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Background: Dyslipidemia is commonly observed in various kidney diseases, renal specific secreted erythropoietin (EPO) may participate in this process. However, how this process is regulated remains elusive. Method: Dyslipidemia was evaluated in chronic kidney disease and ischemia kidney injury animal model. Primary cultured adipocytes were harvested to investigate the lipid metabolic effect of EPO. Lipidemia was evaluated in EPO treated animals. Blood samples from cardiac surgery-induced kidney injury patient were collected to assess correlationship between EPO and lipidemia. Findings: We found a decrease in secreted EPO and hypertriglyceridemia in chronic kidney disease (CKD) mice. In contrast, in renal ischemia animal model, increased EPO triggered by hypoxia signaling activation, was accompanied by decreased triglyceride (TG) in serum. Mechanistically, circulating EPO modulated JAK2-STAT5 signaling, which in turn enhanced lipid catabolism in peripheral adipose tissue and contributed to dysregulated lipidemia. Delivering of recombinant EPO into both wild type and CKD mice suppressed TG in serum by accelerating lipid catabolism in adipose tissue. In a cohort of patients diagnosed with acute kidney injury after cardiopulmonary bypass surgery, the decreased TG and cholesterol negatively correlated with increased EPO in serum. Interpretation: This study depicted a new mechanism by which renal secreted EPO controlled lipidemia in kidney diseases including chronic kidney disease. Circulating EPO stimulated lipid catabolism by targeting JAK2-STATA5 signaling in peripheral adipose tissue, providing new therapeutic target for dyslipidemia treatment. Funding: This work was supported by grants from the National Natural Science Foundation of China (Nos. 81700640 and 81970608). Keywords: Dyslipidemia, Erythropoietin, Kidney disease, Lipid catabolism, Adipose tissue

Abstract. Hematopoietic stem cells (HSCs) are considered to originate from the aorta-gonad-mesonephros, migrate into fetal liver for a rapid expansion, and eventually reside into a unique hypoxic bone marrow niche, where they maintain their homeostasis throughout their life span. HSCs have been widely used for the treatment of many begin or malignant hematopoietic disorders. However, the unavailability of sufficient amount of HSCs still impedes their applications in the clinic. It is urgent to understand how HSC stemness or cell fates are determined at different developmental stages. Although many intrinsic and extrinsic factors (niche components) have been identified in the regulation of HSC origination, expansion, migration, and localization, the underlying mechanisms remain largely unknown. In this article, we summarize current views on the metabolic profiles of HSCs and related regulatory networks, which shows that intrinsic metabolic regulation may be critical for the cell fate determinations of HSCs: HSCs utilize glycolysis as their major energy sources; mitochondrial respiration is also required for the homeostasis of HSCs; amino acids, lipids, or other nutrient metabolisms also have unique roles in sustaining HSC activities. Mechanistically, many important regulatory pathways, such as MEIS1/HIF1A, MYC, PPM1K/CDC20, and ROS signals, are identified to fine-tune the nutrient metabolisms and cell fate commitments in HSCs. Nevertheless, more effort is required for the optimization or establishment of sensitive and specific metabolic techniques/systems for the metabolism studies in HSCs with limited cell numbers and exploring the metabolic profiles and fundamental regulatory mechanisms of different types of nutrients at each developmental stage of HSCs.

The melt infiltration method is one of the main preparation method of SiC matrix composites. Complex reactions and multi-component diffusion are involved in molten-Si infiltration of a C-based preform. In this study, SiC-TiSi2 was fabricated by Si melt infiltration and the TiSi2 was in-situ formed in the matrix of SiC. In order to explore the reaction mechanism of SiC-TiSi2, SEM, EDS and micro-beam XRD were determined to characterize the phase constitute and micro-structure in different regions along the Si melt infiltration direction. The results demonstrate that SiC, TiSi2 and Ti5Si3 which concentrate on the Si/SiC interface are found to be formed through the Si melt infiltration into the C-TiC preform. With the increase of temperature, the liquid phase of Ti-Si appears when exceeding the Si-TiSi2 eutectic temperature. And the liquid Ti-Si eutectic precipitates TiSi2 in the Si region during the cooling period of the sample. Moreover, the isolated SiC grain in Si region is produced by the precipitation from the dissolution of solid C in liquid Si.

Abstract We develop our recent work on quantum error correction (QEC) and entanglement spectrum (ES) in tensor networks (arXiv:1806.05007). We propose a general framework for planar tensor network state with tensor constraints as a model for AdS 3/CFT 2 correspondence, which could be viewed as a generalization of hyperinvariant tensor networks recently proposed by Evenbly. We elaborate our proposal on tensor chains in a tensor network by tiling H 2 space and provide a diagrammatical description for general multi-tensor constraints in terms of tensor chains, which forms a generalized greedy algorithm. The behavior of tensor chains under the action of greedy algorithm is investigated in detail. In particular, for a given set of tensor constraints, a critically protected (CP) tensor chain can be figured out and evaluated by its average reduced interior angle. We classify tensor networks according to their ability of QEC and the flatness of ES. The corresponding geometric description of critical protection over the hyperbolic space is also given.

There are distinct hypermethylation patterns in gene promoters in hepatocellular carcinomas (HCCs). Here, the authors show that the enhancer of C/EBPβ is recurrently hypomethylated in human HCCs, recapitulating this in a transgenic murine model and linking aberrant enhancer hypomethylation to hepatocarcinogenesis.

Hydrocortisone (HYD) is one of the corticosteroids that illegally used in cosmetic products, which could lead to a potential health problem. In this work, HYD was conjugated to bovine serum albumin via a succinic anhydride spacer arm to yield an immunogen. New Zealand rabbits were immunized to obtain a polyclonal antibody against HYD. Based on the pAb, a heterologous competitive indirect enzyme-linked immunosorbent assay (ciELISA) by using progesterone carboxylic acid as a competitive hapten was developed. The assay showed an IC50 of 0.50 ng mL−1, detection limit of 0.04 ng mL−1 and a linear range of 0.10–2.00 ng mL−1. The assay was applied to determine HYD in cosmetic samples. Recoveries from 82.5% to 118.9% and CV from 1.3% to 9.5% were obtained using a simple pretreatment. Good correlation between the results of ciELISA and standard LC–MS/MS was obtained, suggesting its potential usage in HYD monitoring in cosmetic samples.

Diaphorina citri Kuwayama is the vector of HLB and one of the most common pests in citrus orchards in southern China. One of the most significant genes in D. citri’s growth and development is the chitin synthase gene. In this study, the CHS gene (DcCHSA) of D. citri was cloned and analyzed by bioinformatics. According to RT-qPCR findings, DcCHSA was expressed at many growth processes of D. citri, with the greatest influence in the fifth-instar nymph. The molting failure rate and mortality of D. citri rose as DFB concentration increased in this research, as did the expression level of DcCHSA. Feeding on DcCHSA caused a large drop in target gene expression, affected nymph molting, caused failure or even death in freshly eclosion adults, increased mortality, and reduced the molting success rate over time. These findings showed that DcCHSA was involved in nymph to adult development and may aid in the identification of molecular targets for D. citri regulation. It provided new ideas for further control of D. citri.

Atherosclerosis is a risk factor for various cardiovascular diseases, and is linked to high rates of morbidity and mortality across the globe. Although numerous complex processes are involved in the development and progression of atherosclerosis, the exact mechanisms behind its pathogenesis remain unclear. Inflammation and endothelial cell damage exert a lasting effect on atherosclerosis, causing lipid and fibrous tissue accumulation in the intima of the artery to form plaques, and subsequently promoting atherosclerosis. Nod-like receptor protein 3 (NLRP3) inflammatory corpuscle is thought to be the link between lipid metabolism and inflammation. Long Potassium outflow is a vital activator of NLRP3, with a simultaneous effect as a start-up and adjustment. The majority of existing drugs for atherosclerosis targeting the NLRP3 signaling pathway target IL-1, whereas drugs targeting the critical link of potassium efflux are relatively new. This review discusses the NLRP3 inflammatory corpuscle as a critical regulator of the immunological inflammatory pathway in atherosclerosis. Moreover, current knowledge on NLRP3 inflammatory corpuscle start and activation pathways were integrated, emphasizing potassium-involved outflow-related proteins. We highlight potential treatment approaches for NLRP3 inflammatory corpuscle pathways, specifically targeting potassium outflow channels of targeted drugs. Collectively, these insights indicate that targeting the NLRP3 inflammatory corpuscle is a vital anti-inflammatory therapy for treating atherosclerosis.

The newly emerged tigecycline-inactivating enzymes Tet(X3) and Tet(X4), which are associated with high-level tigecycline resistance, demonstrated significantly higher activities in comparison to that of the prototypical Tet(X) enzyme, threatening the clinical efficacy of tigecycline as a last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections. However, the molecular mechanisms leading to high-level tigecycline resistance remain elusive.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) share a target receptor with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The use of ACEIs/ARBs may cause angiotensin-converting enzyme 2 receptor upregulation, facilitating the entry of SARS-CoV-2 into host cells. There is concern that the use of ACEIs/ARBs could increase the risks of severe COVID-19 and mortality. The impact of discontinuing these drugs in patients with COVID-19 remains uncertain. We aimed to assess the association between the use of ACEIs/ARBs and the risks of mortality and severe disease in patients with COVID-19. A systematic search was performed in PubMed, EMBASE, Cochrane Library, and MedRxiv.org from December 1, 2019, to June 20, 2020. We also identified additional citations by manually searching the reference lists of eligible articles. Forty-two observational studies including 63,893 participants were included. We found that the use of ACEIs/ARBs was not significantly associated with a reduction in the relative risk of all-cause mortality [odds ratio (OR) = 0.87, 95% confidence interval (95% CI) = 0.75–1.00; I2 = 57%, p = 0.05]. We found no significant reduction in the risk of severe disease in the ACEI subgroup (OR = 0.95, 95% CI = 0.88–1.02, I2 = 50%, p = 0.18), the ARB subgroup (OR = 1.03, 95% CI = 0.94–1.13, I2 = 62%, p = 0.48), or the ACEI/ARB subgroup (OR = 0.83, 95% CI = 0.65–1.08, I2 = 67%, p = 0.16). Moreover, seven studies showed no significant difference in the duration of hospitalization between the two groups (mean difference = 0.33, 95% CI = −1.75 to 2.40, p = 0.76). In conclusion, the use of ACEIs/ARBs appears to not have a significant effect on mortality, disease severity, or duration of hospitalization in COVID-19 patients. On the basis of the findings of this meta-analysis, there is no support for the cessation of treatment with ACEIs or ARBs in patients with COVID-19.

The small (18S) and large (28S) nuclear ribosomal DNA (rDNA) introns have been researched and sequenced in a variety of ectomycorrhizal fungal taxa in this study, it is found that both 18S and 28S rDNA would contain introns and display some degree variation in size, nucleotide sequences and insertion positions within the same fungi species (Meliniomyces). Under investigations among the tested isolates, 18S rDNA has four sites for intron insertions, 28S rDNA has two sites for intron insertions. Both 18S and 28S rDNA introns among the tested isolates belong to group I introns with a set of secondary structure elements designated P1-P10 helics and loops. We found a 12 nt nucleotide sequences TACCACAGGGAT at site 2 in the 3'-end of 28S rDNA, site 2 introns just insert the upstream or the downstream of the12 nt nucleotide sequences. Afters sequence analysis of all 18S and 28S rDNA introns from tested isolates, three high conserved regions around 30 nt nucleotides (conserved 1, conserved 2, conserved 3) and identical nucleotides can be found. Conserved 1, conserved 2 and conserved 3 regions have high GC content, GC percentage is almost more than 60%. From our results, it seems that the more convenient host sites, intron sequences and secondary structures, or isolates for 18S and 28S rDNA intron insertion and deletion, the more popular they are. No matter 18S rDNA introns or 18S rDNA introns among tested isolates, complementary base pairing at the splicing sites in P1-IGS-P10 tertiary helix around 5'-end introns and exons were weak.

Potato starch is an essential nutrient for humans and is widely used worldwide. Locating relevant genomic regions, mining stable genes and developing candidate gene markers can promote the breeding of new high-starch potato varieties. A total of 106 F1 individuals and their parents (YSP-4 × MIN-021) were used as test materials, from which 20 plants with high starch content and 20 with low starch content were selected to construct DNA pools for site-specific amplified fragment sequencing (SLAF-seq) and bulked segregation analysis (BSA). A genomic region related to the starch traits was first identified in the 0-5.62 Mb of chromosome 2 in tetraploid potato. In this section, a total of 41 non-synonymous genes, which were considered as candidate genes related to the starch trait, were annotated through a basic local alignment search tool (BLAST) search of multiple databases. Six candidate genes for starch (PGSC0003DMG400017793, PGSC0003DMG400035245, PGSC0003DMG400036713, PGSC0003DMG400040452, PGSC0003DMG400006636 and PGSC0003DMG400044547) were further explored. In addition, cleaved amplified polymorphic sequence (CAPS) markers were developed based on single nucleotide polymorphism (SNP) sites associated with the starch candidate genes. SNP-CAPS markers chr2-CAPS6 and chr2-CAPS21 were successfully developed and validated with the F2 population and 24 tetraploid potato varieties (lines). Functional analysis and cloning of the candidate genes associated with potato starch will be performed in further research, and the SNP-CAPS markers chr2-CAPS6 and chr2-CAPS21 can be further used in marker-assisted selection breeding of tetraploid potato varieties with high starch content.

Recent developments in menin inhibitors for relapsed or refractory acute myeloid leukemia (AML) were highlighted at the 2023 ASH Annual Meeting. Notably, revumenib showed promising efficacy, achieving a 100% ORR when combined with decitabine/cedazuridine and venetoclax. These findings underscore the potential of menin inhibitors in transforming AML treatment, particularly in genetically defined subgroups, offering hope for improved patient outcomes. Ongoing studies, like KOMET-008, further explore the synergistic potential of menin inhibitors in combination regimens, shaping future AML management strategies. [ABSTRACT FROM AUTHOR]

We report the synthesis of a polycrystalline specimen of TiC1−x under high-pressure and high-temperature (HPHT) conditions. The carbon vacancy, crystal structure, Vicker hardness, elastic constants, and bond features of the synthesized specimen were investigated. Though the specimens were synthesized with stoichiometric ratio at high pressure, a robust carbon vacancy was observed using energy dispersive and X-ray photoelectron spectrum. TiC1−x exhibits almost the highest asymptotic Vickers hardness in transition-metal light-element (TMLE) compounds. In this study, using Vickers hardness characterization, the asymptotic hardness was found to be 27.1 GPa. This exceeds the hardness of most transition metal borides with high boron concentrations. Based on the first-principles calculation of the Mulliken population of Ti-C bonds, the intrinsic high Vickers hardness of TiC1−x is attributed to the combination of covalent Ti-C bonds and the optimized eight-valence-electron structure, while the extrinsic contribution comes from the harden effect of carbon defects. This work demonstrates that a higher concentration of light elements or a higher-dimensional light element framework is not the critical factor for higher hardness, and carbon vacancy is another way to strengthen the crystal structure.

Pyrochlore-type (P-type) and thortveitite-type (T-type) Sc2Ge2O7 were prepared through different methods. The phase stability and compressibility of the two polymorphs of Sc2Ge2O7 were studied using in situ synchrotron x-ray diffraction. An irreversible phase transition of monoclinic (C2/m) T-type Sc2Ge2O7 induced by a pressure of 4.8 GPa was observed. However, the cubic (Fd-3m) P-type Sc2Ge2O7 can resist a much higher pressure of up to 30.6 GPa.

Helping B cells and antibody responses is a major function of CD4+T helper cells. Follicular helper T (Tfh) cells are identified as a subset of CD4+T helper cells, which is specialized in helping B cells in the germinal center reaction. Tfh cells express high levels of CXCR5, PD-1, IL-21, and other characteristic markers. Accumulating evidence has demonstrated that the dysregulation of Tfh cells is involved in infectious, inflammatory, and autoimmune diseases, including lymphocytic choriomeningitis virus (LCMV) infection, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), IgG4-related disease (IgG4-RD), Sjögren syndrome (SS), and type 1 diabetes (T1D). Activation of subset-specific transcription factors is the essential step for Tfh cell differentiation. The differentiation of Tfh cells is regulated by a complicated network of transcription factors, including positive factors (Bcl6, ATF-3, Batf, IRF4, c-Maf, and so on) and negative factors (Blimp-1, STAT5, IRF8, Bach2, and so on). The current knowledge underlying the molecular mechanisms of Tfh cell differentiation at the transcriptional level is summarized in this paper, which will provide many perspectives to explore the pathogenesis and treatment of the relevant immune diseases.

Genome-wide association analyses have uncovered multiple genomic regions associated with T2D, but identification of the causal variants at these remains a challenge. There is growing interest in the potential of deep learning models - which predict epigenome features from DNA sequence - to support inference concerning the regulatory effects of disease-associated variants. Here, we evaluate the advantages of training convolutional neural network (CNN) models on a broad set of epigenomic features collected in a single disease-relevant tissue – pancreatic islets in the case of type 2 diabetes (T2D) - as opposed to models trained on multiple human tissues. We report convergence of CNN-based metrics of regulatory function with conventional approaches to variant prioritization – genetic fine-mapping and regulatory annotation enrichment. We demonstrate that CNN-based analyses can refine association signals at T2D-associated loci and provide experimental validation for one such signal. We anticipate that these approaches will become routine in downstream analyses of GWAS.

Background: Androgen receptor (AR) plays a crucial role as a transcription factor in promoting the development of hepatocellular carcinoma (HCC) which is prone to aberrant chromatin modifications. However, the regulatory effects of AR on epigenetic mediators in HCC remain ill-defined. Enhancer of zeste homolog 2 (EZH2), an oncogene responsible for the tri-methylation of histone H3 at lysine 27 (H3K27me3), was identified to be overexpressed in approximate 70–90% of HCC cases, which prompted us to investigate whether or how AR regulates EZH2 expression. Methods: Colony formation, soft agar assay, xenograft and orthotopic mouse models were used to determine cell proliferation and tumorigenicity of gene-manipulated HCC cells. Gene regulation was assessed by chromatin immunoprecipitation, luciferase reporter assay, quantitative RT-PCR and immunoblotting. Clinical relevance of candidate proteins in patient specimens was examined in terms of pathological parameters and postsurgical survival rates. Findings: In this study, we found that AR upregulated EZH2 expression by binding to EZH2 promoter and stimulating its transcriptional activity. EZH2 overexpression increased H3K27me3 levels and thereby silenced the expression of Wnt signal inhibitors, resulting in activation of Wnt/β-catenin signaling and subsequently induction of cell proliferation and tumorigenesis. In a cohort of human HCC patients, concordant overexpression of AR, EZH2, H3K27me3 and active β-catenin was observed in tumor tissues compared with paired non-tumor tissues, which correlated with tumor progression and poor prognosis. These findings demonstrate a novel working model in which EZH2 mediates AR-induced Wnt/β-catenin signaling activation through epigenetic modification, and support the application of EZH2-targeted reagents for treating HCC patients. Keywords: Androgen receptor, EZH2, Wnt/β-catenin signaling, Hepatocarcinogenesis, Epigenetics

Summary: In addition to acting as building blocks for biosynthesis, amino acids might serve as signaling regulators in various physiological and pathological processes. However, it remains unknown whether amino acid levels affect the activities of hematopoietic stem cells (HSCs). By using a genetically encoded fluorescent sensor of the intracellular levels of branched-chain amino acids (BCAAs), we could monitor the dynamics of BCAA metabolism in HSCs. A mitochondrial-targeted 2C-type Ser/Thr protein phosphatase (PPM1K) promotes the catabolism of BCAAs to maintain MEIS1 and p21 levels by decreasing the ubiquitination-mediated degradation controlled by the E3 ubiquitin ligase CDC20. PPM1K deficiency led to a notable decrease in MEIS1/p21 signaling to reduce the glycolysis and quiescence of HSCs, followed by a severe impairment in repopulation activities. Moreover, the deletion of Ppm1k dramatically extended survival in a murine leukemia model. These findings will enhance the current understanding of nutrient signaling in metabolism and function of stem cells. : Liu et al. show that the dynamics of BCAA metabolism in hematopoietic stem cells (HSCs) and leukemia-initiating cells (LICs) can be monitored by a genetically encoded fluorescent sensor. PPM1K promotes BCAA catabolism and maintains the glycolysis and quiescence of HSCs/LICs through the downregulation of CDC20-mediated ubiquitination of MEIS1 and p21. Keywords: branched-chain amino acids, PPM1K, ubiquitination, CDC20, MEIS1/p21, hematopoietic stem cells, leukemia-initiating cells

Two series of 1,4-naphthoquinone-chromone hybrids 4a (4aa–4ao) and 4b (4ba–4bq) were designed, synthesized and evaluated as antitumor agents. Most of the compounds exhibited moderate to excellent cytotoxicity to tumor cells (K562 and A549), especially the 4a series compounds that showed equal or stronger antiproliferative activity compared to positive control cisplatin on two different types of cells (except for 4al and 4an). Among them, compound 4ac showed significant inhibitory activity on A549 cells with an IC50 value of 2.93 μM, and was 5.2 times more active than cisplatin (IC50 = 15.32 ± 2.64 μM). Meanwhile, AO/EB staining, flow cytometry, cell morphology, and ultrastructural analysis revealed that compound 4ac could induce A549 cell apoptosis and arrest at the G1 phase. Further mechanism studies speculated that compound 4ac may regulate the p53-MDM2 pathway, alter the Bax/Bcl-2 ratio to release Cyt c, activate the mitochondrial apoptosis pathway to induce cell apoptosis, and inhibit A549 cell proliferation through cycle arrest. Collectively, compound 4ac could be used as a potential candidate compound for anti-lung cancer drugs. [ABSTRACT FROM AUTHOR]