ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary ...tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.
Display omitted
•ARID1A promotes cancer initiation by increasing CYP450-mediated oxidative stress•ARID1A was frequently overexpressed in primary HCC but lost in metastatic clones•In established tumors, Het and Homo loss promoted progression and metastasis•Arid1a loss increased chromatin occupancy, downregulated metastasis suppressors
Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Droplet arrays show great significance in biosensing and biodetection because of low sample consumption and easy operation. However, inevitable water evaporation in open environment severely limits ...their applications in time‐consuming reactions. Herein, inspired by the unique water retention features of leaves, it is demonstrated that an open droplet array on patterned organohydrogel surface with water evaporating replenishment (POWER) for ultrawide time‐range biosensing, which integrated hydrophilic hydrogel domains and hydrophobic organogel background. The hydrogel domains on the surface can supply water to the pinned droplets through capillary channels formed in the nether organohydrogel bulk. The organogel background can inhibit water evaporation like the wax coating of leaves. Such a unique bioinspired design enables ultrawide time‐range biosensing in open environment from a few minutes to more than five hours involving a variety of analytes such as ions, small molecules, and macromolecules. The POWER provides a feasible and open biosensing platform for ultrawide time‐range reactions.
The authors prepare a
novel droplet array on patterned organohydrogel surface with water evaporating replenishment (POWER), enabling ultrawide biosensing time from minutes to hours with negligible sample diffusion. The POWER platform can be applied to almost all biosensing with different time ranges in an open environment, shedding new light on the design of next‐generation water retention platforms without additional equipment appendix.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human ...metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Tbx3, Bcl6, or Smyd2 resulted in protection against hepatic steatosis. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.
Display omitted
•Clones with Mboat7 loss-of-function mutations are selected against in NASH livers•Clones with Gpam loss-of-function mutations are positively selected for in NASH•In vivo screening was built to identify genes that alter cell fitness and steatosis•Screening of transcription and epi-factors identified unexpected NASH target genes
An in vivo lineage tracing platform was developed to identify somatically mutated clones that are positively selected in chronic liver disease, revealing genes that modify hepatocyte fitness in the context of fatty liver disease in a high-throughput manner.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thirty to 90% of hepatocytes contain whole-genome duplications, but little is known about the fates or functions of these polyploid cells or how they affect development of liver disease. We ...investigated the effects of continuous proliferative pressure, observed in chronically damaged liver tissues, on polyploid cells.
We studied Rosa-rtTa mice (controls) and Rosa-rtTa;TRE-short hairpin RNA mice, which have reversible knockdown of anillin, actin binding protein (ANLN). Transient administration of doxycycline increases the frequency and degree of hepatocyte polyploidy without permanently altering levels of ANLN. Mice were then given diethylnitrosamine and carbon tetrachloride (CCl4) to induce mutations, chronic liver damage, and carcinogenesis. We performed partial hepatectomies to test liver regeneration and then RNA-sequencing to identify changes in gene expression. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. We imaged dividing hepatocytes to estimate the frequency of mitotic errors during regeneration. We also performed whole-exome sequencing of 54 liver nodules from patients with cirrhosis to quantify aneuploidy, a possible outcome of polyploid cell divisions.
Liver tissues from control mice given CCl4 had significant increases in ploidy compared with livers from uninjured mice. Mice with knockdown of ANLN had hepatocyte ploidy above physiologic levels and developed significantly fewer liver tumors after administration of diethylnitrosamine and CCl4 compared with control mice. Increased hepatocyte polyploidy was not associated with altered regenerative capacity or tissue fitness, changes in gene expression, or more mitotic errors. Based on lineage-tracing experiments, non-hepatocytes did not contribute to liver regeneration in mice with increased polyploidy. Despite an equivalent rate of mitosis in hepatocytes of differing ploidies, we found no lagging chromosomes or micronuclei in mitotic polyploid cells. In nodules of human cirrhotic liver tissue, there was no evidence of chromosome-level copy number variations.
Mice with increased polyploid hepatocytes develop fewer liver tumors following chronic liver damage. Remarkably, polyploid hepatocytes maintain the ability to regenerate liver tissues during chronic damage without generating mitotic errors, and aneuploidy is not commonly observed in cirrhotic livers. Strategies to increase numbers of polypoid hepatocytes might be effective in preventing liver cancer.
Display omitted
Social determinants of health (SDOH) play a significant role in the development of cardiovascular risk factors. We investigated SDOH associations with cardiovascular risk factors among Asian American ...subgroups.
We utilized the National Health Interview Survey, a nationally representative survey of US adults, years 2013 to 2018. SDOH variables were categorized into economic stability, neighborhood and social cohesion, food security, education, and health care utilization. SDOH score was created by categorizing 27 SDOH variables as 0 (favorable) or 1 (unfavorable). Self-reported cardiovascular risk factors included diabetes, high cholesterol, high blood pressure, obesity, insufficient physical activity, suboptimal sleep, and nicotine exposure. Among 6395 Asian adults aged ≥18 years, 22.1% self-identified as Filipino, 21.6% as Asian Indian, 21.0% as Chinese, and 35.3% as other Asian. From multivariable-adjusted logistic regression models, each SD increment of SDOH score was associated with higher odds of diabetes among Chinese (odds ratio OR, 1.45; 95% CI, 1.04-2.03) and Filipino (OR, 1.24; 95% CI, 1.02-1.51) adults; high blood pressure among Filipino adults (OR, 1.28; 95% CI, 1.03-1.60); insufficient physical activity among Asian Indian (OR, 1.42; 95% CI, 1.22-1.65), Chinese (OR, 1.58; 95% CI, 1.33-1.88), and Filipino (OR, 1.24; 95% CI, 1.06-1.46) adults; suboptimal sleep among Asian Indian adults (OR, 1.20; 95% CI, 1.01-1.42); and nicotine exposure among Chinese (OR, 1.56; 95% CI, 1.15-2.11) and Filipino (OR, 1.50; 95% CI, 1.14-1.97) adults.
Unfavorable SDOH are associated with higher odds of cardiovascular risk factors in Asian American subgroups. Culturally specific interventions addressing SDOH may help improve cardiovascular health among Asian Americans.
Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific ...vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment.
The emergence and spread of artemisinin-tolerant malaria parasites threatens malaria control programmes worldwide. Mutations in the propeller domain of the Kelch13 protein confer Plasmodium ...falciparum artemisinin resistance (ART-R). ART-R is linked to the reduced susceptibility of temporary growth-arrested ring-stage parasites, but the metabolic mechanisms remain elusive. We generated two PfKelch13 mutant lines via CRISPR-Cas9 gene editing which displayed a reduced susceptibility accompanied by an extended ring stage. The metabolome of ART-induced ring-stage growth arrest parasites carrying PfKelch13 mutations showed significant alterations in the tricarboxylic acid (TCA) cycle, glycolysis, and amino acids metabolism, pointing to altered energy and porphyrin metabolism with metabolic plasticity. The critical role of these pathways was further confirmed by altering metabolic flow or through chemical inhibition. Our findings uncover that the growth arrestment associated with ART-R is potentially attributed to the adaptative metabolic plasticity, indicating that the defined metabolic remodeling turns out to be the trigger for ART-R.
Display omitted
•Typical PfKelch13 mutant parasite lines confer to ART resistance have been constructed•Modified SLOPE protocol allows for the enrichment of early ring-stage parasites•Metabolomics screening points to altered energy metabolism with metabolic plasticity•Altering metabolic flow or chemical inhibition confirms the screening results
Multidrug resistant organisms; Parasitology
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Shuyu decoction (SYD), an effective traditional Chinese medicine (TCM), has been widely used for treating deficiency-related diseases for thousands of years. Meanwhile, exercise-induced fatigue (EF), ...a common physiological phenomenon observed in physical training, has been treated as a deficient condition in TCM for decades. Currently, not many studies have been conducted on the effect of SYD on EF and little is known about its underlying pharmacological mechanism.
This current study was designed to assess the anti-fatigue roles of SYD and explore its effect on exercise-induced immune dysfunction.
Eighteen rats were randomly divided into three groups: normal control (NC) group, model (M) group, and SYD group (27.8g/kg). All rats were given treadmill training for 6 weeks. From the fourth week, the SYD group was administered SYD intragastrically for 3 consecutive weeks. After three weeks of treatment, the rats were anesthetized, and the blood and spleen tissue samples were dissected. The blood sample was devoted to the blood biochemical-related indicators, which were used to evaluate the anti-fatigue of SYD. The expression of Interleukin(IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), IL-17, CD3+, and CD4+ were detected by ELISA and the level of CD8+ of blood was measured through Flow Cytometry (FC). The histopathological changes of spleen tissue samples were determined by Hematoxylin and eosin (H&E) staining and an estimation of CD3+, CD4+, and CD8+ expression of spleen tissues were calculated through FC.
Compared with the M group, the SYD group observed an increase in tensile force and the ratio of cortisol to testosterone (TTE/COR), whereas a reduction in the levels of lactic acid (LAC), blood urea nitrogen (BUN), creatine kinase (CK), (P < 0.01 or P < 0.05). ELISA experiments showed that SYD reduced the expressions of IL-6, IL-1β, and TNF-α, IL-17 and increased the expression of IL-10 (P < 0.01 or P < 0.05). In the HE test, SYD treatment transformed the structure of the spleen. FC experiments further showed that SYD increased the expressions of CD3+, CD4+, and CD8+ in blood and spleen tissues (P < 0.01 or P < 0.05).
Our findings indicate that SYD can alleviate EF by improving inflammation and immunity. However, the relationship between inflammatory factors and the related immune response remains to be further investigated.
Display omitted
•It is confirmed that exercise-induced fatigue can lead to immune dysfunction.•SYD can remarkablely alleviate exercise-induced fatigue by improving immune suppression, and its mechanism may be related to ameliorating muscle fatigue, changing the structure of the spleen, enhancing cellular immunity, and inhibiting the secretion of inflammatory factors, specifically manifested as reducing blood LAC,BUN,CK content and TTE/COR, changing the number of CD3+, CD4+, CD8+ cells and CD4+/CD8+ in blood and spleen, decreasing the serum level of IL-6,IL-1 β,TNF- α,IL-17 and improve IL-10.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Few studies have explored transcriptome of the peripheral blood mononuclear cells (PBMCs) of atopic dermatitis (AD). Parameters for prediction of the efficacy of dupilumab in AD remain obscure.
To ...explore transcriptome signature of the PBMCs from Chinese AD patients and the usage in predication for the efficacy of dupilumab.
A total of 56 moderate-to-severe adult AD patients were enrolled and followed up for 16 week-dupilumab treatment. PBMCs samples were collected at baseline and 16 weeks after dupilumab treatment. Thirty-five patients were subjected to RNA-sequencing. Weighted gene co-expression network analysis (WGCNA) was used to find genes for prediction of dupilumab efficacy, which was validated in the rest 21 AD patients. Another 30 healthy individuals were enrolled and subjected to RNA-sequencing as healthy controls.
Upregulation of the T helper (Th) 2/Th22 pathway, Th17 antimicrobial genes, and natural T-regulatory cell abundance in the PBMCs of AD cases was observed, whereas TGF-β signaling and NK-cell signaling were decreased. Dupilumab treatment reversed the increase in the expression of Th2 cytokine receptors. WGCNA identified two immune-related modules that were correlated significantly with the efficacy of dupilumab. Hub gene MAP2K3 and UBE2L3 of these two modules demonstrated potential predictive ability for efficacy in the RNA-sequencing group by Spearman correlation, ROC analysis, and regression analysis, which was further validated in additional 21 AD cases.
We firstly revealed the molecular phenotype of PBMCs in Chinese patients with AD, and uncovered two molecules that might be useful for prediction of the efficacy of dupilumab.
•Blood molecular phenotype was revealed by analyzing the transcriptome of PBMCs from AD patients.•Alterations in the transcriptome of PBMCs reflected the changes in systemic inflammation of AD patients upon dupilumab treatment.•Two molecules, MAP2K3 and UBE2L3, were identified for prediction of dupilumab efficacy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Heterochromatin-associated gene silencing controls multiple physiological processes in malaria parasites, however, little is known concerning the regulatory network and cis-acting sequences ...involved in the organization of heterochromatin and how they modulate heterochromatic gene expression. Based on systematic profiling of genome-wide occupancy of eighteen Apicomplexan AP2 transcription factors by ChIP-seq analysis, we identify and characterize eight heterochromatin-associated factors (PfAP2-HFs), which exhibit preferential enrichment within heterochromatic regions but with differential coverage profiles. Although these ApiAP2s target euchromatic gene loci via specific DNA motifs, they are likely integral components of heterochromatin independent of DNA motif recognition. Systematic knockout screenings of ApiAP2 factors coupled with RNA-seq transcriptomic profiling revealed three activators and three repressors of heterochromatic gene expression including four PfAP2-HFs. Notably, expression of virulence genes is either completely silenced or significantly reduced upon the depletion of PfAP2-HC. Integrated multi-omics analyses reveal autoregulation and feed-forward loops to be common features of the ApiAP2 regulatory network, in addition to the occurrence of dynamic interplay between local chromatin structure and ApiAP2s in transcriptional control. Collectively, this study provides a valuable resource describing the genome-wide landscape of the ApiAP2 family and insights into functional divergence and cooperation within this family during the blood-stage development of malaria parasites.
PDF
