Single-cell landscape of immunological responses in patients with COVID-19.

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.

Sex differences orchestrated by androgens at single-cell resolution.

Sex differences in mammalian complex traits are prevalent and are intimately associated with androgens1-7. However, a molecular and cellular profile of sex differences and their modulation by androgens is still lacking. Here we constructed a high-dimensional single-cell transcriptomic atlas comprising over 2.3 million cells from 17 tissues in Mus musculus and explored the effects of sex and androgens on the molecular programs and cellular populations. In particular, we found that sex-biased immune gene expression and immune cell populations, such as group 2 innate lymphoid cells, were modulated by androgens. Integration with the UK Biobank dataset revealed potential cellular targets and risk gene enrichment in antigen presentation for sex-biased diseases. This study lays the groundwork for understanding the sex differences orchestrated by androgens and provides important evidence for targeting the androgen pathway as a broad therapeutic strategy for sex-biased diseases.

Formation and Oxidation Reactivity of MnO2+(HCO3-)n in the MnII(HCO3-)-H2O2 System.

The MnII(HCO3-)-H2O2 (MnII-BAP) system shows high reactivity toward oxidation of electron-rich organic substrates; however, the predominant oxidizing species and its formation pathways involved in the MnII-BAP system are still under debate. In this study, we used the MnII-BAP system to oxidize As(III) in that As(III), Mn2+, and HCO3- are common components in As(III)-contaminated groundwater. Kinetic results show that MnII(HCO3-)n [including MnII(HCO3)+ and MnII(HCO3)2] is a key factor in the MnII-BAP system to oxidize As(III). Quenching experiments rule out contributions of OH• and 1O2 to As(III) oxidation and reveal that O2•- and the oxidizing species generated from O2•- play predominant roles in the oxidation of As(III). We further reveal that the MnO2+(HCO3-)n intermediate generated in the reaction between MnII(HCO3-)n and O2•-, instead of O2•-, is the predominant oxidizing species. Although CO3•- also contributes to As(III) oxidation, the high reaction rate constant between CO3•- and O2•- indicates that CO3•- is not the predominant oxidizing species in the As(III)-MnII-BAP system. In addition, the presence of Mn(III) further indicates the important Mn(II)-Mn(III) cycling in the MnII-BAP system. We therefore suggest two important roles of MnII(HCO3-)n in the MnII-BAP system: (i) MnII(HCO3-)n reacts with H2O2 to form the MnIII(HCO3)3 intermediate, followed by a subsequent reaction between MnIII(HCO3)3 and H2O2 to produce O2•-; (ii) MnII(HCO3-)n can also stabilize O2•- with the formation of MnO2+(HCO3-)n. MnO2+(HCO3-)n is an electrophilic reagent and plays the predominant role in the oxidation of As(III) to As(V).

Formation of hydroperoxo (-OOH) species on the surface of self-doped Bi2.15WO6: reactivity towards As(iii) oxidation.

Bi2+xWO6 is a cost-effective and environmentally friendly photocatalyst that shows high reactivity in the oxidation of various contaminants under visible light. However, under alkaline conditions, the reactive oxidative species in the Bi2+xWO6 system are still not clear yet. In this study, it is observed that the oxidation rates of As(iii) increase with increasing pH values in the Bi2.15WO6 system. Photoluminescence and the Mott-Schottky analyses confirm that OH- promotes the separation and transfer of photogenerated electron-hole pairs over Bi2.15WO6, thus facilitating the oxidation of As(iii). Electron spin resonance spectra analysis and quenching experiments rule out contributions of •OH, O2˙-, 1O2 and superoxo species to As(iii) oxidation and indicate that surface -OOH and/or H2O2 are indeed the predominant species under alkaline conditions. The improved production of H2O2 by H-donors such as glucose and phenol, as well as the UV-vis diffuse reflectance and Raman analyses, further confirms the formation of surface -OOH on Bi2.15WO6 under alkaline conditions. In the dark, the significant higher oxidation rate of As(iii) by H2O2-Bi2.15WO6 than that by H2O2 alone reveals that surface -OOH, instead of H2O2, plays an important role in As(iii) oxidation. This study enriches our understanding of the diversity of reactive oxygen species (ROS) in the Bi2.15WO6 system and gives new insight into the mechanism involved in the oxidation of As(iii) under alkaline conditions.

Functional Metabolomics Characterizes a Key Role for N-Acetylneuraminic Acid in Coronary Artery Diseases.

BACKGROUND: As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. METHODS: A cohort of 2324 patients who underwent coronary angiography from 4 independent centers was studied. A combination of ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode was used for untargeted analysis of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liquid chromatography-mass spectrometry-based approach using isotope-labeled standard addition was subsequently performed for targeted analysis of the metabolic marker N-acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models. RESULTS: We identified a total of 36 differential metabolites, 35 of which were confirmed with reference compounds. Elevation of Neu5Ac was observed in plasma during CAD progression in center 1 (P=4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation-induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacological inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury. CONCLUSIONS: Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.

Dynein and EFF-1 control dendrite morphology by regulating the localization pattern of SAX-7 in epidermal cells.

Our previous work showed that the cell adhesion molecule SAX-7 forms an elaborate pattern in Caenorhabditis elegans epidermal cells, which instructs PVD dendrite branching. However, the molecular mechanism forming the SAX-7 pattern in the epidermis is not fully understood. Here, we report that the dynein light intermediate chain DLI-1 and the fusogen EFF-1 are required in epidermal cells to pattern SAX-7. While previous reports suggest that these two molecules act cell-autonomously in the PVD, our results show that the disorganized PVD dendritic arbors in these mutants are due to the abnormal SAX-7 localization patterns in epidermal cells. Three lines of evidence support this notion. First, the epidermal SAX-7 pattern was severely affected in dli-1 and eff-1 mutants. Second, the abnormal SAX-7 pattern was predictive of the ectopic PVD dendrites. Third, expression of DLI-1 or EFF-1 in the epidermis rescued both the SAX-7 pattern and the disorganized PVD dendrite phenotypes, whereas expression of these molecules in the PVD did not. We also show that DLI-1 functions cell-autonomously in the PVD to promote distal branch formation. These results demonstrate the unexpected roles of DLI-1 and EFF-1 in the epidermis in the control of PVD dendrite morphogenesis.

PDGFRα Regulated by miR-34a and FoxO1 Promotes Adipogenesis in Porcine Intramuscular Preadipocytes through Erk Signaling Pathway.

Suitable intramuscular fat (IMF) content improves porcine meat quality. The vital genes regulating IMF deposition are necessary for the selection and breeding of an IMF trait. However, the effect and mechanism of PDGFRα on IMF deposition are still unclear. Here, PDGFRα is moderately expressed in porcine longissimus dorsi muscle (LD), whereas it highly expressed in white adipose tissue (WAT). Moreover, PDGFRα-positive cells were located in the gaps of LD fibers which there were IMF adipocytes. Compared with 180-day-old and lean-type pigs, the levels of PDGFRα were much higher in one-day-old and fat-type pigs. Meanwhile the levels of PDGFRα gradually decreased during IMF preadipocyte differentiation. Furthermore, PDGFRα promoted adipogenic differentiation through activating Erk signaling pathway. Based on PDGFRα upstream regulation analysis, we found that the knockdown of FoxO1 repressed lipogenesis by downregulating PDGFRα, and miR-34a inhibited adipogenesis through targeting PDGFRα. Collectively, PDGFRα is a positive regulator of IMF deposition. Therefore, we suggest that PDGFRα is a possible target to improve meat quality.

CAPN10 SNP43 G>A gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta-analysis of 9353 participants.

A correlation between the single nucleotide polymorphism (SNP)43 G>A in the calpain-10 (CAPN10) gene (i.e., CAPN10 SNP43) and type 2 diabetes mellitus (T2DM) susceptibility has been suggested, but the evidence for such a relationship remains controversial. To explore the association of the CAPN10 SNP43 with T2DM in Asian populations, a meta-analysis including 9,353 participants from 20 individual studies in Asian populations was conducted. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by a fixed-effect model or random-effect model. The relationship between CAPN10 SNP43 and T2DM was significant under allelic (OR: 1.18, 95% CI: 1.01-1.38, P = 0.03), recessive (OR: 1.236, 95% CI: 1.038-1.472, P =0.017), heterozygous (OR: 1.261, 95% CI: 1.053-1.512, P = 0.012), and additive (OR: 1.183, 95% CI: 1.014-1.381, P = 0.033) genetic models but not under dominant (OR: 1.12, 95% CI: 0.78-1.62, P = 0.53) or homozygous (OR: 0.937, 95% CI: 0.648-1.355, P = 0.730) genetic models. CAPN10 SNP43 was significantly associated with T2DM susceptibility in Asian populations, especially in Chinese populations. Asians, particularly Chinese people with the SNP43 G allele of the CAPN10 gene may have an increased risk of developing T2DM.

KCNQ1 rs2237892 C→T gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta-analysis of 15,736 patients.

The KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta-analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random-effect or fixed-effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic (OR, 1.350; 95% CI, 1.240-1.480; P < 0.00001), recessive (OR: 0.650; 95% CI: 0.570-0.730; P < 0.00001), dominant (OR: 1.450; 95% CI: 1.286-1.634; P < 0.00001), and additive (OR: 1.346; 95% CI: 1.275-1.422; P < 0.00001) genetic models. In the subgroup analysis by race, a significant association was found in Chinese, Korean and Malaysia population, but not in Indian population. KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM.

TAP1 I333V gene polymorphism and type 1 diabetes mellitus: a meta-analysis of 2248 cases.

Transporter associated with antigen processing 1 (TAP1) I333V gene polymorphism has been suggested to be associated with type 1 diabetes mellitus (T1DM) susceptibility. However, the results from individual studies are inconsistent. To explore the association of TAP1 I333V gene polymorphisms with T1DM, a meta-analysis involving 2246 cases from 13 individual studies was conducted. The pooled odd ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by a fixed-effect model. A significant relationship was observed between TAP1 I333V gene polymorphism and T1DM in allelic (OR: 1.35, 95% CI: 1.08-1.68, P = 0.007), dominant (OR: 1.462, 95% CI: 1.094-1.955, P = 0.010), homozygous (OR: 1.725, 95% CI: 1.082-2.752, P = 0.022), heterozygous (OR: 1.430, 95% CI: 1.048-1.951, P = 0.024) and additive (OR: 1.348, 95% CI: 1.084-1.676, P = 0.007) genetic models. No significant association between TAP1 I333V gene polymorphism and T1DM was detected in a recessive genetic model (OR: 1.384, 95% CI: 0.743-2.579, P = 0.306) in the entire population, especially among Caucasians. No significant association between them was found in an Asian or African population. TAP1 I333V gene polymorphism was significantly associated with increased T1DM risk. V allele carriers might be predisposed to T1DM susceptibility.

A fire risk pre-warning framework for high-rise buildings based on unascertained method.

The growing global interest in preventing and controlling fires in high-rise buildings reflects the increasing significance of this issue today. This research aims to establish an early warning framework for fire risk in high-rise buildings. Firstly, considering the importance of a scientific indicator system for the application of the model, this study combines the event analysis method with the building design fire code to identify 11 key risk factors that have a far-reaching impact on the prevention of fires in high-rise buildings. Based on identifying the risk factors, a high-rise building fire risk warning tree is also established, which scientifically solves the problem of the indicator system of the warning object. Subsequently, in response to the various complex issues arising from the uncertainty of fire occurrence in high-rise buildings, this study adopts the unascertained method to model the fire risk of high-rise buildings for early warning. In addition, the developed methodology was empirically validated through case studies and analyses of empirical data on fire risks in nine representative high-rise buildings. The results of the unascertained method were also compared with the results of the K-means method, from which it was concluded that the unascertained method can predict building fires more accurately. The research results provide a reliable decision support system for fire disaster prevention and control in high-rise buildings.

A comprehensive investigation regarding the clinical significance of ITGB4 in oral squamous cell carcinoma combining immunohistochemistry, RNA-seq, and microarray data.

OBJECTIVE: Integrin subunit beta 4 (ITGB4), a receptor for laminins, was an oncoprotein in several malignancies. However, its clinical role in oral squamous cell carcinoma (OSCC) remains unclear. MATERIALS AND METHODS: Firstly, 99 OSCC and 13 normal oral epithelium samples were employed for immunohistochemistry (IHC) for detecting the expression level of ITGB4 protein in OSCC. Subsequently, 971 OSCC and 281 non-cancerous specimens from RNA-seq and 18 microarrays were applied for investigating the expression of ITGB4 mRNA. Furthermore, to explore the potential mechanism of ITGB4 in OSCC, the co-expressed genes of ITGB4 were initially screened using all available datasets, and were further utilized for the gene enrichment analysis. RESULTS: First, IHC showed a distinctively higher expression level of the ITGB4 protein in the OSCC group than that in the normal controls. Second, expression profile from RNA-seq and microarrays reflected that ITGB4 mRNA was dramatically overexpressed in OSCC tissues compared with non-tumor tissues. Third, standardized mean difference (SMD) with the area under the summary receiver operating characteristic (sROC) curve combining all incorporated data revealed that ITGB4 was consistently significantly upregulated in OSCC tissues, with the SMD value being 1.31 and the area under the sROC curve being 0.82. Lastly, 184 upregulated and 179 downregulated co-expressed genes of ITGB4 were utilized for enrichment analysis, which demonstrated that ITGB4 might influence the pathogenesis of OSCC through cell cycle, ECM-receptor interaction and focal adhesion pathways. CONCLUSIONS: ITGB4 might play a pivotal role in the tumorigenesis and progression of OSCC, making it a promising biomarker of OSCC.

A comparison of the use of contrast media with different iodine concentrations for enhanced computed tomography.

Objective: In this study, we compared the enhancement of blood vessels and liver parenchyma on enhanced computed tomography (CT) of the upper abdomen with two concentrations of contrast media (400 and 300 mg I/mL) based on similar iodine delivery rate (IDR) of 0.88 and 0.9 g I/s and iodine load of 450 mg I/kg. Methods: We randomly assigned 160 patients into two groups: iomeprol 400 mg I/mL (A group) and iohexol 300 mg I/mL (B group). The CT attenuation values of the main anatomical structures in the two groups with different scanning phases were measured and the image quality of the two groups was analyzed and compared. The peak pressure and local discomfort (including fever and pain) during contrast medium injection were recorded. Results: The mean attenuation value of the abdominal aorta was 313.6 ± 29.6 in the A group and 322.4 ± 30.1 in the B group during the late arterial phase (p = 0.8). Meanwhile, the mean enhancement values of the portal vein were 176.2 ± 19.3 and 165.9 ± 24.5 in the A and B groups, respectively, during the portal venous phase (p = 0.6). The mean CT values of liver parenchyma were 117.1 ± 15.3 and 108.8 ± 18.7 in the A and B groups, respectively, during the portal venous phase (p = 0.9). There was no statistical difference in image quality, peak injection pressure (psi), and local discomfort between the two groups (p > 0.05). Conclusion: When a similar IDR and the same iodine load are used, CT images with different concentrations of contrast media have the same subjective and objective quality, and can meet the diagnostic needs.

Fire Behavior and Failure Model of Multilayered Wood Flour/HDPE/Polycarbonate Composites with a Sandwich Structure.

The flame retardancy of wood-polymer composites significantly affects their potential applications. Thus, multilayered wood flour/high-density polyethylene (HDPE)/polycarbonate (PC) composites were prepared via thermocompression to improve the fire retardancy of wood-polymer composites in this paper. Thermal degradation behavior, flame retardancy, and flexural strengths of the resulting composites were investigated using a thermogravimetric analysis, cone calorimetry, and mechanical testing machine, respectively. Results revealed that the boric acid treatment reduced the heat release rate and total heat release of the wood flour/HDPE composites and increased their mass of residues. However, boric acid reduced the flexural strength of the resulting composites. The combustion test indicated that PC cap layers suppressed the combustion of the resulting composites via the formation of carbon layers. Adding PC layers reduced heat release and increased the flexural strength of the resulting composites. Finally, the failure mode of the multilayered wood flour/HDPE/PC composites in the three-point flexural test was simulated by finite element analysis.

TDO2+ myofibroblasts mediate immune suppression in malignant transformation of squamous cell carcinoma.

Characterization of the dynamic change in the immunological landscape during malignant transformation from precancerous lesions to cancerous lesions in squamous cell carcinoma (SCC) is critical for the application of immunotherapy. Here, we performed single-cell RNA-Seq (scRNA-Seq) of 131,702 cells from 13 cancerous tissues of oral squamous cell carcinoma (OSCC), 3 samples of precancerous oral leukoplakia, and 8 adjacent normal samples. We found that tumor-infiltrating CD4+ and CD8+ T cells were functionally inhibited by immunosuppressive ligands expressed on various types of myeloid cells or neutrophils in the process of oral carcinogenesis. Notably, we identified a subset of myofibroblasts that exclusively expressed tryptophan 2,3-dioxygenase (TDO2). These TDO2+ myofibroblasts were located distally from tumor nests, and both CD4+ and CD8+ T cells were enriched around them. Functional experiments revealed that TDO2+ myofibroblasts were more likely to possess the ability for chemotaxis toward T cells but induced the transformation of CD4+ T cells into Tregs and caused CD8+ T cell dysfunction. We further showed that use of the TDO2 inhibitor LM10 attenuated the inhibitory states of T cells, restored the T cell antitumor response, and prevented the progression of OSCC malignant transformation in murine models. Our study reveals a multistep transcriptomic landscape of OSCC and demonstrates that TDO2+ myofibroblasts are potential targets for immunotherapy.

Global transcriptomic characterization of T cells in individuals with chronic HIV-1 infection.

To obtain a comprehensive scenario of T cell profiles and synergistic immune responses, we performed single-cell RNA sequencing (scRNA-seq) on the peripheral T cells of 14 individuals with chronic human immunodeficiency virus 1 (HIV-1) infection, including nine treatment-naive (TP) and eight antiretroviral therapy (ART) participants (of whom three were paired with TP cases), and compared the results with four healthy donors (HD). Through analyzing the transcriptional profiles of CD4+ and CD8+ T cells, coupled with assembled T cell receptor sequences, we observed the significant loss of naive T cells, prolonged inflammation, and increased response to interferon-α in TP individuals, which could be partially restored by ART. Interestingly, we revealed that CD4+ and CD8+ Effector-GNLY clusters were expanded in TP cases, and persistently increased in ART individuals where they were typically correlated with poor immune restoration. This transcriptional dataset enables a deeper understanding of the pathogenesis of HIV-1 infection and is also a rich resource for developing novel immune targeted therapeutic strategies.

Fire Retardancy, Water Absorption, and Viscoelasticity of Borated Wood-Polycarbonate Biocomposites.

Demand for high-performance biocomposites is increasing due to their ease of processing, low environmental impact, and in-service performance. This study investigated the effect of boric acid modification of wood flour on polycarbonate (PC) wood composites' thermal stability, fire retardancy, water absorption, and creep behavior. The composites' fire retardancy increased with increasing wood flour content, and their char residue increased by 102.3% compared to that of pure PC. However, the water absorption of the resulting composites increased due to the hydroxyl groups of the wood flour. Wood flour also improved the composites' anti-creep properties. The excellent fire retardancy and anti-creep properties of wood-PC composites expand their use in the construction sector.

Clinical Value and Potential Mechanism of miRNA-33a-5p in Lung Squamous Cell Carcinoma.

This study is aimed at thoroughly exploring the expression status, clinical significance, and underlying molecular mechanism of miRNA-33a-5p in lung squamous cell carcinoma (LUSC). Here, we detected miRNA-33a-5p in 20 samples from patients with LUSCs and 20 matching non-LUSC specimens by in-house quantitative real-time PCR (RT-qPCR). Relationship between miRNA-33a-5p expression and clinicopathological traits was investigated from materials derived from miRNA sequencing and miRNA microarrays. A pool standard mean difference (SMD) and summary receiver operating characteristic curves (SROC) were calculated to evaluate the integrated expression value of miRNA-33a-5p in LUSC. Twelve online platforms were applied to select potential target genes of miRNA-33a-5p. The differentially expressed genes (DEGs) of LUSC and the candidate target genes of miRNA-33a-5p were overlapped to acquire a set of specific genes for further analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and protein-protein interaction (PPI) network. miRNA-33a-5p overexpressed in LUSC was supported by 706 LUSC and 261 non-LUSC samples gathering from RT-qPCR, miRNA-seq, and public miRNA microarrays. The pooled SMD was 0.56 (95% CI: -0.01-1.05), and the area under the curve (AUC) of the SROC was 0.78 (95% CI: 0.74-0.82). A total of 240 genes were identified as potential target genes of miRNA-33a-5p for functional enrichment analyses; the results suggested that these target genes may participate in several vital biological processes that promote the proliferation and progression of LUSC. miRNA-33a-5p may play an essential role in the occurrence and development of LUSC by targeting hub genes (ETS1, EDNRB, CYR61, and LRRK2) derived from the PPI network. In summary, our results indicated that miRNA-33a-5p may contribute as a prospective therapeutic target in LUSC.

Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p.

Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance (MDR). Reversing the function of drug efflux pumps is a promising approach to overcome MDR. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily (MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to MDR. Here we report a counterintuitive case of reversing MDR in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. This results in the selective elimination of Mdr1p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time of mice with blood-borne dissemination of Mdr1p overexpressed multidrug-resistant candidiasis. This study provides a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.