Resistin induces multidrug resistance in myeloma by inhibiting cell death and upregulating ABC transporter expression

Despite advances in therapy, multiple myeloma remains incurable, with a high frequency of relapse. This suggests the need to identify additional factors that contribute to drug resistance. Our previous studies revealed that bone marrow adipocytes promote resistance to chemotherapy in myeloma through adipocyte-secreted adipokines, but the mechanism underlying this effect and the specific adipokines involved are not well understood. We proposed to determine the role of resistin, an adipokine that is secreted by adipocytes, in chemotherapy resistance in myeloma. We found that resistin abrogated chemotherapy-induced apoptosis in established myeloma cell lines and primary myeloma samples. Resistin inhibited chemotherapy-induced caspase cleavage through the NF-κB and PI3K/Akt pathways. Resistin also increased the expression and drug efflux function of ATP-binding cassette (ABC) transporters in myeloma cells through decreasing the expression of both DNA methyltransferases DNMT1 and DNMT3a and the methylation levels of ABC gene promoters. In vivo studies further demonstrated the protective effect of resistin in chemotherapy-induced apoptosis. Our study thus reveals a new biological function of resistin in the pathogenesis of myeloma, with the implication that targeting resistin could be a potential strategy to prevent or overcome multidrug resistance in myeloma

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Design of LQG Controller for Active Suspension without Considering Road Input Signals

As the road conditions are completely unknown in the design of a suspension controller, an improved linear quadratic and Gaussian distributed (LQG) controller is proposed for active suspension system without considering road input signals. The main purpose is to optimize the vehicle body acceleration, pitching angular acceleration, displacement of suspension system, and tire dynamic deflection comprehensively. Meanwhile, it will extend the applicability of the LQG controller. Firstly, the half-vehicle and road input mathematical models of an active suspension system are established, with the weight coefficients of each evaluating indicator optimized by using genetic algorithm (GA). Then, a simulation model is built in Matlab/Simulink environment. Finally, a comparison of simulation is conducted to illustrate that the proposed LQG controller can obtain the better comprehensive performance of vehicle suspension system and improve riding comfort and handling safety compared to the conventional one

Ferulic acid combined with different dietary fibers improve glucose metabolism and intestinal barrier function by regulating gut microbiota in high-fat diet-fed mice

Consuming whole grains contributes to the preservation of glucose homeostasis and supports intestinal health, primarily attributed to the presence of functional components like polyphenols and dietary fiber. However, it is not well understood how the combined influence of cereal polyphenols and dietary fiber could benefit the glucose metabolism and alter the gut microbiota. Our results showed that compared to ferulic acid alone, ferulic acid combined with arabinoxylan or β-glucan could significantly improve glucose tolerance and maintain intestinal homeostasis in high-fat diet-fed mice. Ferulic acid combined with β-glucan significantly increased serum GLP-1 level and tight junction proteins expression in colon. Ferulic acid combined arabinoxylan increased the abundance of Bifidobacterium and Faecalibaculum. Ferulic acid combined with β-glucan increased the abundance of Akkermansia and norank_f_Muribaculaceae, which were negatively correlated with impaired glucose tolerance. Therefore, ferulic acid combined with arabinoxylan or β-glucan ameliorates glucose metabolism and protects intestinal barrier integrity by regulating gut microbiota

Establishment of a Seven-Gene Signature Associated with CD8⁺ T Cells through the Utilization of Both Single-Cell and Bulk RNA-Sequencing Techniques in Clear Cell Renal Cell Carcinoma

Tumor immune microenvironment constituents, such as CD8+ T cells, have emerged as crucial focal points for cancer immunotherapy. Given the absence of reliable biomarkers for clear cell renal cell carcinoma (ccRCC), we aimed to ascertain a molecular signature that could potentially be linked to CD8+ T cells. The differentially expressed genes (DEGs) linked to CD8+ T cells were identified through an analysis of single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database. Subsequently, immune-associated genes were obtained from the InnateDB and ImmPort datasets and were cross-referenced with CD8+ T-cell-associated DEGs to generate a series of DEGs linked to immune response and CD8+ T cells. Patients with ccRCC from the Cancer Genome Atlas (TCGA) were randomly allocated into testing and training groups. A gene signature was established by conducting LASSO-Cox analysis and subsequently confirmed using both the testing and complete groups. The efficacy of this signature in evaluating immunotherapy response was assessed on the IMvigor210 cohort. Finally, we employed various techniques, including CIBERSORT, ESTIMATE, ssGSEA, and qRT-PCR, to examine the immunological characteristics, drug responses, and expression of the signature genes in ccRCC. Our findings revealed 206 DEGs linked to immune response and CD8+ T cells, among which 65 genes were correlated with overall survival (OS) in ccRCC. A risk assessment was created utilizing a set of seven genes: RARRES2, SOCS3, TNFSF14, XCL1, GRN, CLDN4, and RBP7. The group with a lower risk showed increased expression of CD274 (PD-L1), suggesting a more favorable response to anti-PD-L1 treatment. The seven-gene signature demonstrated accurate prognostic prediction for ccRCC and holds potential as a clinical reference for treatment decisions

Mapping of district-scale potential targets using fractal models

The Pulang porphyry-Cu deposit is one of the most important copper deposits discovered in China in the last five years. In this deposit, the irregular distributions of high concentrations of metals are associated with four intrusive complexes and fault structures. In the present study, fractal models including box-counting dimension (Bd), power-law frequency and Hurst exponent are applied to characterize the vertical distributions of Cu values along boreholes in the deposit, and to delineate target areas in the Pulang copper district. The resulting box-counting model shows that the vertical distributions of Cu in both mineralized and nonmineralized boreholes exhibit self-similarity, with values of Bd ranging from 1.01 to 1.43, and mineralized boreholes have values of Bd higher than those of non-mineralized boreholes. The resulting power-law frequency model shows that the vertical distributions of Cu in mineralized boreholes are bifractal whereas they are monofractal in non-mineralized boreholes. The bifractal vertical distributions of Cu values are generally associated with multiple ore-forming stages/periods or complicated ore-forming functions of geological background. The Hurst exponents of Cu data from all continuously mineralized boreholes are >0.5, indicating that the Pulang porphyry-Cu deposit has good vertical continuity of mineralization, or that the development of orebodies was relatively stable in this geological setting. High Hurst exponents (>0.85) can be utilized to identify subsurface mineralized targets, whereas lower Hurst exponents (<0.85) represent discontinuous mineralized rocks along the margins of the porphyry-Cu deposit near country rocks. Based on calculated values of average Cu grade, coefficient of variation, Bd and Hurst exponent for the Cu data along boreholes, interpolated values of these variables are excellent for mapping of potential targets. The results show that the Complex II (intrusive body) is a potential copper target in the north of the Pulang district, because it has a similar Bd as the Complex I that hosts the Pulang porphyry-Cu orebody in the south of the Pulang district. In addition, the Complex I has a potential porphyry-Cu target at depth between explorations lines 7 and 15 based on high Hurst exponents and favorable geological setting. The application of the fractal models discussed in this study is convenient, simple, rapid and direct for outlining potential exploration targets without processing multiple geological, geophysical, and geochemical datasets from disparate sources

DNA methyltransferase 1 deficiency improves macrophage motility and wound healing by ameliorating cholesterol accumulation

Abstract Healing of the cutaneous wound requires macrophage recruitment at the sites of injury, where chemotactic migration of macrophages toward the wound is regulated by local inflammation. Recent studies suggest a positive contribution of DNA methyltransferase 1 (Dnmt1) to macrophage pro-informatory responses; however, its role in regulating macrophage motility remains unknown. In this study, myeloid-specific depletion of Dnmt1 in mice promoted cutaneous wound healing and de-suppressed the lipopolysaccharides (LPS)-inhibited macrophage motility. Dnmt1 inhibition in macrophages eliminated the LPS-stimulated changes in cellular mechanical properties in terms of elasticity and viscoelasticity. LPS increased the cellular accumulation of cholesterol in a Dnmt1-depedent manner; cholesterol content determined cellular stiffness and motility. Lipidomic analysis indicated that Dnmt1 inhibition altered the cellular lipid homeostasis, probably through down-regulating the expression of cluster of differentiation 36 CD36 (facilitating lipid influx) and up-regulating the expression of ATP-binding cassette transporter ABCA1 (mediating lipid efflux) and sterol O-acyltransferase 1 SOAT1 (also named ACAT1, catalyzing the esterification of cholesterol). Our study revealed a Dnmt1-dependent epigenetic mechanism in the control of macrophage mechanical properties and the related chemotactic motility, indicating Dnmt1 as both a marker of diseases and a potential target of therapeutic intervention for wound healing