A natural gene drive system confers reproductive isolation in rice.

Hybrid sterility restricts the utilization of superior heterosis of indica-japonica inter-subspecific hybrids. In this study, we report the identification of RHS12, a major locus controlling male gamete sterility in indica-japonica hybrid rice. We show that RHS12 consists of two genes (iORF3/DUYAO and iORF4/JIEYAO) that confer preferential transmission of the RHS12-i type male gamete into the progeny, thereby forming a natural gene drive. DUYAO encodes a mitochondrion-targeted protein that interacts with OsCOX11 to trigger cytotoxicity and cell death, whereas JIEYAO encodes a protein that reroutes DUYAO to the autophagosome for degradation via direct physical interaction, thereby detoxifying DUYAO. Evolutionary trajectory analysis reveals that this system likely formed de novo in the AA genome Oryza clade and contributed to reproductive isolation (RI) between different lineages of rice. Our combined results provide mechanistic insights into the genetic basis of RI as well as insights for strategic designs of hybrid rice breeding.

EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.

MACC: a visual interactive knowledgebase of metabolite-associated cell communications.

Metabolite-associated cell communications play critical roles in maintaining the normal biological function of human through coordinating cells, organs and physiological systems. Though substantial information of MACCs has been continuously reported, no relevant database has become available so far. To address this gap, we here developed the first knowledgebase (MACC), to comprehensively describe human metabolite-associated cell communications through curation of experimental literatures. MACC currently contains: (a) 4206 carefully curated metabolite-associated cell communications pairs involving 244 human endogenous metabolites and reported biological effects in vivo and in vitro; (b) 226 comprehensive cell subtypes and 296 disease states, such as cancers, autoimmune diseases, and pathogenic infections; (c) 4508 metabolite-related enzymes and transporters, involving 542 pathways; (d) an interactive tool with user-friendly interface to visualize networks of multiple metabolite-cell interactions. (e) overall expression landscape of metabolite-associated gene sets derived from over 1500 single-cell expression profiles to infer metabolites variations across different cells in the sample. Also, MACC enables cross-links to well-known databases, such as HMDB, DrugBank, TTD and PubMed etc. In complement to ligand-receptor databases, MACC may give new perspectives of alternative communication between cells via metabolite secretion and adsorption, together with the resulting biological functions. MACC is publicly accessible at: http://macc.badd-cao.net/.

Auxin regulates source-sink carbohydrate partitioning and reproductive organ development in rice.

Carbohydrate partitioning between the source and sink tissues plays an important role in regulating plant growth and development. However, the molecular mechanisms regulating this process remain poorly understood. In this study, we show that elevated auxin levels in the rice dao mutant cause increased accumulation of sucrose in the photosynthetic leaves but reduced sucrose content in the reproductive organs (particularly in the lodicules, anthers, and ovaries), leading to closed spikelets, indehiscent anthers, and parthenocarpic seeds. RNA sequencing analysis revealed that the expression of AUXIN RESPONSE FACTOR 18 (OsARF18) and OsARF2 is significantly up- and down-regulated, respectively, in the lodicule of dao mutant. Overexpression of OsARF18 or knocking out of OsARF2 phenocopies the dao mutant. We demonstrate that OsARF2 regulates the expression of OsSUT1 through direct binding to the sugar-responsive elements (SuREs) in the OsSUT1 promoter and that OsARF18 represses the expression of OsARF2 and OsSUT1 via direct binding to the auxin-responsive element (AuxRE) or SuRE in their promoters, respectively. Furthermore, overexpression of OsSUT1 in the dao and Osarf2 mutant backgrounds could largely rescue the spikelets' opening and seed-setting defects. Collectively, our results reveal an auxin signaling cascade regulating source-sink carbohydrate partitioning and reproductive organ development in rice.

Improved redox homeostasis owing to the up-regulation of one-carbon metabolism and related pathways is crucial for yeast heterosis at high temperature.

Heterosis or hybrid vigor is a common phenomenon in plants and animals; however, the molecular mechanisms underlying heterosis remain elusive, despite extensive studies on the phenomenon for more than a century. Here we constructed a large collection of F1 hybrids of Saccharomyces cerevisiae by spore-to-spore mating between homozygous wild strains of the species with different genetic distances and compared growth performance of the F1 hybrids with their parents. We found that heterosis was prevalent in the F1 hybrids at 40°C. A hump-shaped relationship between heterosis and parental genetic distance was observed. We then analyzed transcriptomes of selected heterotic and depressed F1 hybrids and their parents growing at 40°C and found that genes associated with one-carbon metabolism and related pathways were generally up-regulated in the heterotic F1 hybrids, leading to improved cellular redox homeostasis at high temperature. Consistently, genes related with DNA repair, stress responses, and ion homeostasis were generally down-regulated in the heterotic F1 hybrids. Furthermore, genes associated with protein quality control systems were also generally down-regulated in the heterotic F1 hybrids, suggesting a lower level of protein turnover and thus higher energy use efficiency in these strains. In contrast, the depressed F1 hybrids, which were limited in number and mostly shared a common aneuploid parental strain, showed a largely opposite gene expression pattern to the heterotic F1 hybrids. We provide new insights into molecular mechanisms underlying heterosis and thermotolerance of yeast and new clues for a better understanding of the molecular basis of heterosis in plants and animals.

Protein Kinase D2 and D3 Promote Prostate Cancer Cell Bone Metastasis by Positively Regulating Runx2 in a MEK/ERK1/2-Dependent Manner.

Advanced-stage prostate tumors metastasize to the bone, often causing death. The protein kinase D (PKD) family has been implicated in prostate cancer development; however, its role in prostate cancer metastasis remains elusive. This study examined the contribution of PKD, particularly PKD2 and PKD3 (PKD2/3), to the metastatic potential of prostate cancer cells and the effect of PKD inhibition on prostate cancer bone metastasis in vivo. Depletion of PKD2/3 by siRNAs or inhibition by the PKD inhibitor CRT0066101 in AR-positive and AR-negative castration-resistant prostate cancer cells potently inhibited colony formation and cell migration. Depletion or inhibition of PKD2/3 significantly blocked tumor cell invasion and suppressed the expression of genes related to bone metastasis in the highly invasive PC3-ML cells. The reduced invasive activity resulting from PKD2/3 depletion was in part mediated by the transcription factor Runx2, as its silencing decreased PKD2/3-mediated metastatic gene expression through the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling axis. Furthermore, inhibition of PKD by CRT0066101 potently decreased the frequency of bone micrometastases in a mouse model of bone metastasis based on intracardiac injection of PC3-ML cells. These results indicate that PKD2/3 plays an important role in the bone metastasis of prostate cancer cells, and its inhibition may be beneficial for the treatment of advanced prostate cancer.

Facility for spectral radiance calibration at low light level.

The spectral radiance measurement at daytime level can be realized with high accuracy, while it's difficult when the spectral radiance is at nighttime level. We design a spectral radiance calibration facility which has the characteristics of completely unchanged spectrum over 3 orders of magnitude and approximately unchanged spectrum for about 6 orders of magnitude. It combines a spectral radiance light source, a precision aperture and a white diffuser together, make it easy to reproduce the spectral radiance at 380 nm from 4 × 10-9 W/(m2·sr·nm) to 4 × 10-3 W/(m2·sr·nm). The facility can be easily used to calibrate a spectroradiometer at nighttime level. When the spectral radiance from 380 nm to 780 nm is around 1 × 10-7W/(m2·sr·nm), the calibration uncertainty of the spectroradiometer is 0.87%∼1.0% (k = 1).

Integrated mendelian randomization analyses highlight AFF3 as a novel eQTL-mediated susceptibility gene in renal cancer and its potential mechanisms.

BACKGROUNDS: A growing number of expression quantitative trait loci (eQTLs) have been found to be linked with tumorigenesis. In this article, we employed integrated Mendelian randomization (MR) analyses to identify novel susceptibility genes in renal cancer (RC) and reveal their potential mechanisms. METHODS: Two-sample MR analyses were performed to infer causal relationships between eQTLs, metabolites, and RC risks through the "TwoSampleMR" R package. Sensitivity analyses, such as heterogeneity, pleiotropy, and leave-one-out analysis, were used to assess the stability of our outcomes. Summary-data-based MR (SMR) analyses were used to verify the causal relationships among cis-eQTLs and RC risks via the SMR 1.3.1 software. RESULTS: Our results provided the first evidence for AFF3 eQTL elevating RC risks, suggesting its oncogenic roles (IVW method; odds ratio (OR) = 1.0005; 95% confidence interval (CI) = 1.0001-1.0010; P = 0.0285; heterogeneity = 0.9588; pleiotropy = 0.8397). Further SMR analysis validated the causal relationships among AFF3 cis-eQTLs and RC risks (P < 0.05). Moreover, the TCGA-KIRC, the ICGC-RC, and the GSE159115 datasets verified that the AFF3 gene was more highly expressed in RC tumors than normal control via scRNA-sequencing and bulk RNA-sequencing (P < 0.05). Gene set enrichment analysis (GSEA) analysis identified six potential biological pathways of AFF3 involved in RC. As for the potential mechanism of AFF3 in RC, we concluded in this article that AFF3 eQTL could negatively modulate the levels of the X-11,315 metabolite (IVW method; OR = 0.9127; 95% CI = 0.8530-0.9765; P = 0.0081; heterogeneity = 0.4150; pleiotropy = 0.8852), exhibiting preventive effects against RC risks (IVW method; OR = 0.9987; 95% CI = 0.9975-0.9999; P = 0.0380; heterogeneity = 0.5362; pleiotropy = 0.9808). CONCLUSIONS: We concluded that AFF3 could serve as a novel eQTL-mediated susceptibility gene in RC and reveal its potential mechanism of elevating RC risks via negatively regulating the X-11,315 metabolite levels.

Wickerhamomyces corioli f.a., sp. nov., a novel yeast species discovered in two mushroom species.

Two yeast strains, designated as 19-39-3 and 19-40-2, obtained from the fruiting bodies of Trametes versicolor and Marasmius siccus collected in Yunwu Mountain Forest Park, PR China, have been identified as representing a novel asexual ascomycetous yeast species. From the results of phylogenetic analyses of the sequences of the D1/D2 domains of the large subunit (LSU) rRNA, small subunit (SSU) rRNA and translation elongation factor 1-α (TEF1) genes, it was determined that these strains represent a member of the genus Wickerhamomyces, with Wickerhamomyces alni and Candida ulmi as the closest relatives. The novel species exhibited 6.6 and 6.7% differences in the D1/D2 domains compared with W. alni and C. ulmi, respectively. Additionally, distinct biochemical and physiological differences were observed between the novel species and its related counterparts. No sexual reproduction was observed in these strains, leading to the proposal of the name Wickerhamomyces corioli f.a., sp. nov. for this newly discovered species.

Comparison of microbial abundance and diversity in uterine and peritoneal fluid in infertile patients with or without endometriosis.

INTRODUCTION: Endometriosis (EM) is a multifactorial disease that affects 10 - 15% of women of reproductive age. Additionally, 30-50% of women with EM suffer from infertility. The mechanism of infertility caused by EM has not yet been consistently explained. In recent years, studies have shown a link between infertility associated with EM and changes in the reproductive tract microbiota. METHODS: In this study, we involved 26 EM patients (8 cases of stage I-II and 18 cases of stage III-IV) and 31 control subjects who were tubal obstruction-related infertility (TORI). The samples from peritoneal fluid (PF) and uterine fluid (UF) were collected and sequenced by 16 S rRNA amplicon. RESULTS: In the comparison of microbial diversity, we found no significant differences in the microbial diversity of PF and UF between patients with stage I-II EM and those with TORI. However, there was a significant difference in microbial diversity among patients with stage III-IV EM compared to the previous two groups. Lactobacillus decreased in PF of EM compared to the control group, while it increased in UF. In PF, the abundance of Pseudomonas, Enterococcus, Dubosiella and Klebsiella was significantly higher in patients with stage III-IV compared to TORI patients. And in UF, the main differences existed between stage I-II EM compared to the other two groups. The abundance of pontibacter, aquabacterium, Rikenellaceae and so on at the genus level was significantly enriched in the EM patients with stage I-II. In the analysis based on KEGG database, EM may affect the receptivity related pathways of the endometrium by influencing changes in the uterine microbiota. CONCLUSION: Our results indicated that as EM progresses, the microorganisms in UF and PF keep changing. These changes in the microbiota, as well as the resulting alternations in gene functional classification, may play an important role in the infertility associated with EM.

Nakazawaea tricholomae f.a., sp. nov., a Novel Ascomycetous Yeast Species Isolated from Two Mushroom Species in China.

Two yeast strains designated as 20-27-1 and 20-28 were isolated from the fruiting bodies of Tricholoma gambosum and Marasmius maximus, respectively, which were collected in Wudaogou, Weichang county, Chengde area, Hebei Province, China. The multi-locus analysis of the sequences of the rDNA ITS, D1/D2 LSU, and SSU regions, together with partial sequences of two protein-coding genes RPB1 and TEF1 indicates that the two strains are closely related to Nakazawaea ernobii and Nakazawaea holstii, showing the similarity values of 99.3-98.7%, 97.2-97.1%, 91.9-92.5%, and 84.6% in D1/D2 LSU, ITS, TEF1, and RPB1, respectively. Physiologically, the two strains are different from N. ernobii and N. holstii in the assimilation of melibiose, inulin, and DL-lactic acid. Both the phenotypic and phylogenetic analyses indicate that those two strains represent a novel species in the genus Nakazawaea, for which the name Nakazawaea tricholomae f.a., sp. nov. (Fungal Names: FN 571492) is proposed.

Photosynthesis-assisted remodeling of three-dimensional printed structures.

The mechanical properties of engineering structures continuously weaken during service life because of material fatigue or degradation. By contrast, living organisms are able to strengthen their mechanical properties by regenerating parts of their structures. For example, plants strengthen their cell structures by transforming photosynthesis-produced glucose into stiff polysaccharides. In this work, we realize hybrid materials that use photosynthesis of embedded chloroplasts to remodel their microstructures. These materials can be used to three-dimensionally (3D)-print functional structures, which are endowed with matrix-strengthening and crack healing when exposed to white light. The mechanism relies on a 3D-printable polymer that allows for an additional cross-linking reaction with photosynthesis-produced glucose in the material bulk or on the interface. The remodeling behavior can be suspended by freezing chloroplasts, regulated by mechanical preloads, and reversed by environmental cues. This work opens the door for the design of hybrid synthetic-living materials, for applications such as smart composites, lightweight structures, and soft robotics.

Study on the genotypes of Echinococcus granulosus in yaks and sheep from Langkazi County in Tibet Autonomous Region of China based on mitochondrial cox1 and nad1.

To determine the genotypes of the epidemic strains of Echinococcus granulosus in livestock in Tibet, samples of E. granulosus cysts were collected from 11 yaks and 62 sheep. Genomic DNA was extracted from these samples, and gene fragments of mitochondrial cytochrome c oxidase subunit I (cox1) and NADH dehydrogenase subunit I (nad1) were amplified by PCR and sequenced. DNASTAR and MAGA7.0 were employed for homology analysis and phylogenetic tree construction. Echinococcus granulosus cysts were detected in 56.2% (41/73) of the samples screened. Of these, 63.4% (26/41) were identified as E. granulosus G1 genotype (common sheep strain), 24.4% (10 /41) as G3 genotype (buffalo strain), and 12.2% (5/41) were G6 genotype (camel strain). The study concludes that yaks and sheep in Langkazi county, Tibet, carry three E. granulosus genotypes (G1, G3, and G6), with the G1 genotype the predominant genotype in the region. This study clarifies the distribution of E. granulosus genotypes, providing genetic data and insight for the surveillance and prevention of echinococcosis.

Comparative genomics of smut fungi suggest the ability of meiosis and mating in asexual species of the genus Pseudozyma (Ustilaginales).

BACKGROUND: The Ustilaginales comprise hundreds of plant-parasitic fungi with a characteristic life cycle that directly links sexual reproduction and parasitism: One of the two mating-type loci codes for a transcription factor that not only facilitates mating, but also initiates the infection process. However, several species within the Ustilaginales have no described parasitic stage and were historically assigned to the genus Pseudozyma. Molecular studies have shown that the group is polyphyletic, with members being scattered in various lineages of the Ustilaginales. Together with recent findings of conserved fungal effectors in these non-parasitic species, this raises the question if parasitism has been lost recently and in multiple independent events or if there are hitherto undescribed parasitic stages of these fungi. RESULTS: In this study, we sequenced genomes of five Pseudozyma species together with six parasitic species from the Ustilaginales to compare their genomic capability to perform two central functions in sexual reproduction: mating and meiosis. While the loss of sexual capability is assumed in certain lineages and asexual species are common in Asco- and Basidiomycota, we were able to successfully annotate potentially functional mating and meiosis genes that are conserved throughout the whole group. CONCLUSION: Our data suggest that at least the key functions of a sexual lifestyle are maintained in the analyzed genomes, challenging the current understanding of the so-called asexual species with respect to their evolution and ecological role.

Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR-mutant non-small-cell lung cancer.

BACKGROUND: RNA 5-methylcytosine (m5C) modification plays critical roles in the pathogenesis of various tumors. However, the function and molecular mechanism of RNA m5C modification in tumor drug resistance remain unclear. METHODS: The correlation between RNA m5C methylation, m5C writer NOP2/Sun RNA methyltransferase family member 2 (NSUN2) and EGFR-TKIs resistance was determined in non-small-cell lung cancer (NSCLC) cell lines and patient samples. The effects of NSUN2 on EGFR-TKIs resistance were investigated by gain- and loss-of-function assays in vitro and in vivo. RNA-sequencing (RNA-seq), RNA bisulfite sequencing (RNA-BisSeq) and m5C methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the target gene of NSUN2 involved in EGFR-TKIs resistance. Furthermore, the regulatory mechanism of NSUN2 modulating the target gene expression was investigated by functional rescue and puromycin incorporation assays. RESULTS: RNA m5C hypermethylation and NSUN2 were significantly correlated with intrinsic resistance to EGFR-TKIs. Overexpression of NSUN2 resulted in gefitinib resistance and tumor recurrence, while genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib in vitro and in vivo. Integrated RNA-seq and m5C-BisSeq analyses identified quiescin sulfhydryl oxidase 1 (QSOX1) as a potential target of aberrant m5C modification. NSUN2 methylated QSOX1 coding sequence region, leading to enhanced QSOX1 translation through m5C reader Y-box binding protein 1 (YBX1). CONCLUSIONS: Our study reveals a critical function of aberrant RNA m5C modification via the NSUN2-YBX1-QSOX1 axis in mediating intrinsic resistance to gefitinib in EGFR-mutant NSCLC.

Yueomyces silvicola sp. nov., a novel ascomycetous yeast species unable to utilize ammonium, glutamate, and glutamine as sole nitrogen sources.

Five yeast strains isolated from tree bark and rotten wood collected in central and southwestern China, together with four Brazilian strains (three from soil and rotting wood collected in an Amazonian rainforest biome and one from Bromeliad collected in Alagoas state) and one Costa Rican strain isolated from a flower beetle, represent a new species closely related with Yueomyces sinensis in Saccharomycetaceae, as revealed by the 26S ribosomal RNA gene D1/D2 domain and the internal transcribed spacer region sequence analysis. The name Yueomyces silvicola sp. nov. is proposed for this new species with the holotype China General Microbiological Culture Collection Center 2.6469 (= Japan Collection of Microorganisms 34885). The new species exhibits a whole-genome average nucleotide identity value of 77.8% with Y. sinensis. The two Yueomyces species shared unique physiological characteristics of being unable to utilize ammonium and the majority of the amino acids, including glutamate and glutamine, as sole nitrogen sources. Among the 20 amino acids tested, only leucine and tyrosine can be utilized by the Yueomyces species. Genome sequence comparison showed that GAT1, which encodes a GATA family protein participating in transcriptional activation of nitrogen-catabolic genes in Saccharomyces cerevisiae, is absent in the Yueomyces species. However, the failure of the Yueomyces species to utilize ammonium, glutamate, and glutamine, which are generally preferred nitrogen sources for microorganisms, implies that more complicated alterations in the central nitrogen metabolism pathway might occur in the genus Yueomyces.

Ocular Toxicities of MEK Inhibitors in Patients With Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Mitogen-activated protein kinase (MEK) inhibitors, which integrate the important signaling chain of the RAS-RAF-MEK-ERK1/2 pathway, regulate cell functions such as division and proliferation for patients with solid tumors. However, various ocular adverse effects (AEs) affect patients during clinical treatment. This systematic review aimed to assess the occurrence of AEs during treatment with MEK inhibitors plus targeted therapy or chemotherapy. METHODS: A scientific literature search was conducted in PubMed, the Cochrane Library, Embase, and several Chinese databases to identify randomized controlled trials. Overall, ocular AEs were assessed as the primary end point; blurred vision, chorioretinopathy, and retinal detachment were assessed as secondary end points. RESULTS: Seventeen randomized controlled trials were included. Overall, the use of MEK inhibitors combined with other targeted inhibitors or chemotherapy was significantly associated with a nearly 7.3% increased risk of overall ocular toxicities vs therapy without MEK inhibitors (risk ratio [RR], 2.88; 95% CI, 1.42-5.85, P < .05). An increased risk of blurred vision (RR, 4.10; 95% CI, 2.55- 6.58; P < .05), chorioretinopathy (RR, 8.36; 95% CI, 3.42-20.47; P < .05), and retinal detachment (RR, 8.98; 95% CI, 3.92-20.57; P < .05) was demonstrated. CONCLUSIONS: Treatment with MEK inhibitors combined with targeted drugs or chemotherapy seems to increase overall ocular AEs. A more practical algorithm for the screening of ocular AEs was suggested to be conducted whenever new or worsening ocular toxicities occur.

Green tea consumption and the risk of coronary heart disease: A systematic review and meta-analysis of cohort studies.

BACKGROUND AND AIMS: Conflicting evidence exists regarding the association between green tea consumption and the risk of coronary heart disease (CHD). We performed a meta-analysis to determine whether an association exists between them in cohort studies. METHODS AND RESULTS: We searched the PubMed and EMBASE databases for studies conducted until September 2022. Prospective cohort studies that provided relative risk (RR) estimates with 95% confidence intervals (CIs) for the association were included. Study-specific risk estimates were combined using a random-effects model. A total of seven studies, with 9211 CHD cases among 772,922 participants, were included. We observed a nonlinear association between green tea consumption and the risk of CHD (P for nonlinearity = 0.0009). Compared with nonconsumers, the RRs (95% CI) of CHD across levels of green tea consumption were 0.89 (0.83, 0.96) for 1 cup/day (1 cup = 300 ml), 0.84 (0.77, 0.93) for 2 cups/day, 0.85 (0.77, 0.92) for 3 cups/day, 0.88 (0.81, 0.96) for 4 cups/day, and 0.92 (0.82, 1.04) for 5 cups/day. CONCLUSIONS: This updated meta-analysis of studies from East Asia suggests that green tea consumption may be associated with a reduced risk of CHD, especially among those with low-to-moderate consumption. Additional cohorts are still needed before we could draw a definitive conclusion. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022357687.

The First Complete Genome Resource for the Plant-Pathogenic Fungus Exobasidium rhododendri.

Exobasidium rhododendri is a parasite of Rhododendron and also infects apples. A chromosome-level genome of E. rhododendri was assembled using the PacBio and Illumina datasets. The complete genome length is 17.6 Mb, with N50 of 5.45 Mb, and its GC content is 50.08%. The assembly obtained contains four scaffolds, including three nuclear chromosomes and one mitochondrion. There are a total of 6,982 predicted protein-encoding genes containing 406 fungal secretion proteins and 249 candidate effectors in the E. rhododendri genome. This high-quality genome will help understand the pathogenic mechanism of this fungus.

SIRT3-dependent mitochondrial redox homeostasis mitigates CHK1 inhibition combined with gemcitabine treatment induced cardiotoxicity in hiPSC-CMs and mice.

Administration of CHK1-targeted anticancer therapies is associated with an increased cumulative risk of cardiac complications, which is further amplified when combined with gemcitabine. However, the underlying mechanisms remain elusive. In this study, we generated hiPSC-CMs and murine models to elucidate the mechanisms underlying CHK1 inhibition combined with gemcitabine-induced cardiotoxicity and identify potential targets for cardioprotection. Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. hiPSC-CMs and NMCMs were incubated with 0.5 uM AZD7762 and 0.1 uM gemcitabine for 24 h. Both pharmacological inhibition or genetic deletion of CHK1 and administration of gemcitabine induced mtROS overproduction and pyroptosis in cardiomyocytes by disrupting mitochondrial respiration, ultimately causing heart atrophy and cardiac dysfunction in mice. These toxic effects were further exacerbated with combination administration. Using mitochondria-targeting sequence-directed vectors to overexpress CHK1 in cardiomyocyte (CM) mitochondria, we identified the localization of CHK1 in CM mitochondria and its crucial role in maintaining mitochondrial redox homeostasis for the first time. Mitochondrial CHK1 function loss mediated the cardiotoxicity induced by AZD7762 and CHK1-knockout. Mechanistically, mitochondrial CHK1 directly phosphorylates SIRT3 and promotes its expression within mitochondria. On the contrary, both AZD7762 or CHK1-knockout and gemcitabine decreased mitochondrial SIRT3 abundance, thus resulting in respiration dysfunction. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine.