation method has been the focus of research in recent years. An artificial saliva system was developed to establish an accurate and reliable evaluation method for the astringency intensity of dry red wines based on saliva precipitation index (SPI). To achieve this, five key protein families, which presented high reactivities and sensitivities in protein-tannin binding reactions, were selected from human whole saliva. The concentrations of the five proteins (proline-rich protein, α-amylase, lactoferrin, lysozyme, and albumin) and pH were optimized using response surface methodology based on the human salivary conditions to simulate the real salivary environment. The artificial saliva precipitation index method was applied to 60 commercial dry red wines and it exhibited a high correlation (Coef ASPI  = 0.94) with the sensory scores, indicating better performance than the traditional SPI method and other analytical approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Postoperative cognitive dysfunction (POCD) is common in aged patients after major surgery and is associated with increased risk of long-term morbidity and mortality. However, the underlying mechanism remains largely unknown and the clinical management of POCD is still controversial. Stellate ganglion block (SGB) is a clinical treatment for nerve injuries and circulatory issues. Recent evidence has identified the benefits of SGB in promoting learning and memory. We thus hypothesize that SGB could be effective in improving cognitive function after surgery. In present study, we established POCD model in aged rats via partial liver resection surgery. We found that the development of POCD was associated with the activation of toll-like receptor 4/nuclear factor kapa-B (TLR4/NF-κB) signaling pathway in the microglia in dorsal hippocampus, which induced the production of pro-inflammatory mediators (TNF-α, IL-1β, IL-6) and promoted neuroinflammation. More importantly, we showed evidence that preoperative treatment with SGB could inhibit microglial activation, suppress TLR4/NF-κB-mediated neuroinflammation and effectively attenuate cognitive decline after the surgery. Our study suggested that SGB may serve as a novel treatment to prevent POCD in elderly patients. As SGB is safe procedure widely used in clinic, our findings can be easily translated into clinical practice and benefit more patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) is overexpressed in various cancer types. We found that Bmi-1 mRNA levels were elevated in nasopharyngeal carcinoma (NPC) cell lines. In immunohistochemical analyses, high Bmi-1 levels were observed in not only 5 of 38 non-cancerous nasopharyngeal squamous epithelial biopsies, but also in 66 of 98 NPC specimens (67.3%). High Bmi-1 levels were detected more frequently in T3-T4, N2-N3 and stage III-IV NPC biopsies than in T1-T2, N0-N1 and stage I-II NPC samples, indicating that Bmi-1 is upregulated in advanced NPC. In 5-8F and SUNE1 NPC cells, stable depletion of Bmi-1 using lentiviral RNA interference greatly suppressed cell proliferation, induced G1-phase cell cycle arrest, reduced cell stemness and suppressed cell migration and invasion. Likewise, knocking down Bmi-1 inhibited NPC cell growth in nude mice. Both chromatin immunoprecipitation and Western blotting assays demonstrated that Hairy gene homolog (HRY) upregulated Bmi-1 by binding to its promoter, thereby increasing the stemness of NPC cells. Immunohistochemistry and quantitative real-time PCR analyses revealed that HRY expression correlated positively with Bmi-1 expression in a cohort of NPC biopsies. These findings suggested that HRY promotes NPC cell stemness by upregulating Bmi-1, and that silencing Bmi-1 can suppress NPC progression.

Objective: Friend leukaemia virus integration 1 (Fli-1) regulates chemokine/cytokine expression and thus plays an important role in the development of lupus nephritis. Chemokine CXC ligand 13 (CXCL13) is a chemokine that promotes the formation of ectopic lymphoid structures and has been reported to be associated with the pathogenesis of lupus nephritis. The relationship between Fli-1 and CXCL13 is unknown. This study aims to elucidate whether Fli-1 impacts CXCL13 expression and contributes to the progression of lupus-like nephritis in adult MRL/lpr mouse., Methods: Serum CXCL13 levels were measured in adult wild-type (WT) MRL/lpr mice and Fli-1 heterozygote knockout (Fli-1 +/- ) MRL/lpr mice (4 months old or older) using ELISA. Renal mRNA expression (CXCL13 and related molecules) was measured using real-time PCR method. Kidneys were removed, stained and evaluated using a pathology scoring system. The grade of CXCL13 or CXC-chemokine receptor type 5 (CXCR5)-positive immune cell infiltration into the kidney was evaluated using immunostaining with anti-CXCL13 or anti-CXCR5 antibodies. We also used immunofluorescence staining with CXCL13- and CD11b-specific antibodies to detect the infiltration of CXCL13/CD11b double-positive immune cells., Results: Serum CXCL13 levels in Fli-1 +/- MRL/lpr mice were significantly lower than that in WT MRL/lpr mice (545.5 and 960.5 pg/mL, p=0.02). Renal expression of CXCL13 mRNA and SRY-related HMG box4 (Sox4) (an important factor for B-cell development) levels were significantly lower in Fli-1 +/- MRL/lpr mice. Renal histology scores in WT MRL/lpr mice revealed significantly increased glomerular inflammation. Despite similar interstitial immune cell infiltration into the kidney, the number of CXCL13- and CXCR5-positive cells was significantly lower in Fli-1 +/- MRL/lpr mice than in WT mice. Furthermore, immunofluorescence staining revealed that Fli-1 +/- MRL/lpr mice had significantly fewer CXCL13/CD11b double-positive immune cells., Conclusion: Fli-1 regulates renal Sox4 mRNA expression and infiltration of CXCR5-positive cells as well as CXCL13/CD11b double-positive immune cells into the kidney, which affects CXCL13 expression and lupus-like nephritis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time- and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence (AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of medium-resolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery., (© 2023. The Author(s).)

As one of the most promising wine regions in China, the eastern foothills of the Helan Mountain (EFHM) in the Ningxia Hui Autonomous Region has attracted great attention recently. Geographically, EFHM is divided into six sub-regions, namely Shizuishan, Xixia, Helan, Qingtongxia, Yongning and Hongsipu. However, there have been few reports on the character and differences between wines in the six sub-regions. In this experiment, a total of 71 commercial Cabernet Sauvignon wines from six sub-regions were collected, and their phenolic compounds, visual properties and mouthfeel were investigated. The results showed that wines from the six sub-regions of EFHM showed distinctive phenolic profiles and could be distinguished through the OPLS-DA mode using 32 potential markers. In terms of color, Shizuishan wines showed higher a * values and lower b * values. The sensory evaluation showed that Hongsipu wines had higher astringency strength and lower tannin texture. The overall results implied that the phenolic compounds of wines in different sub-regions were affected by terroir conditions. To the best of our knowledge, this is the first time that a wide coverage of phenolic compounds has been analysed for wines from the sub-regions of EFHM, which could provide valuable information in deciphering the terroir of EFHM.