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Abstract Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls. We find that LFS individuals exhibit an increased prevalence of A/T nucleotides at fragment ends, dysregulated nucleosome positioning at p53 binding sites, and loci-specific changes in chromatin accessibility at development-associated transcription factor binding sites and at cancer-associated open chromatin regions. Machine learning classification resulted in robust differentiation between TP53 mutant versus wildtype cfDNA samples (AUC-ROC = 0.710–1.000) and intra-patient longitudinal analysis of ctDNA fragmentation signal enabled early cancer detection. These results suggest that cfDNA fragmentation may be a useful diagnostic tool in LFS patients and provides an important baseline for cancer early detection.

Abstract Background High-risk human papillomavirus (HR-HPV) infection is an important factor for the development of cervical cancer. HPV18 is the second most common HR-HPV after HPV16. Methods In this study, MEGA11 software was used to analyze the variation and phylogenetic tree of HPV18 E6-E7 and L1 genes. The selective pressure to E6, E7 and L1 genes was estimated using pamlX. In addition, the B cell epitopes of L1 amino acid sequences and T cell epitopes of E6-E7 amino acid sequences in HPV18 were predicted by ABCpred server and IEDB website, respectively. Results A total of 9 single nucleotide variants were found in E6-E7 sequences, of which 2 were nonsynonymous variants and 7 were synonymous variants. Twenty single nucleotide variants were identified in L1 sequence, including 11 nonsynonymous variants and 9 synonymous variants. Phylogenetic analysis showed that E6-E7 and L1 sequences were all distributed in A lineage. In HPV18 E6, E7 and L1 sequences, no positively selected site was found. The nonconservative substitution R545C in L1 affected hypothetical B cell epitope. Two nonconservative substitutions, S82A in E6, and R53Q in E7, impacted multiple hypothetical T cell epitopes. Conclusion The sequence variation data of HPV18 may lay a foundation for the virus diagnosis, further study of cervical cancer and vaccine design in central China.

Abstract The rubber tree, Hevea brasiliensis (Willd. ex Adr. de Juss.) Muell. Arg., is the sole plant worldwide utilized for the commercial production of natural rubber. Following years of breeding, there exists a wide array of germplasm differentiation in rubber trees. The exploration of diversity and population structure within rubber tree germplasm resources, alongside the establishment of core germplasm resources, is instrumental in elucidating the genetic background and facilitating the effective utilization and management of these resources. By employing SNP molecular marker technology, 195 rubber tree resources were amplified, their genetic diversity analyzed, and a fingerprint map was subsequently constructed. Through this process, the cold-resistant core germplasm of rubber trees was identified. The results revealed that the PIC, He, and pi values ranged from 0.0905 to 0.3750, 0.095 to 0.5000, and 0.0953 to 0.5013, respectively. Both group structure analysis and cluster analysis delineated the accessions into two groups, signifying a simple group structure. A core germplasm bank was established with a sampling ratio of 10%, comprising 21 accessions divided into two populations. Population G1 consists of 20 accessions, while population G2 comprises 1 accession. The research findings have led to the creation of a molecular database that is anticipated to contribute to the management and subsequent breeding applications of rubber tree accessions.

Abstract Background Rose (Rosa hybrida) is a globally recognized ornamental plant whose growth and distribution are strongly limited by drought stress. The role of Mediator, a multiprotein complex crucial for RNA polymerase II-driven transcription, has been elucidated in drought stress responses in plants. However, its physiological function and regulatory mechanism in horticultural crop species remain elusive. Results In this study, we identified a Tail module subunit of Mediator, RhMED15a-like, in rose. Drought stress, as well as treatment with methyl jasmonate (MeJA) and abscisic acid (ABA), significantly suppressed the transcript level of RhMED15a-like. Overexpressing RhMED15a-like markedly bolstered the osmotic stress tolerance of Arabidopsis, as evidenced by increased germination rate, root length, and fresh weight. In contrast, the silencing of RhMED15a-like through virus induced gene silencing in rose resulted in elevated malondialdehyde accumulation, exacerbated leaf wilting, reduced survival rate, and downregulated expression of drought-responsive genes during drought stress. Additionally, using RNA-seq, we identified 972 differentially expressed genes (DEGs) between tobacco rattle virus (TRV)-RhMED15a-like plants and TRV controls. Gene Ontology (GO) analysis revealed that some DEGs were predominantly associated with terms related to the oxidative stress response, such as ‘response to reactive oxygen species’ and ‘peroxisome’. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment highlighted pathways related to ‘plant hormone signal transduction’, in which the majority of DEGs in the jasmonate (JA) and ABA signalling pathways were induced in TRV-RhMED15a-like plants. Conclusion Our findings underscore the pivotal role of the Mediator subunit RhMED15a-like in the ability of rose to withstand drought stress, probably by controlling the transcript levels of drought-responsive genes and signalling pathway elements of stress-related hormones, providing a solid foundation for future research into the molecular mechanisms underlying drought tolerance in rose.

Abstract Background Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. Results In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. Conclusion In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment. Graphical Abstract

Background: Though anterior cruciate ligament (ACL) tear has been widely accepted as an important accelerator for knee osteoarthritis (KOA), the role of intrinsic ACL degeneration in developing KOA has not been fully investigated. Purpose: To determine whether ACL degeneration, in the absence of ACL tear, is associated with incident KOA over 4 years. Study design: Cohort study; Level of evidence, 2. Methods: Participants’ knees in this nested case–control study were selected from the Osteoarthritis Initiative (OAI) study, with Kellgren–Lawrence grading (KLG) of 0 or 1 ​at baseline (BL). Case knees which had incident KOA (KLG ≥2) over 4 years, were matched 1:1 with control knees by gender, age and radiographic status. ACL signal intensity alteration (0–3 scale) and volume were assessed as compositional feature and morphology of ACL degeneration, using knee MRI at P0 (time of onset of incident KOA), P-1 (1 year prior to P0) and baseline. Conditional logistic regression was applied to analyze the association between measures of ACL degeneration and incident KOA. Results: 337 case knees with incident KOA were matched to 337 control knees. Participants were mostly female (68.5%), with an average age of 59.9 years old. ACL signal intensity alterations at BL, P-1 and P0 were significantly associated with an increased odds of incident KOA respectively (all P for trend ≤0.001). In contrast, ACL volumes were not significantly associated with incident KOA at any time points. Conclusions: ACL signal intensity alteration is associated with increased incident KOA over 4 years, whereas ACL volume is not.The translational potential of this article: This paper focused on ACL signal intensity alteration which could better reflect ACL degeneration rather than ACL tear during the progression of KOA and explored this topic in a nested case–control study. Utilizing MR images from KOA participants, we extracted the imaging features of ACL. In addition, we established a semi-quantitative score for ACL signal intensity alteration and found a significant correlation between it and KOA incidence. Our findings confirmed that the more severe the ACL signal intensity alteration, the stronger relationship with the occurrence of KOA. This suggests that more emphasis should be placed on ACL degeneration rather than ACL integrity in the future.

Histone demethylase JMJD2D (also known as KDM4D) can specifically demethylate H3K9me2/3 to activate its target gene expression. Our previous study has demonstrated that JMJD2D can protect intestine from dextran sulfate sodium (DSS)-induced colitis by activating Hedgehog signaling; however, its involvement in host defense against enteric attaching and effacing bacterial infection remains unclear. The present study was aimed to investigate the role of JMJD2D in host defense against enteric bacteria and its underlying mechanisms. The enteric pathogen Citrobacter rodentium (C. rodentium) model was used to mimic clinical colonic infection. The responses of wild-type and JMJD2D-/- mice to oral infection of C. rodentium were investigated. Bone marrow chimeric mice were infected with C. rodentium. JMJD2D expression was knocked down in CMT93 cells by using small hairpin RNAs, and Western blot and real-time PCR assays were performed in these cells. The relationship between JMJD2D and STAT3 was studied by co-immunoprecipitation and chromatin immunoprecipitation. JMJD2D was significantly up-regulated in colonic epithelial cells of mice in response to Citrobacter rodentium infection. JMJD2D-/- mice displayed an impaired clearance of C. rodentium, more body weight loss, and more severe colonic tissue pathology compared with wild-type mice. JMJD2D-/- mice exhibited an impaired expression of IL-17F in the colonic epithelial cells, which restricts C. rodentium infection by inducing the expression of antimicrobial peptides. Accordingly, JMJD2D-/- mice showed a decreased expression of β-defensin-1, β-defensin-3, and β-defensin-4 in the colonic epithelial cells. Mechanistically, JMJD2D activated STAT3 signaling by inducing STAT3 phosphorylation and cooperated with STAT3 to induce IL-17F expression by interacting with STAT3 and been recruited to the IL-17F promoter to demethylate H3K9me3. Our study demonstrates that JMJD2D contributes to host defense against enteric bacteria through up-regulating IL-17F to induce β-defensin expression.

Background: Previous studies have found electroacupuncture could improve the clinical symptoms of first-episode major depressive disorder (MDD), but the exact neural mechanism of action needs to be further elucidated. Methods: Twenty-eight first-episode MDD patients were randomly divided into 14 electro-acupuncture stimulation (EAS) groups and 14 sham-acupuncture stimulation (SAS) groups, and clinical symptoms were assessed and functional magnetic resonance imaging (fMRI) scans were done in both groups. Amplitude of low-frequency fluctuations (ALFF) was used to observe the changes between the pre-treatment and post-treatment in the two groups, and the altered brain areas were selected as region of interest (ROI) to observe the FC changes. Meanwhile, the correlation between the altered clinical symptoms and the altered ALFF and FC of brain regions in the two groups was analyzed. Results: The EAS significantly decreased the HAMD-24 and HAMA-14 scores of MDD than SAS group. The imaging results revealed that both groups were able to increase the ALFF of the left middle temporal gyrus and the left cerebellar posterior lobe. When using the left middle temporal gyrus and the left posterior cerebellar lobe as ROIs, EAS group increased the FC between the left middle temporal gyrus with the left superior frontal gyrus, the left middle frontal gyrus, and the left hippocampus, and decreased the FC between the left posterior cerebellar lobe and the left calcarine gyrus, while SAS group only increased the FC between the left middle temporal gyrus with the left superior frontal gyrus. The alternations in clinical symptoms after EAS treatment were positively correlated with the altered ALFF values in the left middle temporal gyrus and the altered FC values in the left middle temporal gyrus and the left middle frontal gyrus. Conclusion: EA demonstrates modulation of functional activity in the default mode network (DMN), sensorimotor network (SMN), cognitive control network (CCN), limbic system, and visual network (VN) for the treatment of the first-episode MDD. Our findings contribute to the neuroimaging evidence for the efficacy of EAS.

Abstract Aim This research aims to offer a reference point for relevant departments to enhance the allocation of ageing resources and formulate policies accordingly. Design This study is designed as empirical quantitative research. Methods Data from the National Bureau of Statistics and the Ministry of Civil Affairs regarding older adults (aged≥60) from 2000 to 2022 and nursing beds from 1978 to 2022 were analysed. The differential autoregressive integrated moving averages model and Monte Carlo simulation were used to predict the growth of nursing beds per 1000 older people in China for the Years 2023–2025. Results It is projected that from 2023 to 2025, China will experience a further increase in its ageing population, with an average annual growth rate of 3.1%. By 2025, the number of older people in China is expected to surpass 300 million. Additionally, there will be a rise in the number of nursing beds, with an average annual growth rate of 1.9%, leading to a total of 8.79 million nursing beds by 2025. However, due to the rapid growth of the older population, there will be a slight decline in the number of nursing beds per 1000 older people in China, with an average annual growth rate of −1.00%.

ObjectiveThe purpose of this meta-analysis was to investigate the effect of high-intensity interval training (HIIT) on arterial stiffness (AS) and vascular function in persons at high risk of cardiovascular disease (CVD).MethodsWe conducted a comprehensive search of randomized controlled trials (RCTs) published in electronic databases (PubMed, Web of Science, Cochrane, Embase, and Ebsco) since their inception through October 2023 to evaluate the effect of HIIT on AS and vascular function in persons at high risk for CVD. The weighted mean difference (WMD) and 95% confidence intervals (95% CI) were calculated, and heterogeneity was assessed using the I2 test.ResultsThis study included 661 participants from 16 studies. HIIT significantly reduced pulse wave velocity (PWV) in persons at high risk for CVD [weighted mean difference (WMD), −0.62; 95% CI, −0.86–−0.38; P

Abstract Background Diminished ovarian reserve (DOR) is defined as a reduction in ovarian reserve and oocyte quality. The pathophysiology of DOR has not been completely explained as of yet. Scholars have uncovered a large number of exosomes that have been detected in follicular fluid, and exosomal miRNAs have been proven to play a critical role in controlling ovarian disorders and follicle formation. We focused on the expression profile of follicular fluid-derived exosomal microRNAs (miRNAs) and attempted to understand if their role is connected to the pathomechanism of DOR. Methods The follicular fluid-derived differentially expressed exosomal miRNAs (DEmiRs) between patients with DOR and those with normal ovarian function were investigated using the next-generation sequencing (NGS) method. The main metabolic and signaling pathways of DEmiRs were identified using the KEGG pathway database, disease ontology (DO) analysis, and gene ontology (GO) analysis. In the end, a Protein-Protein Interaction (PPI) network was built to search for exosomal miRNAs and their target genes that were potentially strongly connected with DOR. Results In comparison to normal controls, 52 DEmiRs were discovered in follicular fluid-derived exosomes of DOR patients, of which 19 were up-regulated and 33 were down-regulated (|log2(fold change) |>2, P 6.0 (MCODE score = 15) had six hub genes, including IGFR, VEGFA, KRAS, ERBB2, RHOA, and PTEN (MCODE score = 11.472). Conclusion Our data suggested a special expression profile of follicular fluid-derived exosomal miRNAs in patients with DOR, which was probably correlated to ovarian dysfunction and follicle formation. These results may give a unique insight into a better understanding of the molecular process in the pathogenesis of DOR or other ovarian diseases.

Abstract The coronavirus disease 2019 (COVID-19), which affects multiple organs, is causing an unprecedented global public health crisis. Most COVID-19 patients recover gradually upon appropriate interventions. Viruses were reported to utilize the small extracellular vesicles (sEVs), containing a cell-specific cargo of proteins, lipids, and nucleic acids, to escape the attack from the host’s immune system. This study aimed to examine the sEVs lipid profile of plasma of recovered COVID-19 patients (RCs). Plasma sEVs were separated from 83 RCs 3 months after discharge without underlying diseases, including 18 recovered asymptomatic patients (RAs), 32 recovered moderate patients (RMs), and 33 recovered severe and critical patients (RSs), and 19 healthy controls (HCs) by Total Exosome Isolation Kit. Lipids were extracted from sEVs and then subjected to targeted liquid chromatography-mass spectrometry. The size, concentration, and distribution of sEVs did not differ in RCs and HCs as validated by transmission electron microscopy, nanoparticle tracking analysis, and immunoblot analysis. Fifteen subclasses of 508 lipids were detected in plasma sEVs from HCs, RAs, RMs, and RSs, such as phosphatidylcholines (PCs) and diacylglycerols (DAGs), etc. Total lipid intensity displayed downregulation in RCs compared with HCs. The relative abundance of DAGs gradually dropped, whereas PCs, lysophosphatidylcholines, and sphingomyelins were higher in RCs relative to HCs, especially in RSs. 88 lipids out of 241 in sEVs of RCs were significantly different and a conspicuous increase was revealed with disease status. The sEVs lipids alternations were found to be significantly correlated with the clinical indices in RCs and HCs, suggesting that the impact of COVID-19 on lipid metabolism lingered for a long time. The lipid abnormalities bore an intimate link with glycerophospholipid metabolism and glycosylphosphatidylinositol anchor biosynthesis. Furthermore, the lipidomic analysis showed that RCs were at higher risk of developing diabetes and sustaining hepatic impairment. The abnormality of immunomodulation in RCs might still exist. The study may offer new insights into the mechanism of organ dysfunction and help identify novel therapeutic targets in the RCs.

The legs of insects play an important role in their daily behaviour, especially reproduction. Entomologists have performed much research on the role of the leg in different behaviours of beetles, an important group in the insect family, but relatively little has been done to study the ultrastructure and transcriptome of their legs. Hence, we systematically studied the ultrastructure and gene expression of the leg of G. cantor, a polygynous beetle, and compared its male and female diversity. In this study, we found the fore-leg, mid-leg and hind-leg of the female were significantly longer than those of the male. From the perspective of intuitive structural differences, we also compared the ultrastructures of the adhesion structure (tarsal) of males and females. The tarsal functional structure of the adult leg mainly includes sensilla and an adhesion structure. The sensilla on the tarsal joint mainly include sensilla chaetica (SCh II, SCh III) and sensilla trichodea (ST II). The adhesion structure includes disc-shaped bristles (di), lanceolate bristles (la), serrated bristles (se), spatula-shaped bristles (spl) and mushroom-shaped bristles (mus). Although there was no significant difference in sensillum distribution or type between males and females, there were significant differences in the distribution and species of adhesion structures between the fore-leg, mid-leg, and hind-leg of the same sex and between males and females. Therefore, different adhesion structures play different roles in various behaviours of beetles. On the other hand, the transcriptome results of male and female legs were screened for a subset of olfaction- and mechanics-related genes. We discovered that the male leg showed upregulation of 1 odorant binding protein (OBP), 2 Olfactory receptors (ORs) and 2 Chemosensory proteins (CSPs). Meanwhile, the female leg showed upregulation of 3 OBPs, 1 OR, 1 Gustatory receptor (GR) and 3 Mechanosensitive proteins (MSPs). An in-depth examination of the ultrastructure and molecular composition of the legs can elucidate its function in the reproductive behavior of G. cantor. Moremore, this investigation will serve as a cornerstone for subsequent research into the underlying behavioral mechanisms.

IntroductionWe aimed to investigate the relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression levels, lupus nephritis (LN) disease activity, and the degree of renal injury (based on the estimated glomerular filtration rate [eGFR]) in patients with LN.MethodsWe selected 40 healthy control participants and 102 patients with LN who were treated in the Second Hospital of Jilin University, China, for inclusion in this study. Patients with LN were classified into LN with high-eGFR and LN with low-eGFR groups. Nrf2 protein levels were measured in the serum and renal tissues of the participants in both groups to assess the correlation between Nrf2 protein levels and different LN disease states.ResultsThere was a significantly positive correlation between serum Nrf2 protein levels, the degree of renal injury, and systemic lupus erythematosus disease activity index (SLEDAI) scores in patients with LN. Nrf2 protein levels were higher in the LN with high-eGFR group than in the healthy control and LN with low-eGFR groups. In follow-up patients in the LN high eGFR group, Nrf2 protein levels decreased significantly after remission of disease activity.ConclusionNrf2 protein expression has a dual role in patients with LN. Nrf2 protein levels not only correlate with disease activity in patients with LN, but also with the degree of kidney injury. Before implementing targeted therapy for Nrf2, evaluating both Nrf2 protein expression and the disease state in patients with LN is necessary to better identify and place each patient in an appropriate patient group.

Abstract The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.

Abstract Background Dihydromyricetin (DMY) is a natural flavonoid with anti-nonalcoholic steatohepatitis (NASH) activity. However, the effects of DMY on the composition of lipids and bile acids (BAs) in serum, and gut microbiota (GM) in ileum of mice with NASH are not clear. Methods After male C57BL/6 mice was fed with methionine and choline deficiency (MCD) diet and simultaneously administered with DMY (300 mg/kg/day) by gavage for 8 weeks, the pathological changes of liver tissue were observed by Oil Red O, hematoxylin eosin and Masson staining, the levels of serum alaninea minotransferase, aspartate aminotransferase and liver triglyceride, malonic dialdehyde were detected by the detection kits, the composition and contents of serum lipids and BAs were detected by Liquid Chromatograph-Mass Spectrometry, the mRNA levels of hepatic BAs homeostasis-related genes were detected by RT-qPCR, and microbiological diversity in ileum was analyzed by 16S rDNA sequencing. Results The results showed that the significant changes including 29 lipids, 4 BAs (23-nor-deoxycholic acid, ursodeoxycholic acid, 7-ketodeoxycholic acid and cholic acid), 2 BA transporters (Mrp2 and Oatp1b2) and 8 GMs between MCD and DMY groups. Among them, DMY treatment significantly down-regulated 21 lipids, 4 BAs mentioned above, the ratio of Firmicutes/Bacteroidota and the abundance of Erysipelotrichaceae, Faecalibacuium, significantly up-regulated 8 lipids and 5 GMs (Verrucomicrobiota, Bacteroidota, Actinobacteria, Akkermansiaceae and Akkermansia). Conclusions The results suggested that DMY may alleviate MCD diet-induced NASH through decreasing the serum levels of toxic BAs which regulated by liver Oatp1b2 and Mrp2, regulating the metabolism of related lipids, and up-regulating intestinal probiotics (Actinobacteria and Verrucomicrobiota at the phylum level; Akkermansiaceae at the family level; Akkermansiaat at the genus level) and inhibiting intestinal harmful bacteria (Firmicutes at the phylum level; Erysipelotrichaceae at the family level; Faecalibaculum at the genus level).

From the Late Carboniferous to the end of Middle Permian, the most intense glacial event in history of Phanerozoic occurred and it is also the last transition period from icehouse stage to greenhouse stage in geological history. In this paper, the paleotemperature and paleoclimate in the first member of the Middle Permian Maokou Formation (Mao-1) were restored by means of thin section identification, scanning electron microscope, major elements, trace elements, carbon isotopes, oxygen isotopes and strontium isotopes, and the major climate evolution process and its driving mechanism in the Middle Permian were discussed. The results show that the biological assemblage type (mainly composed of foraminifera, brachiopods and molluscs, without reef-building organisms or calcareous green algae) and rock structure characteristics (supported by bioclastic and plaster, without oolitic or other non-skeletal particles) of the limestone-marl alternations in the Mao-1 member are similar to those of the international typical cool-water carbonate. During the limestone sedimentary period, the paleotemperature of seawater was 3.72 to 12.38 ℃ (8.15 ℃ in average, δ18O standard) or 13.79 to 14.28 ℃ (13.90 ℃ in average, ω(Mg)/ ω(Ca) standard), while during the marl sedimentary period, the paleotemperature of seawater was 7.00 to 14.24 ℃ (10.97 ℃ in average, δ18O standard) and 13.82 to 15.41 ℃ (14.27 ℃ in average, ω(Mg)/ω(Ca) standard). The paleotemperature changes in the sedimentary period of Mao-1 Member was mainly driven by the short eccentricity cycle of Milankovitch. The cyclical change of the short eccentricity was the driving mechanism of paleotemperature and paleoclimate cycle changes.

This paper proposes an improved method to calculate the mutual capacitance between interdigital transducer (IDT) electrodes to enhance the accuracy of the traditional coupling-of-modes (COM) model, which is commonly used to simulate surface acoustic wave (SAW) filters and duplexers. In this method, the boundary element method (BEM) is adopted to obtain the capacitance per unit length in a layered medium, while the partial capacitance (PC) method is used to derive the effective relative permittivity of the multi-layered IDT. Numerical results from commercially available software are provided for comparison with the results calculated using the proposed method. The consistent results verify the validity and accuracy of this method, which also demonstrates significantly faster calculation speed compared to commercially available software. Precise electrical response prediction of a dual-mode SAW (DMS) filter can be achieved by applying this method to the COM model, and this ultra-fast calculation method can also be included in filter design optimization.

This paper aims at extending the method of Zhang et al. (2023) to produce not only portrait bas-reliefs from single photographs, but also high-depth reliefs with reasonable depth ordering. We cast this task as a problem of style-aware photo-to-depth translation, where the input is a photograph conditioned by a style vector and the output is a portrait relief with desired depth style. To construct ground-truth data for network training, we first propose an optimization-based method to synthesize high-depth reliefs from 3D portraits. Then, we train a normal-to-depth network to learn the mapping from normal maps to relief depths. After that, we use the trained network to generate high-depth relief samples using the provided normal maps from Zhang et al. (2023). As each normal map has pixel-wise photograph, we are able to establish correspondences between photographs and high-depth reliefs. By taking the bas-reliefs of Zhang et al. (2023), the new high-depth reliefs and their mixtures as target ground-truths, we finally train a encoder-to-decoder network to achieve style-aware relief modeling. Specially, the network is based on a U-shaped architecture, consisting of Swin Transformer blocks to process hierarchical deep features. Extensive experiments have demonstrated the effectiveness of the proposed method. Comparisons with previous works have verified its flexibility and state-of-the-art performance.

AbstractAmphotericin B (AmB) is regarded as a first-line therapy against life-threatening invasive fungal infections. Due to its poor oral bioavailability, AmB is restricted to intravenous administration in clinical practice. As science continues to move forward, two lipid-based formulations are successfully developed for oral AmB administration, currently undergoing phase I clinical trials. Encouragingly, lipid-AmB conjugates with emulsions also exhibit a better bioavailability, which may be another strategy to design oral AmB formulation in clinical practice. Thus, this review mainly focused on the two lipid-based formulations in clinical trials, and discussed the potential perspectives of AmB-lipid conjugation-loaded nanocochleates and emulsions.

Summary: Background: Pegmolesatide, a synthetic peptide-based erythropoietin (EPO) receptor agonist, is being evaluated as an alternative to epoetin alfa for treating anemia of chronic kidney disease (CKD) in Chinese dialysis patients. There is a critical need for a long-acting, cost-effective erythropoiesis-stimulating agent that does not produce EPO antibodies. Methods: A randomized, open-label, active-comparator, non-inferiority phase three trial was conducted at 43 dialysis centers in China between May 17th, 2019, and March 28th, 2022. Eligible patients aged 18–70 years were randomly assigned (2:1) to receive pegmolesatide once every four weeks or epoetin alfa one to three times per week, with doses adjusted to maintain a hemoglobin level between 10.0 and 12.0 g/dL. The primary efficacy endpoint was the mean change in hemoglobin level from baseline to the efficacy evaluation period in the per-protocol set (PPS) population. Non-inferiority of pegmolesatide to epoetin alfa was established if the lower limit of the two-sided 95% confidence interval for the between-group difference was ≥ −1.0 g/dL. Safety assessment included adverse events and potential anaphylaxis reactions. This trial is registered at ClinicalTrials.gov, NCT03902691. Findings: Three hundreds and seventy-two patients were randomly assigned to the pegmolesatide group (248 patients) or the epoetin alfa group (124 patients). A total of 347 patients (233 in the pegmolesatide group and 114 in the epoetin alfa group) were included in the PPS population. In the PPS, the mean change (standard deviation, SD) in hemoglobin level from baseline to the efficacy evaluation period was 0.07 (0.92) g/dL in the pegmolesatide group and −0.22 (0.97) g/dL in the epoetin alfa group. The between-group difference was 0.29 g/dL (95% confidence interval: 0.11–0.47), verifying non-inferiority of pegmolesatide to epoetin alfa. Adverse events occurred in 231 (94%) participants in the pegmolesatide group and in 110 (89%) in the epoetin alfa group. Hypertension was the most common treatment-related adverse event. No fatal cases of anaphylaxis or hypotension were reported. Interpretation: Monthly subcutaneously injection of pegmolesatide was as effective and safe as conventional epoetin alfa administrated one to three times a week in treating anemia in Chinese dialysis patients. Funding: The study was supported by Hansoh Medical Development Group.

Background and purposeSilibinin (SIL) is a flavonoid lignin isolated from the fruit and seeds of silybum marianum that exhibits good therapeutic potential for NASH. However, the effects of SIL on serum lipids, bile acids (BAs), and gut microbiota (GM) in NASH mice remain unknown. The present work aimed to explore the beneficial effects of SIL supplementation on serum lipids, bile acids, and gut microbiota in MCD mice.Experimental approachAfter male C57BL/6 mice were fed with a methionine-choline deficient (MCD) diet and simultaneously gavaged with SIL (20 mg/kg. d) for 8 weeks, the pathological changes of liver tissue were observed by oil red O, haematoxylin-eosin, and Masson tricolor staining; the levels of serum AST and ALT, and liver TG and MDA were detected by assay kits; metabonomics and 16S rDNA sequencing were used to analyze the composition of serum lipids and BAs and the abundance of GM; and the mRNA expression levels of hepatic genes related to BAs homeostasis were detected by RT-qPCR.ResultsThe results indicated that SIL treatment decreased the levels of 26 lipids (including four arachidonic acids, seven FFAs, 12 acyl carnitines, and three GPs) and two BAs (23-DCA, GLCA), while Dubosiella increased the levels of 10 lipids (including TxB3, PG16:0_18:1, Cer t18:0/24:0 and 7 TGs), five BAs (β-MCA, α-MCA, UDCA, 3-oxo-DCA and HCA), and two GMs (Verrucomicrobiota and Akkermansiaceae) of MCD mice, but had no significant effect on the mRNA expression of CYP7A1, CYP27A1, Bsep, Mrp2, Ntcp, or Oatp1b2. Therefore, influencing GM composition and then regulating the levels of serum lipids and BAs through enterohepatic axis should be an important mechanism of SIL-induced alleviative effect on MCD mice. More importantly, we found that SIL had a good coordination in regulating the abundance of GM and the contents of serum lipids and BAs in MCD mice, that is, when the abundance of probiotics was up-regulated, the content of beneficial unsaturated fatty acids in serum was up-regulated, while the serum levels of harmful lipids and BAs were down-regulated.ConclusionThe alleviating effect of SIL on NASH may be closely related to the correction of intestinal bacteria disorder, serum bile acid, and lipid metabolic disturbance in mice.

Abstract Background Toll-like receptors (TLRs) may be involved in the natural history of human papillomavirus (HPV) infection. In our study, we aimed to investigate the association of TLR4 (rs10116253, rs1927911, rs10759931) and TLR9 (rs187084, rs352140) gene polymorphisms with cervical persistent high-risk HPV (HR-HPV) infection, as well as multiple HR-HPV infections. Methods A total of 269 study subjects were enrolled and grouped by retrospectively analyzing the HR-HPV testing results and other clinical data of 2647 gynecological outpatients from Jingzhou Hospital Affiliated to Yangtze University. We conducted a case–control study to compare the role of TLR4/TLR9 gene polymorphisms between HR-HPV transient and persistent infections, as well as between HR-HPV single and multiple infections. HR-HPV genotypes were detected using Real-time polymerase chain reaction (RT-PCR). PCR-restriction fragment length polymorphism (PCR–RFLP) was used to determine TLR4 and TLR9 gene polymorphisms. Analyses of the different outcome variables (HR-HPV infection status and time for HR-HPV clearance) with respect to TLR4/TLR9 polymorphisms were carried out. Logistic regression analysis was used to determine the association of TLR4/TLR9 genotypes and alleles with HR-HPV infection status. The Kaplan–Meier method with the log-rank test was used to analyze the relationship between TLR4/TLR9 genotypes and the time for HR-HPV clearance. Results The mutant genotypes of TLR9 rs187084 and rs352140 were associated with persistent (rs187084: CT and CT+CC; rs352140: CT and CT+TT) and multiple (rs187084: CT and CT+CC; rs352140: CT+TT) (all P

Abstract Attenuated Salmonella Typhimurium is a promising antigen delivery system for live vaccines such as polysaccharides. The length of polysaccharides is a well-known key factor in modulating the immune response induced by glycoconjugates. However, the relationship between the length of Lipopolysaccharide (LPS) O-antigen (OAg) and the immunogenicity of S. Typhimurium remains unclear. In this study, we assessed the effect of OAg length determined by wzz ST on Salmonella colonization, cell membrane permeability, antimicrobial activity, and immunogenicity by comparing the S. Typhimurium wild-type ATCC14028 strain to those with various OAg lengths of the Δwzz ST mutant and Δwzz ST::wzz ECO2. The analysis of the OAg length distribution revealed that, except for the very long OAg, the short OAg length of 2–7 repeat units (RUs) was obtained from the Δwzz ST mutant, the intermediate OAg length of 13–21 RUs was gained from Δwzz ST::wzz ECO2, and the long OAg length of over 20 RUs was gained from the wild-type. In addition, we found that the OAg length affected Salmonella colonization, cell permeability, and antibiotic resistance. Immunization of mice revealed that shortening the OAg length by altering wzz ST had an effect on serum bactericidal ability, complement deposition, and humoral immune response. S. Typhimurium mutant strain Δwzz ST::wzz ECO2 possessed good immunogenicity and was the optimum option for delivering E. coli O2 O-polysaccharides. Furthermore, the attenuated strain ATCC14028 ΔasdΔcrpΔcyaΔrfbPΔwzz ST::wzz ECO2-delivered E. coli O2 OAg gene cluster outperforms the ATCC14028 ΔasdΔcrpΔcyaΔrfbP in terms of IgG eliciting, cytokine expression, and immune protection in chickens. This study sheds light on the role of OAg length in Salmonella characteristics, which may have a potential application in optimizing the efficacy of delivered polysaccharide vaccines.

ABSTRACT: Deep learning architectures have yielded a significant leap in target detection performance. However, the high cost of deep learning impedes real-world applications, especially for UAV and UGV platforms. Moreover, detecting small targets is still of lower accuracy in contrast to the large ones. Aiming to comprehensively handle these two issues, a novel SP-CBAM-YOLOv5 architecture is proposed. The main novelty of our hybrid model lies in the cooperation of the attention mechanism and the typical YOLOv5 architecture, which can largely improve the performance of the small target detection. Moreover, the depth convolution and knowledge distillation are jointly introduced for lightening the model architecture. To evaluate the performance of our proposed SP-CBAM-YOLOv5, we built a novel dataset containing challenging scenes of power engineering. Experimental results on this benchmark demonstrate that our proposed SP-CBAM-YOLOv5 achieves a competitive performance in contrast to the other YOLO architectures. Besides, our lightweight YOLOv5 has more than 70% decrease of parameters. Moreover, the ablation study is conducted to demonstrate the compact architecture of SP-CBAM-YOLOv5.

Rolling machinery is ubiquitous in power transmission and transformation equipment, but it suffers from severe faults during long-term running. Automatic fault diagnosis plays an important role in the production safety of power equipment. This paper proposes a novel cross-domain co-attention network (CDCAN) for fault diagnosis of rolling machinery. Multiscale features cross time and frequency domains are respectively extracted from raw vibration signal, which are then fused with a co-attention mechanism. This architecture fuses layer-wise activations to enable CDCAN to fully learn the shared representation with consistency across time and frequency domains. This characteristic helps CDCAN provide more faithful diagnoses than state-of-the-art methods. Experiments on bearing and gearbox datasets are conducted to evaluate the fault-diagnosis performance. Extensive experimental results and comprehensive analysis demonstrate the superiority of the proposed CDCAN in term of diagnosis correctness and adaptability.

The highly conserved actin depolymerizing factor (ADF) plays an important role in plant growth, development and responses to biotic and abiotic stresses. A total of 72 ADF genes in Arabidopsis, wheat, rice and sorghum can be divided into four groups. The multicollinearity analysis revealed that the maize ADF gene family exhibited more collinearity events with closely related gramineous plants. Fifteen ADF genes in maize were screened from the latest database, and bioinformatics analysis showed that these ADF genes were distributed across seven chromosomes in maize. The gene structure of the ADF gene family in maize exhibits significant conservation and cluster consistency. The promoter region contains rich regulatory elements that are involved in various regulations related to growth, development and adverse stresses. The drought-tolerant ZmADF5 gene in maize was further studied, and it was found that the allelic variations in ZmADF5 were mainly concentrated in its promoter region. A superior haplotype, with drought tolerance, was identified by candidate-gene association analysis of 115 inbred lines. By comparing the phenotypes of anthesis silking interval, grain yield and ear height, it was found that Hap2 performed better than Hap1 under drought stress. This study provides a theoretical reference for understanding the function of the ADF gene family and proposes further investigation into the role of ZmADF5 in abiotic-stress tolerance.

The last-mile logistics in cities have become an indispensable part of the urban logistics system. This study aims to explore the effective selection of last-mile logistics nodes to enhance the efficiency of logistics distribution, strengthen the image of corporate distribution, further reduce corporate operating costs, and alleviate urban traffic congestion. This paper proposes a clustering-based approach to identify urban logistics nodes from the perspective of geographic information fusion. This method comprehensively considers several key indicators, including the coverage, balance, and urban traffic conditions of logistics distribution. Additionally, we employed a greedy algorithm to identify secondary nodes around primary nodes, thus constructing an effective nodal network. To verify the practicality of this model, we conducted an empirical simulation study using the logistics demand and traffic conditions in the Xianlin District of Nanjing. This research not only identifies the locations of primary and secondary logistics nodes but also provides a new perspective for constructing urban last-mile logistics systems, enriching the academic research related to the construction of logistics nodes. The results of this study are of significant theoretical and practical importance for optimizing urban logistics networks, enhancing logistics efficiency, and promoting the improvement of urban traffic conditions.

Drought stress is seriously affecting the growth and production of crops, especially when agricultural irrigation still remains quantitatively restricted in some arid and semi-arid areas. The identification of drought-tolerant genes is important for improving the adaptability of maize under stress. Here, we found that a new member of the actin-depolymerizing factor (ADF) family; the ZmADF5 gene was tightly linked with a consensus drought-tolerant quantitative trait locus, and the significantly associated signals were detected through genome wide association analysis. ZmADF5 expression could be induced by osmotic stress and the application of exogenous abscisic acid. Its overexpression in Arabidopsis and maize helped plants to keep a higher survival rate after water-deficit stress, which reduced the stomatal aperture and the water-loss rate, as well as improved clearance of reactive oxygen species. Moreover, seventeen differentially expressed genes were identified as regulated by both drought stress and ZmADF5, four of which were involved in the ABA-dependent drought stress response. ZmADF5-overexpressing plants were also identified as sensitive to ABA during the seed germination and seedling stages. These results suggested that ZmADF5 played an important role in the response to drought stress.

Mediator is a multiprotein complex integral to the transcription machinery, mediated by RNA polymerase II. Some Mediator subunits have been found to have critical functions in plants’ responses to abiotic stresses. However, the role of plant Mediator subunits in drought responses remains largely enigmatic. Here, we identified a Mediator subunit, RhMED15a, in roses (Rosa hybrida). Its expression was greatly and swiftly induced by dehydration treatment in the root. The promoter sequence of RhMED15a contains cis-acting elements that respond to abscisic acid (ABA) and methyl jasmonate (MeJA). In addition, the expression of RhMED15a was significantly up-regulated with ABA treatment and inversely down-regulated with MeJA treatment. Silencing RhMED15a using virus-induced gene silencing (VIGS) in roses significantly reduced drought tolerance in rose plants. This resulted in a significant increase in the malondialdehyde (MDA) level and a decreased survival rate in comparison to TRV controls. Moreover, we found that the expression of five drought-related genes, including dehydration responsive element binding factor 1B (DREB1B), responsive to desiccation stress 29A (RD29A), responsive to desiccation stress 29B (RD29B), early response to dehydration 14 (ERD14), and 9-cis-epoxycarotenoid dioxygenase 1 (NCED1), was considerably suppressed in RhMED15a-silenced plants during drought stress. Taken together, our results present that the Mediator tail module subunit RhMED15a serves as an enhancer of drought tolerance in rose, probably through the modulation of the expression of some drought-related genes.

Osteosarcoma (OS) is the most common malignant bone tumor in adolescents, and the clinical treatment of OS mainly includes surgery, radiotherapy, and chemotherapy. However, the side effects of chemotherapy drugs are an issue that clinicians cannot ignore. Nanomedicine and drug delivery technologies play an important role in modern medicine. The development of nanomedicine has ushered in a new turning point in tumor treatment. With the emergence and development of nanoparticles, nanoparticle energy surfaces can be designed with different targeting effects. Not only that, nanoparticles have unique advantages in drug delivery. Nanoparticle delivery drugs can not only reduce the toxic side effects of chemotherapy drugs, but due to the enhanced permeability retention (EPR) properties of tumor cells, nanoparticles can survive longer in the tumor microenvironment and continuously release carriers to tumor cells. Preclinical studies have confirmed that nanoparticles can effectively delay tumor growth and improve the survival rate of OS patients. In this manuscript, we present the role of nanoparticles with different functions in the treatment of OS and look forward to the future treatment of improved nanoparticles in OS.

Abstract Background Gestational diabetes mellitus (GDM) is the most common complication during pregnancy, occurring under the combined action of environmental and genetic factors. Genetic variants of glucagon-like peptide-1 receptor (GLP-1R) have been reported to affect insulin secretion and susceptibility to type 2 diabetes. This study aimed to explore the role of GLP-1R polymorphisms in GDM and glucose metabolism. Methods A two-center nested case‒control study was designed, including 200 pregnant women with GDM and 200 pregnant women without GDM genotyped for five tag SNPs of GLP-1R using Sanger sequencing. Logistic regression was used to evaluate the relationship between GLP-1R polymorphisms and GDM risk. Glucose and insulin concentrations were measured based upon the 75 g oral glucose tolerance test (OGTT). Beta cell function of different genotypes was estimated with the 60 min insulinogenic index (IGI60) and OGTT-derived disposition index (DI). Results Mutant genotype AG + GG of tag SNP rs6458093 nominally increased GDM risk (p = 0.049), especially among subjects younger than 35 years (p = 0.024) and with BMI no less than 24 (p = 0.041), after adjusting for confounders. Meanwhile, compared with subjects with wild genotype AA, subjects with genotype AG + GG of rs6458093 also showed nominally significantly lower IGI60 (p = 0.032) and DI (p = 0.029), as well as significantly higher 75 g OGTT-based 1 h glucose load plasma glucose levels (p = 0.045). Moreover, the mutant heterozygous genotype GA of tag SNP rs3765467 nominally decreased GDM risk among subjects older than 35 years (p = 0.037) but showed no association with insulin secretion and glucose homeostasis. Conclusions Tag SNP rs6458093 of GLP-1R was nominally associated with increased GDM risk and affected beta cell function and postprandial glucose metabolism, while tag SNP rs3765467 of GLP-1R was nominally associated with decreased GDM risk, providing evidence for molecular markers and etiological study of GDM.

Abstract The increasing prevalence of antibiotic resistance by Pseudomonas aeruginosa (PA) raises an urgent need for an effective vaccine. The outer membrane proteins of PA, especially those that are upregulated during infection, are ideal vaccine targets. However, the strong hydrophobicity of these proteins hinders their application for this purpose. In this study, we selected eight outer membrane proteins from PA with the most significantly upregulated expression. Their extracellular loops were analyzed and screened by using sera from patients who had recovered from PA infection. As a result, a novel immunogenic epitope (Ep167-193) from PilY1 (PA4554) was found. Moreover, we constructed a macrophage membrane-coated PLGA (poly lactic-co-glycolic acid) nanoparticle vaccine carrying PilY1 Ep167-193 (PNPs@M-Ep167-193) that elicits a Th2 immune response and confers adequate protection in mice. Our data furnished the promising vaccine candidate PNPs@M-Ep167-193 while providing additional evidence for structure-based epitope identification and vaccine design. Graphical Abstract

Background Besides the traditional roles of HBA1 and HBB, recent findings suggest that hemoglobin genes may have roles in other contexts.Objective In the present study, we aim to investigate a possible tumor-suppressor role of HBA1 and HBB in acute myeloid leukemia.Methods Quantitative real-time PCR (RT-qPCR) was performed to detect the expression levels of HBA1 and HBB in acute myeloid leukemia patients and AML cell lines. The transfected cells were analyzed for Cell Counting Kit-8 (CCK-8), apoptosis, and cell cycle assay.Results HBA1 and HBB genes were significantly decreased in acute myeloid leukemia patients and AML cell lines. Furthermore, in vitro approaches showed that overexpression of HBA1 and HBB inhibited proliferation, induced cell apoptosis, and blocked cell cycle process at the G2/M phase in K562 cells.Conclusion Our data indicated that HBA1 and HBB genes may be potential tumor-suppressor genes in acute myeloid leukemia.

Purpose Urgent start peritoneal dialysis (USPD) is an effective therapeutic method for end-stage renal disease (ESRD). However, whether it is safe to initiate peritoneal dialysis (PD) within 24 h unclear. We examined the short-term outcomes of a break-in period (BI) of 24 h for patients undergoing USPD.Methods This real-world, multicenter, retrospective cohort study evaluated USPD patients from five centers from January 2013 to August 2020. Patients were divided into BI ≤ 24 h or BI > 24 h groups. The Primary outcomes included incidence of mechanical and infectious complications. The secondary outcome was technique failure. Moreover, we presented a subgroup analysis for patients who did not receive temporary hemodialysis (HD).Results A total of 871 USPD patients were included: 470 in the BI ≤ 24 h and 401 in the BI > 24 h groups. Mechanical and infectious complications did not differ between the two groups across the follow-up timepoints (2 weeks, 1 month, 3 months, and 6 months) (p > 0.05). Multiple logistic regression analysis revealed that BI ≤ 24 h was not an independent risk factor for mechanical complications, catheter migration, or infectious complications (p > 0.05). A BI ≤ 24 h was not an independent significant risk factor for technique failure by multivariate Cox regression analysis (p > 0.05). The subgroup analysis of patients who did not receive temporary HD returned the same results.Conclusion Initiating PD within 24 h of catheter insertion was not associated with increased mechanical complications, infectious complications, or technique failures.

Residential energy consumption has increased rapidly with the improvement of living standards of Chinese households, in particular, heating demand in North China has a direct impact on the haze. The integration of renewable energy with the combined heat and power (CHP) technology provides an effective method to solve the household energy consumption and environmental impacts, but the construction, capacity, and cost of the system seriously affect the economy of the system, environmental protection, and operational reliability. Therefore, a family-oriented small-scale combined heat and power system was designed based on wind, photovoltaic, fuel cell, and hydrogen storage. The scheduling strategy of heat determined by power, meeting the requirements of all electrical loads and partial heat loads, and the minimum investment for the whole life cycle of 20 years was used as the objective function to design the system. Combined with the actual environmental conditions and thermoelectric load, an adaptive particle swarm optimization algorithm was improved for solving optimal allocation. The system was analyzed through thermal and power conditions, economy, the reliability of meeting the load, and other evaluation criteria in the optimal system configuration, the prediction, and evaluation of the prospects and development of the system provide basis and reference for the family cogeneration micro-grid applications.

Staphylococcus aureus secrete numerous effectors to evade or inhibit the host immune response, yet the mechanism underlying the effectors ability to manipulate the signalling pathways of macrophages remain unclear. Authors utilise in vitro and in vivo models to explore the role of extracellular fibrinogen-binding protein (Efb) in immune response modulation and pathogenicity.

Abstract Objective We investigated the correlation between zinc levels and Nrf2 expression and potential effects on the clinicopathology of patients with diabetic nephropathy (DN). Methods We selected 30 patients with DN, diagnosed via renal biopsy at our hospital from March 2018 to November 2019, and enrolled 30 healthy individuals from a medical examination center as the control group. Patients with DN were divided into normal-zinc and low-zinc groups. We detected the levels of zinc, copper, and Nrf2 mRNA in their serum, and collected the clinical and pathological data of DN patients. Results Serum zinc level and Nrf2 mRNA expression were significantly decreased in patients with DN compared to those of healthy people (P 0.05). However, the expression of Nrf2 in the kidney tissue of the low-zinc group was significantly lower compared to the normal-zinc group (P

Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study.Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn’s disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran’s Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction.Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66–0.89, and p = 3.66 × 10−4), SS (OR: 0.75, CI: 0.58–0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68–0.88, and p = 9.85 × 10−5), hypothyroidism (OR: 0.84, 95% CI: 0.78–0.91, and p = 7,08 × 10−6), hyperthyroidism (OR: 0.60, 95% CI: 0.44–0.83, and p = 1.90 × 10−3), sarcoidosis (OR: 0.67, 95% CI: 0.54–0.83, and p = 2.60 × 10−4), and IPF (OR: 0.41, 95% CI: 0.29–0.58, and p = 4.11 × 10−7) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18–1.94, and p = 9.66 × 10−4). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62–1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37–2.54, and p = 8.01 × 10−5).Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.

Abstract Background Cervical cancer is a common malignant tumor in women, with a high mortality rate, has great harm to women’s health. Long-term and persistent infection of high-risk human papillomavirus (HR-HPV) is the main reason of the occurrence and development of cervical cancer. Methods The infection rate of HPV-58 is higher in the Jingzhou area. In this study, 172 complete HPV-58 E6-E7 sequences were amplified by polymerase chain reaction (PCR), the amplified products were sequenced, and the gene variations of HPV-58 E6-E7 were analyzed. A Neighbor-Joining phylogenetic tree was constructed by MEGA 11. The secondary structure of E6 and E7 protein was investigated. PAML X was used to analyze the selective pressure. The B cell epitopes of E6 and E7 proteins in HPV-58 were predicted by ABCpred server. Results In E6 sequences, 10 single nucleotide variants were observed, including 7 synonymous and 3 non-synonymous variants. In E7 sequences, 12 single nucleotide variants were found, including 3 synonymous variants and 9 non-synonymous variants. There are 5 novel variants. The phylogenetic analysis showed that all the E6-E7 sequences were distributed in A lineage. No positively selected site was found in E6 sequence, but G63 in E7 sequences was identified as positively selected site. Some amino acid substitutions affected multiple B cell epitopes. Conclusion Various E6 and E7 mutational data may prove useful for development of better diagnostic and vaccines for the region of Jingzhou, Hubei province of central China.

Introduction Classical Philadelphia-negative myeloproliferative neoplasm (MPN) includes Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Primary Myelofibrosis (PMF). The JAK2V617F mutation is part of the major criteria for diagnosis of MPN. WT1 is reported to be highly overexpressed in most hematological malignancy. Our aim was to explore the combination value of JAK2V617F allele burden and WT1 expression in distinguishing the subtype of MPN patients. Methods Allele specific real-time quantitative fluorescence PCR (AS-qPCR) was conducted to detect JAK2V617F allele burden. WT1 expression was assessed by RQ-PCR. Our study is a retrospective study. Results JAK2V617F allele burden and WT1 expression were different in MPN subgroups. The expression of WT1 in PMF and PV is higher than in ET. JAK2V617F allele burden in PMF and PV is also higher than in ET. ROC analysis indicated that combination of JAK2V617F allele burden and WT1 expression to discriminate ET and PV, ET and PMF, PV and PMF is 0.956, 0.871, 0.737 respectively. Furthermore, their ability to distinguish ET patients with high Hb levels from PV patients with high platelet counts is 0.891. Conclusions Our data revealed that combination of JAK2V617F allele burden and WT1 expression is useful in distinguishing the subtype of MPN patients.

The rostral ventromedial medulla (RVM) exerts bidirectional descending modulation of pain attributable to the activity of electrophysiologically identified pronociceptive ON and antinociceptive OFF neurons. Here, we report that GABAergic ON neurons specifically express G protein–coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, but their ablation abrogated, pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain, and ameliorated morphine analgesia through desensitizing μ-type opioid receptor–mediated (MOR-mediated) activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia, and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly indicate that GPER is a marker for GABAergic ON cells and illuminate the mechanisms underlying hormonal regulation of pain and analgesia, thus highlighting GPER as a promising target for the treatment of pain and opioid tolerance.

FOXP1, known as a Forkhead-box (FOX) family protein, plays an important role in human tumorigenesis. However, the function and molecular mechanism of FOXP1 in pancreatic cancer (PC) remain unclear. Here, we report that PC patients with FOXP1 overexpression had a higher survival rate compared to patients with low- FOXP1 expression. Additionally, high expression of FOXP1 can markedly inhibit the growth of pancreatic cancer in vivo and in vitro, whereas low expression of FOXP1 effectively promoted the tumorigenesis. Mechanistically, FOXP1 could directly bind the IRF1 promoter, which triggered the transcriptional activity of IRF1. Taken together, FOXP1 suppressed PC growth via IRF1-dependent manner, serving as a potential prognostic biomarker for patients with PC.

Abstract Colorectal cancer (CRC) is one of the most common cancers worldwide and a leading cause of carcinogenic death. To date, surgical resection is regarded as the gold standard by the operator for clinical decisions. Because conventional tissue biopsy is invasive and only a small sample can sometimes be obtained, it is unable to represent the heterogeneity of tumor or dynamically monitor tumor progression. Therefore, there is an urgent need to find a new minimally invasive or noninvasive diagnostic strategy to detect CRC at an early stage and monitor CRC recurrence. Over the past years, a new diagnostic concept called “liquid biopsy” has gained much attention. Liquid biopsy is noninvasive, allowing repeated analysis and real-time monitoring of tumor recurrence, metastasis or therapeutic responses. With the advanced development of new molecular techniques in CRC, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and tumor-educated platelet (TEP) detection have achieved interesting and inspiring results as the most prominent liquid biopsy markers. In this review, we focused on some clinical applications of CTCs, ctDNA, exosomes and TEPs and discuss promising future applications to solve unmet clinical needs in CRC patients.

Tumors are complex biological entities that comprise cell types of different origins, with different mutational profiles and different patterns of transcriptional dysregulation. The exploration of data related to cancer biology requires careful analytical methods to reflect the heterogeneity of cell populations in cancer samples. Single-cell techniques are now able to capture the transcriptional profiles of individual cells. However, the complexity of RNA-seq data, especially in cancer samples, makes it challenging to cluster single-cell profiles into groups that reflect the underlying cell types. We have developed a framework for a systematic examination of single-cell RNA-seq clustering algorithms for cancer data, which uses a range of well-established metrics to generate a unified quality score and algorithm ranking. To demonstrate this framework, we examined clustering performance of 15 different single-cell RNA-seq clustering algorithms on eight different cancer datasets. Our results suggest that the single-cell RNA-seq clustering algorithms fall into distinct groups by performance, with the highest clustering quality on non-malignant cells achieved by three algorithms: Seurat, bigSCale and Cell Ranger. However, for malignant cells, two additional algorithms often reach a better performance, namely Monocle and SC3. Their ability to detect known rare cell types was also among the best, along with Seurat. Our approach and results can be used by a broad audience of practitioners who analyze single-cell transcriptomic data in cancer research.

To elucidate the hardness evolution behaviors for 38MnB5Nb ultra-high-strength hot stamping steel, a series of tempering processes with varying tempering temperatures and times were carried out with a dilatometer. Meanwhile, the hardness of each sample was measured after dilatometer experiments. The results indicated that the tempering process parameters (including the tempering temperature and time) play an important role in the hardness of the studied steel. The hardness of 38MnB5Nb ultra-high-strength hot stamping steel at the quenched state is about 580 Hv, while it is 240 Hv for the quasi-annealed state. As the tempering time extends, the hardness is decreased sharply at the initial stage; then, the hardness is decreased in a quasi-linear trend with a slight slope; finally, the hardness almost keeps a constant value, which depends on the tempering temperature. In addition, the tempering process has a big effect on the mechanical properties of 38MnB5Nb ultra-high-strength hot stamping steel by increasing the product of the strength and elongation by about 40%.

This study aims to determine the association of pregnancy cholesterol metabolism markers with gestational diabetes mellitus (GDM) risk. We performed a nested case–control study in the Tongji Birth Cohort. GDM was diagnosed according to the 75 g 2 h oral glucose tolerance test (OGTT) at 24–28 gestational weeks. Nine cholesterol metabolism markers were detected using gas chromatography-mass spectrometry. Conditional logistic regression models were conducted. A total of 444 pregnant women were matched in a 1:2 ratio. The cholestanolTC and β-sitosterolTC in cholesterol absorption markers presented negative associations with the risks of GDM (adjusted OR: 0.77, 95% CI: 0.61–0.96; adjusted OR: 0.80, 95% CI: 0.64–1.00). The desmosterolTC in cholesterol synthesis markers were positively associated with the risks of GDM (adjusted OR: 1.25, 95% CI: 1.00–1.56), similar in the ratios of cholesterol synthesis to absorption markers. After adjustment for insulin or HOMA-IR, these effects were reduced. In conclusion, higher cholesterol synthesis and lower cholesterol absorption marker levels in the first pregnancy are associated with a higher risk of GDM, and insulin resistance may play a vital role in this association.

Gastric cancer (GC) continues to be the most common gastrointestinal malignancy in China, and tumor metastases are a major reason for poor prognosis. Circular RNAs (circRNAs) are an intriguing type of noncoding RNAs with important regulatory roles. However, the roles of circRNAs in GC metastasis have not been fully elucidated. Here, we reported that circ-transportin 3 (TNPO3) was significantly downregulated in 103 pairs of GC tissues compared with matched noncancerous tissues. The level of circ-TNPO3 expression correlated with differentiation of GC, and plasma circ-TNPO3 could serve as a potential diagnostic biomarker. Functionally, circ-TNPO3 inhibited proliferation and migration of GC in vitro and in vivo. We further verified that circ-TNPO3 competitively interacted with insulin-like growth factor 2 binding protein 3 (IGF2BP3) protein; thus, the role of IGF2BP3 in stabilizing MYC mRNA was weakened, which inhibited the expression of MYC and its target SNAIL. Taken together, circ-TNPO3 acts as a protein decoy for IGF2BP3 to regulate the MYC-SNAIL axis, thereby suppressing the proliferation and metastasis of GC. Therefore, circ-TNPO3 has the potential to serve as a therapeutic target for GC.