Precise control of microtubule disassembly in living cells.

Microtubules tightly regulate various cellular activities. Our understanding of microtubules is largely based on experiments using microtubule-targeting agents, which, however, are insufficient to dissect the dynamic mechanisms of specific microtubule populations, due to their slow effects on the entire pool of microtubules. To overcome this technological limitation, we have used chemo and optogenetics to disassemble specific microtubule subtypes, including tyrosinated microtubules, primary cilia, mitotic spindles, and intercellular bridges, by rapidly recruiting engineered microtubule-cleaving enzymes onto target microtubules in a reversible manner. Using this approach, we show that acute microtubule disassembly swiftly halts vesicular trafficking and lysosomal dynamics. It also immediately triggers Golgi and ER reorganization and slows the fusion/fission of mitochondria without affecting mitochondrial membrane potential. In addition, cell rigidity is increased after microtubule disruption owing to increased contractile stress fibers. Microtubule disruption furthermore prevents cell division, but does not cause cell death during interphase. Overall, the reported tools facilitate detailed analysis of how microtubules precisely regulate cellular architecture and functions.

HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria.

Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.

Genome-wide expression analysis of vegetative organs during developmental and herbicide-induced whole plant senescence in Arabidopsis thaliana.

BACKGROUND: Whole plant senescence represents the final stage in the life cycle of annual plants, characterized by the decomposition of aging organs and transfer of nutrients to seeds, thereby ensuring the survival of next generation. However, the transcriptomic profile of vegetative organs during this death process remains to be fully elucidated, especially regarding the distinctions between natural programmed death and artificial sudden death induced by herbicide. RESULTS: Differential genes expression analysis using RNA-seq in leaves and roots of Arabidopsis thaliana revealed that natural senescence commenced in leaves at 45-52 days after planting, followed by roots initiated at 52-60 days. Additionally, both organs exhibited similarities with artificially induced senescence by glyphosate. Transcription factors Rap2.6L and WKRY75 appeared to serve as central mediators of regulatory changes during natural senescence, as indicated by co-expression networks. Furthermore, the upregulation of RRTF1, exclusively observed during natural death, suggested its role as a regulator of jasmonic acid and reactive oxygen species (ROS) responses, potentially triggering nitrogen recycling in leaves, such as the glutamate dehydrogenase (GDH) shunt. Root senescence was characterized by the activation of AMT2;1 and GLN1;3, facilitating ammonium availability for root-to-shoot translocation, likely under the regulation of PDF2.1. CONCLUSIONS: Our study offers valuable insights into the transcriptomic interplay between phytohormones and ROS during whole plant senescence. We observed distinct regulatory networks governing nitrogen utilization in leaf and root senescence processes. Furthermore, the efficient allocation of energy from vegetative organs to seeds emerges as a critical determinant of population sustainability of annual Arabidopsis.

Ligand-Enabled Cu-Catalyzed Stereoselective Synthesis of P-Stereogenic ProTides.

Nucleoside analogues have seen significant advancements in treating viral infections and cancer through ProTide technology, leading to a series of FDA-approved drugs such as sofosbuvir, tenofovir alafenamide, and remdesivir. The stereochemical configuration at the phosphorus center of ProTides significantly influences their pharmacological properties, necessitating efficient stereoselective synthesis. Traditional methods using chiral auxiliaries or nonracemic phosphorylating agents are labor-intensive and inefficient, while recent organocatalytic approaches, despite their promise, still face limitations. Herein, we present a novel approach employing chiral metal complexes for the stereoselective assembly of P-stereogenic ProTides via asymmetric P-O bond formation. This approach leverages a chiral metal catalyst to activate the electrophilic phosphorylating reagent, facilitating a base-promoted nucleophilic replacement pathway. Our protocol, featuring mild reaction conditions and broad applicability, enables the highly stereoselective synthesis of previously inaccessible (S,RP) and (R,SP)-ProTide derivatives. The practical utility of this method is demonstrated through the preparation of pharmaceutically relevant ProTide targets and mechanistic studies were conducted to elucidate the reaction pathway, offering significant advancements for drug development and pharmaceutical research.

Melatonin prevents pulmonary fibrosis caused by PM2.5 exposure by targeting epithelial-mesenchymal transition.

Pulmonary fibrosis is a lung disorder characterized by the accumulation of abnormal extracellular matrix, scar tissue formation, and tissue stiffness. Type II alveolar epithelial cells (AEII) play a critical role in repairing lung tissue after injury, and repeated injury to these cells is a key factor in the development of pulmonary fibrosis. Chronic exposure to PM2.5, a type of air pollution, has been shown to increase the incidence and severity of pulmonary fibrosis by enhancing the activation of EMT in lung epithelial cells. Melatonin, a hormone with antioxidant properties, has been shown to prevent EMT and reduce fibrosis in previous studies. However, the mechanism through which melatonin targets EMT to prevent pulmonary fibrosis caused by PM2.5 exposure has not been extensively discussed before. In this current study, we found that melatonin effectively prevented pulmonary fibrosis caused by prolonged exposure to PM2.5 by targeting EMT. The study demonstrated changes in cellular morphology and expression of EMT markers. Furthermore, the cell migratory potential induced by prolonged exposure to PM2.5 was greatly reduced by melatonin treatment. Finally, in vivo animal studies showed reduced EMT markers and improved pulmonary function. These findings suggest that melatonin has potential clinical use for the prevention of pulmonary fibrosis.

Microbacterium salsuginis sp. nov., a halotolerant actinobacterium with antimicrobial activity.

A novel Gram-staining-positive actinobacterium with antimicrobial activity, designated CFH 90308T, was isolated from the sediment of a salt lake in Yuncheng, Shanxi, south-western China. The isolate exhibited the highest 16S rRNA gene sequence similarities to Microbacterium yannicii G72T, Microbacterium hominis NBRC 15708T and Microbacterium xylanilyticum S3-ET (98.5, 98.4 and 98.2 %, respectively), and formed a separate clade with M. xylanilyticum S3-ET in phylogenetic trees. The strain grew at 15-40 ºC, pH 6.0-8.0 and could tolerate NaCl up to a concentration of 15 % (w/v). The whole genome of strain CFH 90308T consisted of 4.33 Mbp and the DNA G+C content was 69.6 mol%. The acyl type of the peptidoglycan was glycolyl and the whole-cell sugars were galactose and mannose. The cell-wall peptidoglycan mainly contained alanine, glycine and lysine. The menaquinones of strain CFH 90308T were MK-12, MK-13 and MK-11. Strain CFH 90308T contained anteiso-C15:0, anteiso-C17:0, iso-C16:0 and iso-C15:0 as the predominant fatty acids. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between CFH 90308T and the other species of the genus Microbacterium were found to be low (ANIb <81.3 %, dDDH <25.6 %). The secondary metabolite produced by strain CFH 90308T showed antibacterial activities against Bacillus subtilis, Pseudomonas syringae, Aeromonas hydrophila and methicillin-resistant Staphylococcus aureus. Based on genotypic, phenotypic and chemotaxonomic results, the isolate is considered to represent a novel species of the genus Microbacterium, for which the name Microbacterium salsuginis sp. nov. is proposed. The type strain is CFH 90308T (=DSM 105964T=KCTC 49052T).

Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks.

BACKGROUND: Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors is associated with a lower risk of incident dementia and all-cause mortality, relative to dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). METHODS: In this retrospective, active-comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged ≥50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan-Meier survival analysis to estimate the incidence of dementia and all-cause mortality in our cohort after they had used glucose-lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT-2 inhibitor, DPP-4 inhibitor and GLP-1 RA cohorts. Subgroup analyses for sex and age were also conducted. RESULTS: Our first cohort comprised 193 948 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and DPP-4 inhibitors. In this cohort, the risk of dementia and all-cause mortality was lower in patients treated with SGLT-2 inhibitors than in those treated with DPP-4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59-0.65, for dementia; HR: 0.54, 95% CI: 0.52-0.56, for all-cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and GLP-1 RAs. In this cohort, the risk of dementia and all-cause mortality was lower in those treated with SGLT-2 inhibitors than in those treated with GLP-1 RAs (HR: 0.92, 95% CI: 0.87-0.98, for dementia; HR: 0.88, 95% CI: 0.85-0.91, for all-cause mortality). CONCLUSIONS: The use of SGLT-2 inhibitor was associated with a lower risk of incident dementia and all-cause mortality in older adults with T2D compared to DPP-4 inhibitor and GLP-1 RA.

Taraxasterol attenuates zearalenone-induced kidney damage in mice by modulating oxidative stress and endoplasmic reticulum stress.

Taraxasterol is one of the bioactive ingredients from traditional Chinese herb Taraxacum, which exhibits multiple pharmacological activities and protective effects. However, the underlying influence and mechanism of its use against kidney damage caused from zearalenone (ZEA) remain unexplored. The ZEA-induced kidney damage model of mice was established by feeding diets containing ZEA (2 mg/kg), and taraxasterol (5 and 10 mg/kg) was administered by gavage for 28 days. Results demonstrated taraxasterol increased average daily gain (ADG) and average daily feed intake (ADFI), reduced feed-to-gain ratio (F/G) and kidney index of mice induced by ZEA. Taraxasterol alleviated histopathological changes of kidney, reduced ZEA residue and the levels of blood urea nitrogen (BUN), uric acid (UA), and creatinine (CRE). Concurrently, taraxasterol reduced the contents of oxidative stress indicator reactive oxygen species (ROS) and malondialdehyde (MDA), and increased the activities of antioxidant enzymes catalase (CAT), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px). Further, taraxasterol up-regulated the mRNA and protein expression of nuclear factor erythroid-2-related factor 2 (Nrf2), GSH-Px, NAD(P)H quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1), and down-regulated the mRNA and protein expression of KELCH like ECH associated protein (Keap1) in Nrf2/Keap1 pathway. Taraxasterol down-regulated the mRNA and protein expression of immunoglobulin binding protein (Bip), C/EBP homologous protein (CHOP), Bcl-2 associated X (Bax), cysteine protease (Caspase)-12, and Caspase-3, and up-regulated B-cell lymphoma 2 (Bcl-2) expression in endoplasmic reticulum stress pathway. This study suggests that taraxasterol attenuates ZEA-induced mouse kidney damage through the modulation of Nrf2/Keapl pathway to play antioxidant role and endoplasmic reticulum stress pathway to enhance anti-apoptotic ability. It will provide a basis for taraxasterol as a potential drug to prevent and treat ZEA-induced kidney damage.

The interpersonal effects of emotional expressions with both and single valences on work-related satisfaction: an examination of emotions and perceived openness as mediators.

ABSTRACTWork-related satisfaction has critical benefits. To predict work-related satisfaction, we investigated how a counterpart's expressions of emotional complexity (both positive and negative emotions), positive emotions, and negative emotions influenced a perceiver's work-related satisfaction during discussions over different work-relevant ideas. We conducted a three-wave coworker survey (N = 529) and an experiment with a confederate as a task partner (N = 378). The results consistently showed significant positive impacts of a counterpart's emotional complexity and positive emotion expressions on a perceiver's work-related satisfaction by enhancing the perceiver's positive emotions and evaluation of the counterpart's openness. Conversely, a counterpart's negative emotion expression significantly decreased a perceiver's work-related satisfaction by reducing perceived counterpart openness. We also did not find a perceiver's negative emotion as a significant mediator of the associations between the three emotional expressions and work-related satisfaction. Therefore, our investigation highlights similar positive effects of emotional complexity and positive emotion expressions and suggests that an expression of both positive and negative emotions promotes satisfaction by enhancing positive emotions and openness perception.

Development of a Novel, Potent, and Selective Sialyltransferase Inhibitor for Suppressing Cancer Metastasis.

Sialyltransferase-catalyzed membrane protein and lipid glycosylation plays a vital role as one of the most abundant post-translational modifications and diversification reactions in eukaryotes. However, aberrant sialylation has been associated with cancer malignancy and metastasis. Sialyltransferases thus represent emerging targets for the development of small molecule cancer drugs. Herein, we report the inhibitory effects of a recently discovered lithocholic acid derivative FCW393 on sialyltransferase catalytic activity, integrin sialyation, cancer-associated signal transduction, MDA-MB-231 and B16F10 cell migration and invasion, and in in vivo studies, on tumor growth, metastasis, and angiogenesis. FCW393 showed effective and selective inhibition of the sialyltransferases ST6GAL1 (IC50 = 7.8 µM) and ST3GAL3 (IC50 = 9.45 µM) relative to ST3GAL1 (IC50 > 400 µM) and ST8SIA4 (IC50 > 100 µM). FCW393 reduced integrin sialylation in breast cancer and melanoma cells dose-dependently and downregulated proteins associated with the integrin-regulated FAK/paxillin and GEF/Rho/ROCK pathways, and with the VEGF-regulated Akt/NFκB/HIF-1α pathway. FCW393 inhibited cell migration (IC50 = 2.6 µM) and invasion in in vitro experiments, and in in vivo studies of tumor-bearing mice, FCW393 reduced tumor size, angiogenesis, and metastatic potential. Based on its demonstrated selectivity, cell permeability, relatively low cytotoxicity (IC50 = 55 µM), and high efficacy, FCW393 shows promising potential as a small molecule experimental tool compound and a lead for further development of a novel cancer therapeutic.

Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation.

AIMS/HYPOTHESIS: The mitochondrial chaperonin heat shock protein (HSP) 60 is indispensable in protein folding and the mitochondrial stress response; however, its role in nutrient metabolism remains uncertain. This study investigated the role of HSP60 in diet-induced non-alcoholic fatty liver disease (NAFLD). METHODS: We studied human biopsies from individuals with NAFLD, murine high-fat-diet (HFD; a diet with 60% energy from fat)-induced obesity (DIO), transgenic (Tg) mice overexpressing Hsp60 (Hsp60-Tg), and human HepG2 cells transfected with HSP60 cDNA or with HSP60 siRNA. Histomorphometry was used to assess hepatic steatosis, biochemistry kits were used to measure insulin resistance and glucose tolerance, and an automated home cage phenotyping system was used to assess energy expenditure. Body fat was assessed using MRI. Macrophage infiltration, the lipid oxidation marker 4-hydroxy-2-nonenal (4-HNE) and the oxidative damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) were detected using immunohistochemistry. Intracellular lipid droplets were evaluated by Nile red staining. Expression of HSP60, and markers of lipogenesis and fatty acid oxidation were quantified using RT-PCR and immunoblotting. Investigations were analysed using the two-way ANOVA test. RESULTS: Decreased HSP60 expression correlated with severe steatosis in human NAFLD biopsies and murine DIO. Hsp60-Tg mice developed less body fat, had reduced serum triglyceride levels, lower levels of insulin resistance and higher serum adiponectin levels than wild-type mice upon HFD feeding. Respiratory quotient profile indicated that fat in Hsp60-Tg mice may be metabolised to meet energy demands. Hsp60-Tg mice showed amelioration of HFD-mediated hepatic steatosis, M1/M2 macrophage dysregulation, and 4-HNE and 8-OHdG overproduction. Forced HSP60 expression reduced the mitochondrial unfolded protein response, while preserving mitochondrial respiratory complex activity and enhancing fatty acid oxidation. Furthermore, HSP60 knockdown enhanced intracellular lipid formation and loss of sirtuin 3 (SIRT3) signalling in HepG2 cells upon incubation with palmitic acid (PA). Forced HSP60 expression improved SIRT3 signalling and repressed PA-mediated intracellular lipid formation. SIRT3 inhibition compromised HSP60-induced promotion of AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferator-activated receptor α (PPARα levels), while also decreasing levels of fatty acid oxidation markers. CONCLUSION/INTERPRETATION: Mitochondrial HSP60 promotes fatty acid oxidation while repressing mitochondrial stress and inflammation to ameliorate the development of NAFLD by preserving SIRT3 signalling. This study reveals the hepatoprotective effects of HSP60 and indicates that HSP60 could play a fundamental role in the development of therapeutics for NAFLD or type 2 diabetes.

Leukocyte cell-derived chemotaxin 2 regulates epithelial-mesenchymal transition and cancer stemness in hepatocellular carcinoma.

Leukocyte cell-derived chemotaxin 2 (LECT2) acts as a tumor suppressor in hepatocellular carcinoma (HCC). However, the antineoplastic mechanism of LECT2, especially its influence on hepatic cancer stem cells (CSCs), remains largely unknown. In The Cancer Genome Atlas cohort, LECT2 mRNA expression was shown to be associated with stage, grade, recurrence, and overall survival in human HCC patients, and LECT2 expression was downregulated in hepatoma tissues compared with the adjacent nontumoral liver. Here, we show by immunofluorescence and immunoblot analyses that LECT2 was expressed at lower levels in tumors and in poorly differentiated HCC cell lines. Using functional assays, we also found LECT2 was capable of suppressing oncogenic behaviors such as cell proliferation, anchorage-independent growth, migration, invasiveness, and epithelial-mesenchymal transition in hepatoma cells. Moreover, we show exogenous LECT2 treatment inhibited CSC functions such as tumor sphere formation and drug efflux. Simultaneously, hepatic CSC marker expression was also downregulated, including expression of CD133 and CD44. This was supported by infection with adenovirus encoding LECT2 (Ad-LECT2) in HCC cells. Furthermore, in animal experiments, Ad-LECT2 gene therapy showed potent efficacy in treating HCC. We demonstrate LECT2 overexpression significantly promoted cell apoptosis and reduced neovascularization/CSC expansion in rat hepatoma tissues. Mechanistically, we showed using immunoblot and immunofluorescence analyses that LECT2 inhibited ß-catenin signaling via the suppression of the hepatocyte growth factor/c-MET axis to diminish CSC properties in HCC cells. In summary, we reveal novel functions of LECT2 in the suppression of hepatic CSCs, suggesting a potential alternative strategy for HCC therapy.

Y-box binding protein 1 influences zygotic genome activation by regulating N6-methyladenosine in porcine embryos.

Y-box binding protein 1 (YBX1) is a member of the family of DNA- and RNA-binding proteins that play crucial roles in multiple aspects, including RNA stabilization, translational repression, and transcriptional regulation; however, its roles in embryo development remain less known. In this study, to investigate the function of YBX1 and its mechanism of action in porcine embryo development, YBX1 was knocked down by microinjecting YBX1 siRNA at the one-cell stage. YBX1 is located in the cytoplasm during embryonic development. The mRNA level of YBX1 was increased from the four-cell stage to the blastocyst stage but was significantly decreased in YBX1 knockdown embryos compared with the control. Moreover, the percentage of blastocysts was decreased following YBX1 knockdown compared with the control. Defecting YBX1 expression increased maternal gene mRNA expression and decreased zygotic genome activation (ZGA) gene mRNA expression and histone modification owing to decreased levels of N6-methyladenosine (m6A) writer N6-adenosine-methyltransferase 70 kDa subunit (METTL3) and reader insulin-like growth factor 2 mRNA-binding protein (IGF2BP1). In addition, IGF2BP1 knockdown showed that YBX1 regulated the ZGA process through m6A modification. In conclusion, YBX1 is essential for early embryo development because it regulates the ZGA process.

Thermalbibacter longus gen. nov., sp. nov., isolated from a hot spring.

An isolate, designated CFH 74404T, was recovered from a hot spring in Tengchong, Yunnan province, PR China. Phylogenetic analysis indicated that the isolate belongs to the family Thermomicrobiaceae and showed the highest 16S rRNA gene sequence similarity to Thermorudis peleae KI4T (93.6 %), Thermorudis pharmacophila WKT50.2T (93.1 %), Thermomicrobium roseum DSM 5159T (92.0 %) and Thermomicrobium carboxidum KI3T (91.7 %). The average amino acid identity and average nucleotide identity values between strain CFH 74404T and the closest relatives were 42.0-75.9 % and 67.0-77.3 %, respectively. Cells of strain CFH 74404T stained Gram-positive and were aerobic, non-motile and short rod-shaped. Growth occurred at 20-65 °C (optimum, 55 °C), pH 6.0-8.0 (optimum, pH 7.0) and with up to 2.0 % (w/v) NaCl (optimum 0-1.0 %, w/v). The predominant respiratory quinone was MK-8. The major fatty acids (>10 %) were C18 : 0 (50.8 %) and C20 : 0 (16.8 %). The polar lipid profile of strain CFH 74404T included diphosphatidylglycerol, four unidentified phosphoglycolipids, phosphatidylinositol and three unidentified glycolipids. The G+C content of the genomic DNA was determined to be 67.1 mol% based on the draft genome sequence. On the basis of phenotypic, phylogenetic and genotypic analyses, it is concluded that strain CFH 74404T represents a new species of a novel genus Thermalbibacter of the family Thermomicrobiaceae, for which the name Thermalbibacter longus gen. nov., sp. nov. is proposed. The type strain is CFH 74404T (=KCTC 62930T=CGMCC 1.61585T).

Aryl hydrocarbon receptor-kynurenine axis promotes oncogenic activity in BCP-ALL.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common childhood cancer, originates from lymphoid precursor cells in bone marrow committed to the B-cell lineage. Environmental factors and genetic abnormalities disturb the normal maturation of these precursor cells, promoting the formation of leukemia cells and suppressing normal hematopoiesis. The underlying mechanisms of progression are unclear, but BCP-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. This study hypothesized that air pollution and haze are risk factors for BCP-ALL progression. The current study revealed that indeno(1,2,3-cd)pyrene (IP), a major component of polycyclic aromatic hydrocarbons (PAHs) in air, promotes oncogenic activities (proliferation, transformation, and disease relapse) in vitro and in vivo. Mechanistically, IP treatment activated the aryl hydrocarbon receptor (AHR)-indoleamine-2,3-dioxygenase (IDOs) axis, thereby enhancing tryptophan metabolism and kynurenine (KYN) level and consequent promoting the KYN-AHR feedback loop. IP treatment decreased the time to disease relapse and increased the BCP-ALL cell count in an orthotopic xenograft mouse model. Additionally, in 50 clinical BCP-ALL samples, AHR and IDO were co-expressed in a disease-specific manner at mRNA and protein levels, while their mRNA levels showed a significant correlation with disease-free survival duration. These results indicated that PAH/IP exposure promotes BCP-ALL disease progression.

Development of Two Early Forecasting Models for Predicting Incidence of Rice Panicle Blast in China.

Early forecasting of rice panicle blast is critical to the management of rice blast. To develop early forecasting models for rice panicle blast, the relationship between the seasonal maximum incidence of rice panicle blast (PBx) and the PBx in the preceding crop, weather conditions, location, and acreage of susceptible varieties was analyzed. Results revealed that PBx in the preceding crop, acreage of the susceptible varieties in class (SVC), altitude, weather conditions 120 to 180 days before the PBx date (dbPBx) and 30 to 90 dbPBx were significantly correlated with the PBx. Subsequently, a logistic model and a two-step hurdle model were developed to predict rice panicle blast. The logistic model was developed to predict whether the PBx was 0 or not based on the preceding PBx, altitude, acreage of susceptible varieties, the longest stretch of days with soil temperatures between 16 and 24°C for the period 120 to 150 dbPBx, and the longest stretch of rainy days in the period 120 to 180 dbPBx. The hurdle model predicted if the PBx was greater than 0 at the first step, and if the prediction was greater than 0, then a regression model was developed for predicting PBx based on the preceding PBx, SVC, altitude, and weather data 180 to 30 dbPBx. Validation with the test datasets showed that the logistic model could correctly predict whether PBx was 0 at a mean test accuracy of 78.39% and that the absolute prediction error of PBx by the two-step hurdle model was smaller than 6.16% for 90% of the records. The model developed in this study will be helpful in management decisions for rice growers and policy makers and offer a useful basis for further studies on the epidemiology and forecasting of rice panicle blast.

Correlation between coronary heart disease severity and subsequent chronic rhinosinusitis severity: A retrospective cohort study.

Coronary heart disease (CHD) is associated with the development of several diseases. This retrospective population-based cohort study investigated the association between CHD severity and subsequent chronic rhinosinusitis (CRS) of varying severity. We used data from Taiwan's National Health Insurance Research Database. CHD was categorized as severe if treated using a coronary artery bypass graft (CABG) and as mild if treated with percutaneous coronary intervention (PCI). The primary outcome of this study was the development of CRS or severe CRS treated using functional endoscopic sinus surgery. Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CRS and severe CRS in different patient groups. We included 31,784 patients who received PCI surgery (the CHD-PCI group) and 15,892 patients who received CABG surgery (the CHD-CABG group). A total of 813 and 482 episodes of CRS occurred in the CHD-PCI and CHD-CABG groups, respectively, and 45 and 16 severe CRS events occurred in the CHD-PCI and CHD-CABG groups, respectively. Our multivariable analysis demonstrated that the incidence of CRS in the CHD-CABG group was significantly higher than that in the CHD-PCI group (aHR: 1.196, 95% CI: 1.064-1.280, P = 0.0402), but the two groups had similar incidence rates of severe CRS (aHR: 0.795, 95% CI: 0.456-1.388, P = 0.5534). Subgroup analyses revealed that the association between CHD severity and CRS development was more significant among men (P = 0.0016). In conclusion, we determined that severe CHD treated with CABG was associated with a higher incidence of subsequent CRS, and this association was more prominent among men.

The safety and response of CT guided percutaneous cryoablation for lung nodules by 17-gauge needles.

BACKGROUND: The safety and efficacy of 17-gauge needles used in CT-guided percutaneous cryoablation for lung nodules were explored in this study. The purpose of the study was to compare the findings with earlier research and multi-center clinical trials that used various needle sizes. METHODS: Between 2016 and 2020, a retrospective study was conducted with approval from the institutional review board. A total of 41 patients were enrolled, and 71 lung nodules were treated in 63 cryoablation procedures using local anesthesia. Complication rates were recorded, and overall survival rates as well as tumor progression-free rates were calculated using the Kaplan-Meier method. RESULTS: Self-limited hemoptysis was caused by 12.9% of the procedures, and drainage was required for pneumothoraces resulting from 11.3% of them. The overall survival rates at one, two, three, and four years were 97%, 94%, 82%, and 67%, respectively. The tumor progression-free rates at one, two, three, and four years were 86.2%, 77%, 74%, and 65%, respectively. CONCLUSION: Cryoablation for lung nodules using 17-Gauge needles can achieve similar rates of survival and tumor control rates, similar or even lower complication rates as compared with other studies and multi-center trials using mixed sized needles.

Kae1 of Saccharomyces cerevisiae KEOPS complex possesses ADP/GDP nucleotidase activity.

The KEOPS complex is an evolutionarily conserved protein complex in all three domains of life (Bacteria, Archaea, and Eukarya). In budding yeast Saccharomyces cerevisiae, the KEOPS complex (ScKEOPS) consists of five subunits, which are Kae1, Bud32, Cgi121, Pcc1, and Gon7. The KEOPS complex is an ATPase and is required for tRNA N6-threonylcarbamoyladenosine modification, telomere length maintenance, and efficient DNA repair. Here, recombinant ScKEOPS full complex and Kae1-Pcc1-Gon7 and Bud32-Cgi121 subcomplexes were purified and their biochemical activities were examined. KEOPS was observed to have ATPase and GTPase activities, which are predominantly attributed to the Bud32 subunit, as catalytically dead Bud32, but not catalytically dead Kae1, largely eliminated the ATPase/GTPase activity of KEOPS. In addition, KEOPS could hydrolyze ADP to adenosine or GDP to guanosine, and produce PPi, indicating that KEOPS is an ADP/GDP nucleotidase. Further mutagenesis characterization of Bud32 and Kae1 subunits revealed that Kae1, but not Bud32, is responsible for the ADP/GDP nucleotidase activity. In addition, the Kae1V309D mutant exhibited decreased ADP/GDP nucleotidase activity in vitro and shortened telomeres in vivo, but showed only a limited defect in t6A modification, suggesting that the ADP/GDP nucleotidase activity of KEOPS contributes to telomere length regulation.

Colonic mucosal diffuse congestion associated with Osimertinib.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common histological subtype of lung cancer. Osimertinib has been recommended as first-line treatment of advanced NSCLC with EGFR mutations. Previous studies have only reported cases of gastrointestinal bleeding due to Erlotinib and gefitinib, but to date, always no cases of gastrointestinal bleeding due to Osimertinib have been reported. CASE REPORT: We report a case of a female patient with NSCLC with EFGR mutation. After 1.5 years of treatment with Osimertinib, a colonoscopy showed diffuse congestion of the colonic mucosa. MANAGEMENT AND OUTCOME: The patient's symptoms of blood in the stool disappeared, after stopping Osimertinib and giving mucosal protection treatment for 1 week. DISCUSSION: Osimertinib may have contributed to gastrointestinal bleeding because no recurrent bleeding was observed after discontinuation of treatment. Physicians and patients should be aware that osimertinib may increase the risk of gastrointestinal bleeding.