Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. Despite cure rates of higher than 85 %, refractory or relapsed ALL still exhibits a bleak prognosis indicative of the dearth of treatment modalities specific for relapsed or refractory ALL. Prior research has implicated metabolic alterations in leukemia pathogenesis, and literature on the therapeutic efficacy of arsenic compounds targeting metabolic pathways in B-cell acute lymphoblastic leukemia (B-ALL) cells is scarce. METHODS: A compound extracted from realgar, tetraarsenic tetrasulfide (As4S4), and its antitumor effects on B-ALL were experimentally examined in vitro and in vivo. RESULTS: As4S4 apparently targets B-ALL cells by inducing specific cellular responses, including apoptosis, G2/M arrest, and ferroptosis. Interestingly, these effects are attributed to reactive oxygen species (ROS) accumulation, and increased ROS levels have been linked to both the mitochondria-dependent caspase cascade and the activation of p53 signaling. The ROS scavenger N-acetylcysteine (NAC) can counteract the effects of As4S4 treatment on Nalm-6 and RS4;11 cells. Specifically, by targeting Hexokinase-2 (HK2), As4S4 induces alterations in mitochondrial membrane potential and disrupts glucose metabolism, leading to ROS accumulation, and was shown to inhibit B-ALL cell proliferation in vitro and in vivo. Intriguingly, overexpression of HK2 can partially desensitize B-ALL cells to As4S4 treatment. CONCLUSION: Tetraarsenic tetrasulfide can regulate the Warburg effect by controlling HK2 expression, a finding that provides both new mechanistic insight into metabolic alterations and pharmacological evidence for the clinical treatment of B-ALL.

ZNF384-Related Fusion Genes in Acute Lymphoblastic Leukemia.

Zinc finger protein 384 (ZNF384) encodes a C2H2-type zinc finger protein that can function as a transcription factor. ZNF384 rearrangement in acute lymphoblastic leukemia (ALL) was first reported in 2002. More than 19 different ZNF384 fusion partners have been detected in ALL. These include E1A-binding protein P300 (EP300), CREB-binding protein (CREBBP), transcription factor 3 (TCF3), TATA-box binding protein associated factor 15 (TAF15), Ewing sarcoma breakpoint region 1 gene (EWSR1), AT-rich interactive domain-containing protein 1B (ARID1B), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2), synergin gamma (SYNRG), clathrin heavy chain (CLTC), bone morphogenic protein 2-inducible kinase (BMP2K), Nipped-B-like protein (NIPBL), A Kinase Anchoring Protein 8 (AKAP8), Chromosome 11 Open Reading Frame 74 (C11orf74), DEAD-Box Helicase 42 (DDX42), ATP Synthase F1 Subunit Gamma (ATP2C1), Euchromatic Histone Lysine Methyltransferase 1 (EHMT1), Testic Expressed 41 (TEX41), etc. Patients diagnosed with ALL harboring ZNF384 rearrangements commonly had a good prognosis. The mechanisms, performance, and features of different ZNF384 rearrangements in acute lymphoblastic leukemia have been well evaluated.

Integrative transcriptome and metabolome revealed the molecular mechanism of Bacillus megaterium BT22-mediated growth promotion in Arabidopsis thaliana.

Plant growth-promoting rhizobacteria (PGPR) can promote plant growth and protect plants from pathogens, which contributes to sustainable agricultural development. Several studies have reported their beneficial characteristics in facilitating plant growth and development and enhancing plant stress resistance through different mechanisms. However, there is still a challenge to study the molecular mechanism of plant response to PGPR. We integrated the transcriptome and metabolome of Arabidopsis thaliana (Arabidopsis) to understand its responses to the inoculation with an isolated PGPR strain (BT22) of Bacillus megaterium. Fresh shoot weight, dry shoot weight and leaf number of Arabidopsis were increased by BT22 treatment, showing a positive growth-promoting effect. According multi-omics analysis, 878 differentially expressed genes (296 up-regulated, 582 down-regulated) and 139 differentially expressed metabolites (66 up-regulated, 73 down-regulated) response to BT22 inoculation. GO enrichment results indicate that the up-regulated genes mainly enriched in the regulation of growth and auxin response pathways. In contrast, the down-regulated genes mainly enriched in wounding response, jasmonic acid and ethylene pathways. BT22 inoculation regulated plant hormone signal transduction of Arabidopsis, including auxin and cytokinin response genes AUX/IAA, SAUR, and A-ARR related to cell enlargement and cell division. The contents of nine flavonoids and seven phenylpropanoid metabolites were increased, which help to induce systemic resistance in plants. These results suggest that BT22 promoted Arabidopsis growth by regulating plant hormone homeostasis and inducing metabolome reprogramming.

Species coexistence and niche interaction between sympatric giant panda and Chinese red panda: A spatiotemporal approach.

The giant panda (Ailuropoda melanoleuca) and the Chinese red panda (Ailurus styani) are distributed in the same region in the mountain forest ecosystem on the eastern edge of the Qinghai Tibet Plateau and share the same food sources. In order to understand how sympatric giant pandas and Chinese red pandas maintain interspecific relationships to achieve stable coexistence, we used species distribution models and diurnal activity rhythms to analyze the spatial and temporal niche characteristics of giant pandas and Chinese red pandas in the Daxiangling Mountain system based on 187 camera traps data. The results show that: (1) In the Daxiangling Mountains, the total area of suitable habitats for giant pandas and Chinese red pandas is 717.61 km2 and 730.00 km2, respectively, accounting for 17.78% and 18.25%, respectively, of the study area. (2) The top five environmental factors contributing to the model of giant panda and Chinese red panda are precipitation seasonality, temperature seasonality, distance to the road, and elevation and vegetation type. (3) The total overlapping area of suitable habitats for giant pandas and Chinese red pandas is 342.23 km2, of which the overlapping area of highly suitable habitats is 98.91 km2. The overlapping index of suitable habitats is 0.472, and the overlapping index of highly suitable habitats is 0.348, which indicates that the two achieve spatial niches are separated to achieve stable coexistence. (4) The overlapping index of the daily activity rhythm of giant panda and Chinese red panda is 0.87, which is significantly different (p < .05). The existence of Chinese red panda will significantly affect the daily activity rhythm of giant panda (p < .001). This research can provide scientific reference for the researches about population and habitat protection of giant pandas and Chinese red pandas, so as to understand the driving mechanism of resource allocation and population dynamics of sympatric species.

The positive feedback loop of MAD2L1/TYK2/STAT3 induces progression in B-cell acute lymphoblastic leukaemia.

PURPOSE: Mitotic arrest deficient 2 like 1 (MAD2L1) has been extensively studied in several malignancies; however, its role in B-cell acute lymphoblastic leukaemia (B-ALL) remains unclear. METHODS: The expression of MAD2L1 was evaluated by real-time quantitative polymerase chain reaction. The biological functions of MAD2L1 in B-ALL were explored through Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine assay (EDU), transwell assay, flow cytometry and xenograft models. The Western blotting and co-immunoprecipitation were utilized to evaluate the interplay between MAD2L1 and the TYK2/STAT3 pathway. The luciferase reporter and chromatin immunoprecipitation (ChIP) assay were employed to identify interactions between STAT3 and MAD2L1. RESULTS: We demonstrated that MAD2L1 was markedly upregulated in B-ALL, and its expression level not only correlated with the relapse and remission of the condition but also with a poor prognosis. MAD2L1 promoted the proliferation, migration and invasion of B-ALL cells in vitro and in vivo, whereas MAD2L1 knockdown had the opposite effects. Mechanistically, MAD2L1 induces the progression of B-ALL by activating the TYK2/STAT3 signaling pathway to phosphorylate. Interestingly, STAT3 induces the expression of MAD2L1 by binding directly to its promoter region, resulting in a positive-feedback loop of MAD2L1/TYK2/STAT3. CONCLUSION: This study uncovered a reciprocal loop of MAD2L1/TYK2/STAT3, which contributed to the development of B-ALL. Therefore, MAD2L1 can be considered a potential diagnostic biomarker as well as a novel therapeutic target for B-ALL.

Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice.

Objective: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, is a promising drug for nonalcoholic fatty liver disease (NAFLD); however, it can cause liver injury, especially at high doses. Here, we investigated the role of FXR in the high-dose OCA-induced hepatoxicity in the condition of the NAFLD mouse model. Methods: Wild-type (WT) mice and FXR-/- mice were administered with over-dose OCA (0.40%) and high-dose OCA (0.16%), in a high-fat diet. RNA-seq on liver samples of mice fed with high-dose OCA was performed to dig out the prominent biological events contributing to hepatic fibrosis. Results: Over-dose OCA induced liver injury and shortened survival in WT mice, but not FXR-/- mice. High-dose OCA caused hepatic stellate cell activation and liver fibrosis in the presence of FXR. Furthermore, high-dose OCA induced cholesterol accumulation in livers via the upregulation of genes involved in cholesterol acquisition and downregulation of genes regulating cholesterol degradation in liver, leading to the production of interleukin -1ß and an FXR-mediated inflammatory response. Conclusion: The high-dose OCA induced FXR-dependent hepatic injury via cholesterol accumulation and interleukin -1ß pathway in the NAFLD mice.

Obeticholic acid inhibits hepatic fatty acid uptake independent of FXR in mouse.

OBJECTIVE: Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, is believed to alleviate nonalcoholic fatty liver disease (NAFLD) by decreasing hepatic lipogenesis in an FXR-dependent manner. Here, we revealed a novel mechanism by which OCA improves NAFLD by affecting hepatic long-chain fatty acids (LCFAs) uptake. METHODS: Stably transfected HEK-293 cells expressing fatty acid transport protein 5 (FATP5) were established to examine fatty acid uptake; FXR-/-, human (h) FATP5, and FXR-/-/hFATP5 mouse models were incorporated to explore the effects of OCA on FATP5 ex vivo and in vivo. RESULTS: OCA inhibited hFATP5 (IC50 =0.07 µM) more than murine (m) FATP5 (IC50 =1.04 µM) as measured by LCFAs uptake in FATP5 expressing HEK-293. OCA also inhibited LCFA uptake in primary hepatocytes from hFATP5 mice, FXR-/-/hFATP5 mice more than that from FXR-/- mice, ex vivo. Moreover, OCA inhibited LCFAs uptake by livers in hFATP5 mice and FXR-/-/hFATP5 mice, but not in FXR-/- mice, in vivo. Long-term administration of 0.04% OCA markedly reduced hepatic triglyceride (TG) accumulation in hFATP5 mice and FXR-/-/hFATP5 mice by 63% and 53%, respectively, but not in FXR-/- mice. CONCLUSIONS: OCA ameliorated high-fat diet-induced NAFLD independent of FXR by inhibiting hepatic hFATP5-mediated LCFAs uptake. This suggests that the therapeutic effects of OCA on NAFLD in vivo are mediated by a novel, hFATP5 dependent mechanism.

Interactive spatial scale effects on species distribution modeling: The case of the giant panda.

Research has shown that varying spatial scale through the selection of the total extent of investigation and the grain size of environmental predictor variables has effects on species distribution model (SDM) results and accuracy, but there has been minimal investigation into the interactive effects of extent and grain. To do this, we used a consistently sampled range-wide dataset of giant panda occurrence across southwest China and modeled their habitat and distribution at 4 extents and 7 grain sizes. We found that increasing grain size reduced model accuracy at the smallest extent, but that increasing extent negated this effect. Increasing extent also generally increased model accuracy, but the models built at the second-largest (mountain range) extent were more accurate than those built at the largest, geographic range-wide extent. When predicting habitat suitability in the smallest nested extents (50 km2), we found that the models built at the next-largest extent (500 km2) were more accurate than the smallest-extent models but that further increases in extent resulted in large decreases in accuracy. Overall, this study highlights the impacts of the selection of spatial scale when evaluating species' habitat and distributions, and we suggest more explicit investigations of scale effects in future modeling efforts.

Suitable habitat prediction of Sichuan snub-nosed monkeys (Rhinopithecus roxellana) and its implications for conservation in Baihe Nature Reserve, Sichuan, China.

As an endemic primate species with one of the highest priorities in wildlife conservation in China, Sichuan snub-nosed monkeys (Rhinopithecus roxellana) have undergone a sharp decline and range reduction in recent centuries. Here, we used maximum entropy modelling (MaxEnt) integrated with four types of environmental variables, including three biological climate variables (Bio17, precipitation of the driest quarter; Bio6, min. temperature of the coldest month; and Bio2, mean diurnal range), three topographic variables (altitude, slope, and aspect), two anthropogenic variables (Human Footprint Index and human disturbance), and three vegetation-related variables (enhanced vegetation index, normalized difference vegetation index, and Wet Index) to identify the spatial distribution of suitable habitats for Sichuan snub-nosed monkeys in Baihe Nature Reserve (BNR), which is located in the Minshan Mountains. The average training AUC of our model performance is 0.929 ± 0.003. The model predicted 9.6 km2 of high suitability habitats and 14.1 km2 of moderate suitability habitats for Sichuan snub-nosed monkeys, adding up to only 11.7% of the total area of concern for the study in the BNR. The top four variables ranked in the model (altitude, Human Footprint Index, human disturbance, and Bio17) accounted for relative gain contributions of 23.3%, 19.3%, 14.2%, and 13.4%, respectively. The predicted suitable habitats were confined to an altitude range of 1971-3198 m, Human Footprint Index of mainly 3-5 values, low human disturbance (mainly livestock), and precipitation of the driest (or coldest) quarter of 9-22 mm. Additionally, the suitable habitats were mainly distributed in the core zone (36.1%), buffer zone (26.8%), and experimental zone (29.5%). The remaining habitats (7.6%) were distributed in the 0.5-km buffer zone of the reserve border. The predicted suitable habitats indicated limited suitable habitat space for the Sichuan snub-nosed monkeys, with most of the suitable habitat distributed outside the core zone in the BNR. Our findings highlighted that human activities in all three functional zones could be the most negative factor on suitable habitat distribution of Sichuan snub-nosed monkeys in the BNR.

Genomic Identification and Expression Analysis of the Cathelicidin Gene Family of the Forest Musk Deer.

The forest musk deer (Moschus berezovskii) is a small-sized artiodactyl species famous for the musk secreted by adult males. In the captive population, this species is under the threat of infection diseases, which greatly limits the increase of individual numbers. In the present study, we computationally analyzed the repertoire of the cathelicidin (CATHL) family from the genome of forest musk deer and investigated their expression pattern by real-time PCR. Our results showed that the entire genome of forest musk deer encodes eight cathelicidins, including six functional genes and two pseudogenes. Phylogenetic analyses further revealed that all forest musk deer cathelicidin members have emerged before the split of the forest musk deer and cattle and that forest musk deer CATHL3L2 and CATHL9 are orthologous with two cattle pseudogenes. In addition, the gene expression results showed that the six functional genes are not only abundantly expressed in the spleen and lung, but are also differently expressed in response to abscesses, which suggests that forest musk deer cathelicidins may be involved in infections. Taken together, identification and characterization of the forest musk deer cathelicidins provide fundamental data for further investigating their evolutionary process and biological functions.

Long-term distribution and habitat changes of protected wildlife: giant pandas in Wolong Nature Reserve, China.

Changes in wildlife habitat across space and time, and corresponding changes in wildlife space use, are increasingly common phenomenon. It is critical to study and understand these spatio-temporal changes to accurately inform conservation strategy and manage wildlife populations. These changes can be particularly large and complex in areas that face pressure from human development and disturbance but are also under protection and/or restoration regimes. We analyzed changes in space use and habitat suitability of giant pandas in Wolong Nature Reserve, China, over three decades using kernel density, spatio-temporal analysis of moving polygons (STAMP), and MaxEnt methods, and data from three national censuses. Between 2001 and 2012, there was a slight retraction in total range, and more area of significant space use decreases than increases. Habitat suitability varied spatially and temporally, with a 4.1% decrease in average suitability between 1987 and 2001 and a 3.5% increase in average suitability in between 2001 and 2012. Elevation and bamboo were the most important habitat predictors across the three censuses. Human and natural disturbance variables such as distance to household and the distance to landslide variable in the 4th census were also important predictors, and likely also negatively influenced important habitat variables such as bamboo and forest cover. We were able to measure changes in space utilization and habitat suitability over a large time scale, highlighting the achievements and challenges of giant panda conservation. Long-term monitoring of the changes in distribution and habitat of threatened species, and an analysis of the drivers behind these changes such as undergone here, are important to inform the management and conservation of the world's remaining wildlife populations.