Astragalus membranaceus (Fisch.) Bge. (AM) and Angelica sinensis (Oliv.) Diels (AS) constitute a classic herb pair in prescriptions to treat myocardial fibrosis. To date, research on the AM-AS herb pair has mainly focused on the chemical compositions associated with therapeutic efficacy. However, supermolecules actually exist in herb codecoctions, and their self-assembly mechanism remains unclear. In this study, supermolecules originating from AM-AS codoping reactions (AA-NPs) were first reported. The chemical compositions of AA-NPs showed a dynamic self-assembly process. AA-NPs with different decoction times had similar surface groups and amorphous states; however, the size distributions of these nanoparticles might be different. Taking the interaction between Z-ligustilide and astragaloside IV as an example to understand the self-assembly mechanism of AA-NPs, it was found that the complex could be formed with a molar ratio of 2:1. Later, AA-NPs were proven to be effective in the treatment of myocardial fibrosis both in vivo and in vitro, the in-depth mechanisms of which were related to the recovery of cardiac function, reduced collagen deposition, and inhibition of the endothelial-to-mesenchymal transition that occurred in the process of myocardial fibrosis. Thus, AA-NPs may be the chemical material basis of the molecular mechanism of the AM-AS decoction in treating isoproterenol-induced myocardial fibrosis. Taken together, this work provides a supramolecular strategy for revealing the interaction between effective chemical components in herb-pair decoctions.

The COVID-19 pandemic has the potential to accelerate another pandemic: physical inactivity. Daily steps, a proxy of physical activity, are closely related to health. Recent studies indicate that over 7000 steps per day is the critical physical activity standard for minimizing the risk of all-cause mortality. Moreover, the risk of cardiovascular events has been found to increase by 8% for every 2000 steps per day decrement.

The yellow nutsedge (Cyperus esculentus L. 1753) is an unconventional oil plant with oil-rich tubers, and a potential alternative for traditional oil crops. Here, we reported the first high-quality and chromosome-level genome assembly of the yellow nutsedge generated by combining PacBio HiFi long reads, Novaseq short reads, and Hi-C data. The final genome size is 225.6 Mb with an N50 of 4.3 Mb. More than 222.9 Mb scaffolds were anchored to 54 pseudochromosomes with a BUSCO score of 96.0%. We identified 76.5 Mb (33.9%) repetitive sequences across the genome. A total of 23,613 protein-coding genes were predicted in this genome, of which 22,847 (96.8%) were functionally annotated. A whole-genome duplication event was found after the divergence of Carex littledalei and Rhynchospora breviuscula, indicating the rich genetic resources of this species for adaptive evolution. Several significantly enriched GO terms were related to invasiveness of the yellow nutsedge, which may explain its plastic adaptability. In addition, several enriched Kyoto Encyclopedia of Genes and Genomes pathways and expanded gene families were closely related with substances in tubers, partially explaining the genomic basis of characteristics of this oil-rich tuber.

The long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) plays an oncogenic role in multiple cancers due to its high expression. However, the expression and associated regulatory mechanisms of PVT1 in cutaneous squamous cell carcinoma (cSCC) remain unclear. Our results revealed that PVT1 was highly upregulated in cSCC tissues and cSCC cell lines. To determine the functional role of PVT1 in cSCC, we constructed a stable knockdown cell model of PVT1 in the A431 and COLO16 cell lines using a lentiviral approach. Xenograft tumor experiments of nude mice in vivo, and colony formation, CCK-8, and EdU assays in vitro demonstrated that knockdown of PVT1 could widely suppress cell proliferation in vivo and in vitro. In addition, PVT1 knockdown induced cell cycle arrest and promoted apoptosis, as detected by flow cytometry analysis. Wound healing and transwell assays revealed that PVT1 knockdown significantly inhibited the migration and invasion of CSCC cell lines. To gain insight into the tumorigenic mechanism and explore the potential target molecules of PVT1, we employed label-free quantitative proteomic analysis. The GO, KEGG enrichment, and protein-protein interaction (PPI) networks suggested that 4E-binding protein 1 (4EBP1) is the possible downstream target effector of PVT1, which was validated by western blot analysis. PVT1 silencing markedly decreased 4EBP1 protein expression levels and directly bound 4EBP1 in the cytoplasm of cSCC cells. 4EBP1 overexpression counteracted the effects of PVT1 knockdown on tumorigenesis in cSCC cells, including cell proliferation, apoptosis, migration, and invasion. Our findings provide strong evidence that PVT1 is an oncogene which plays a role in tumorigenesis of cSCC, that PVT1 may interact with 4EBP1 in the cytoplasm as an underlying mechanism in cSCC carcinogenesis, and that PVT1 combined with 4EBP1 may serve as a potential new therapeutic target for cSCC.

The introduction of the anti-PD-1 antibody has greatly improved the clinical outcomes of patients with non-small cell lung cancer (NSCLC). In this study, we retrospectively analyzed the efficacy of PD-1 antibody-based therapy in patients with locally advanced inoperable or metastatic NSCLC and reported an association between peripheral blood biomarkers and clinical response in these patients.

The rumen serves as a complex ecosystem, harboring diverse microbial communities that play crucial ecological roles. Because previous studies have predominantly focused on anaerobic microorganisms, limited attention has been given to aerobic microorganisms in the goat rumen. This study aims to explore the diversity of aerobic microorganisms in the rumen and understand their niche and ecological roles. Rumen fluid samples were collected from 6 goats at different time points post-morning feeding. pH, NH3-N, and volatile fatty acid (TVFA) concentrations were measured, while In vitro cultivation of aerobic microorganisms was performed using PDA medium. Internal Transcribed Spacer (ITS) and 16S sequencing unveiled microbial diversity within the rumen fluid samples. Evidence of obligate aerobic microorganisms in the goat rumen suggests their potential contribution to ecological functionalities. Significantly, certain aerobic microorganisms exhibited correlations with TVFA levels, implying their involvement in TVFA metabolism. This study provides evidence of the existence and potential ecological roles of obligate aerobic microorganisms in the goat rumen. The findings underscore the significance of comprehensively deciphering goat rumen microbial communities and their interactions, with aerobes regarded as permanent residents rather than transients. These insights form a solid foundation for advancing our understanding of the intricate interplay between goat and their aerobic microorganisms in the rumen.

Fritillaria is a well-known health-promoting food, but it has many varieties and its market circulation is chaotic. In order to explore the differences in volatile organic compounds (VOCs) among different varieties of Fritillaria and quickly and accurately determine the variety of Fritillaria, this study selected six varieties of Fritillaria and identified and analyzed their volatile components using gas chromatography-ion mobility spectrometry (GC-IMS), establishing the characteristic fingerprints of VOCs in Fritillaria. In all samples, a total of 76 peaks were detected and 67 VOCs were identified. It was found that the composition of VOCs in different varieties of Fritillaria was similar, but the content was different. Combined with chemometric analysis, the differences between VOCs were clearly shown after principal component analysis, cluster analysis, and partial least-squares discriminant analysis. This may provide theoretical guidance for the identification and authenticity determination of different varieties of Fritillaria.

Clotted plasma proteins are present on the walls of tumor vessels and in tumor stroma. Tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA) could recognize the clotted plasma proteins in tumor vessels. Thermosensitive liposomes could immediately release the encapsulated drug in the vasculature of the heated tumor. In this study, we designed a novel form of targeted thermosensitive liposomes, CREKA-modified lysolipid-containing thermosensitive liposomes (LTSLs), containing doxorubicin (DOX) (DOX-LTSL-CREKA), to investigate the hypothesis that DOX-LTSL-CREKA might target the clotted plasma proteins in tumor vessels as well as tumor stroma and then exhibit burst release of the encapsulated DOX at the heated tumor site. We also hypothesized that the high local drug concentration produced by these thermosensitive liposomes after local hyperthermia treatment will be useful for treatment of multidrug resistance. The multidrug-resistant human breast adenocarcinoma (MCF-7/ADR) cell line was chosen as a tumor cell model, and the targeting and immediate release characteristics of DOX-LTSL-CREKA were investigated in vitro and in vivo. Furthermore, the antitumor activity of DOX-LTSL-CREKA was evaluated in MCF-7/ADR tumor-bearing nude mice in vivo. The targeting effect of the CREKA-modified thermosensitive liposomes on the clotted plasma proteins was confirmed in our in vivo imaging and immunohistochemistry experiments. The burst release of this delivery system was observed in our in vitro temperature-triggered DOX release and flow cytometry analysis and also by confocal microscopy experiments. The antitumor activity of the DOX-LTSL-CREKA was confirmed in tumor-bearing nude mice in vivo. Our findings suggest that the combination of targeting the clotted plasma proteins in the tumor vessel wall as well as tumor stroma by using CREKA peptide and temperature-triggered drug release from liposomes by using thermosensitive liposomes offers an attractive strategy for chemotherapeutic drug delivery to tumors.

P-glycoprotein (P-gp) is encoded by the multidrug resistance (MDR1) gene and is well studied as a multi-drug resistance transporter. Peritoneal adhesion formation following abdominal surgery remains an important clinical problem. Here, we found that P-gp was highly expressed in human adhesion fibroblasts and promoted peritoneal adhesion formation in a rodent model. Knockdown of P-gp expression by intraperitoneal injection of MDR1-targeted siRNA significantly reduced both the peritoneal adhesion development rate and adhesion grades. Additionally, we found that operative injury up-regulated P-gp expression in peritoneal fibroblasts through the TGF-β1/Smad signaling pathway and histone H3 acetylation. The overexpression of P-gp accelerated migration and proliferation of fibroblasts via volume-activated Cl(-) current and cell volume regulation by enhancing phosphorylation of the chloride channel-3. Therefore, P-gp plays a critical role in postoperative peritoneal adhesion formation and may be a valuable therapeutic target for preventing the formation of peritoneal adhesions.

Several susceptibility loci have been reported associated with obesity and T2DM in GWAS. Fat mass and obesity associated gene (FTO) is the first gene associated with body mass index (BMI) and risk for diabetes in diverse patient populations. FTO is highly expressed in the brain and pancreas, and is involved in regulating dietary intake and energy expenditure. While much is known about the epigenetic mutations contributing to obesity and T2DM, less is certain with the expression regulation of FTO gene. In this study, a highly conserved canonical C/EBP α binding site was located around position -45~-54 bp relative to the human FTO gene transcriptional start site. Site-directed mutagenesis of the putative C/EBP α binding sites decreased FTO promoter activity. Overexpression and RNAi studies also indicated that C/EBP α was required for the expression of FTO. Chromatin immunoprecipitation (ChIP) experiment was carried out and the result shows direct binding of C/EBP α to the putative binding regions in the FTO promoter. Collectively, our data suggest that C/EBP α may act as a positive regulator binding to FTO promoter and consequently, activates the gene transcription.

Nail patella syndrome (NPS) is an autosomal dominant disorder characterized by nail malformations, patellar apoplasia, or patellar hypoplasia. Mutations within the LMX1B gene are found in 85% of families with NPS; thus, this gene has been characterized as the causative gene of NPS. In this study, we identified a heterozygous microdeletion of the entire LMX1B gene using multiplex ligation-dependent probe amplification (MLPA) in a Chinese family with NPS. The determination of the deletion breakpoints by Illumina genome-wide DNA analysis beadchip showed that the deletion was located in chromosome 9q33.3 and spanned about 0.66 Mb in size. This heterozygous deletion provides strong evidence for haploinsufficiency as the pathogenic mechanism of NPS.

CD2-associated protein (CD2AP) is an adaptor molecule involved in T cell receptor signaling and podocyte homeostasis. CD2AP-deficient mice develop nephritic syndrome and renal failure caused by glomerulosclerosis. Transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Here we report that E2F1 up-regulates the human CD2AP promoter and further increases the mRNA and protein levels of the human CD2AP in human embryonic kidney (HEK) 293 cells. By semi-quantitative RT-PCR and Western blot analysis we demonstrate that ectopic expression of E2F1 elevates the mRNA and protein levels of CD2AP. Consistently, transient transfection assays prove that overexpression of E2F1 transactivates the CD2AP promoter while knocking-down of endogenous E2F1 by a shRNA strategy results in reduction of the CD2AP promoter activity. Toward understanding the underlying mechanism of this regulation, we performed chromatin immunoprecipitation and mutations of the putative Sp1 binding sites, demonstrating that E2F1 can bind to Sp1 binding site and overexpression of E2F1 is capable of increasing the binding of E2F1 and decreasing the binding of Sp1 to Sp1 binding sites.

Chromosome 4q25 has been identified as a genomic region associated with gout. However, the associations of gout with the genes in this region have not yet been confirmed. Here, we performed two-stage analysis to determine whether variations in candidate genes in the 4q25 region are associated with gout in a male Chinese Han population. We first evaluated 96 tag single nucleotide polymorphisms (SNPs) in eight inflammatory/immune pathway- or glucose/lipid metabolism-related genes in the 4q25 region in 480 male gout patients and 480 controls. The SNP rs12504538, located in the elongation of very-long-chain-fatty-acid-like family member 6 gene (Elovl6), was found to be associated with gout susceptibility (Padjusted = 0.00595). In the second stage of analysis, we performed fine mapping analysis of 93 tag SNPs in Elovl6 and in the epidermal growth factor gene (EGF) and its flanking regions in 1017 male patients gout and 1897 healthy male controls. We observed a significant association between the T allele of EGF rs2298999 and gout (odds ratio = 0.77, 95% confidence interval = 0.67-0.88, Padjusted = 6.42 × 10(-3)). These results provide the first evidence for an association between the EGF rs2298999 C/T polymorphism and gout. Our findings should be validated in additional populations.

NK2 homeobox 5 (Nkx2-5) is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages. Embryos lacking Nkx2-5 are nonviable attributed to growth retardation and gross abnormalities of the heart. However, the role of Nkx2-5 in atherosclerosis remains elusive. This study aims to elucidate the specific functions of Nkx2-5 during atherogenesis and in established atherosclerotic plaques.

Marsdenia tenacissima extract (MTE) is the water-soluble part of a traditional Chinese medicine Marsdenia tenacissima (Roxb.) Wight & Arn, and is commercially available in China for treating cancers. MTE has been revealed to be effective in improving gefitinib efficacy in treating non-small cell lung cancer (NSCLC). However, the mechanisms remain to be defined.

The epidemiologic and clinical characteristics of heart transplant (HTx) recipients during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic remains unclear. We studied the characteristics of HTx recipients from December 20, 2019, to February 25, 2020, in an effort to understand their risk and outcomes.

Solar energy, which is essential for the origin and evolution of all life forms on Earth, can be objectively recorded through attributes such as climatic ambient temperature (CAT), ultraviolet radiation (UVR), and sunlight duration (SD). These attributes have specific geographical variations and may cause different adaptation traits. However, the adaptation profile of each attribute and the selective role of solar energy as a whole during human evolution remain elusive. Here, we performed a genome-wide adaptation study with respect to CAT, UVR, and SD using the Human Genome Diversity Project-Centre Etude Polymorphism Humain (HGDP-CEPH) panel data. We singled out CAT as the most important driving force with the highest number of adaptive loci (6 SNPs at the genome-wide 1 × 10-7 level; 401 at the suggestive 1 × 10-5 level). Five of the six genome-wide significant adaptation SNPs were successfully replicated in an independent Chinese population (N = 1395). The corresponding 316 CAT adaptation genes were mostly involved in development and immunity. In addition, 265 (84%) genes were related to at least one genome-wide association study (GWAS)-mapped human trait, being significantly enriched in anthropometric loci such as those associated with body mass index (χ2; P < 0.005), immunity, metabolic syndrome, and cancer (χ2; P < 0.05). For these adaptive SNPs, balancing selection was evident in Euro-Asians, whereas obvious positive and/or purifying selection was observed in Africans. Taken together, our study indicates that CAT is the most important attribute of solar energy that has driven genetic adaptation in development and immunity among global human populations. It also supports the non-neutral hypothesis for the origin of disease-predisposition alleles in common diseases.

To assess the efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors (CDKi) combined with endocrine therapy (ET) in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and compare the efficacy of different CDKi (palbociclib, ribociclib, or abemaciclib).

The nuclear factor of activated T-cells (NFAT) family was first recognised to play an important role in the differentiation of T cells, but has since been shown to regulate multiple pathophysiological processes. However, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unknown.

Amphicrine carcinoma, in which endocrine and epithelial cell constituents are present within the same cell, is very rare. This study characterized the clinicopathologic and survival analysis of this tumor, further compared the genetic diversities among amphicrine carcinoma and other tumors.