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Hepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC.

Oxoglutarate dehydrogenase-like (OGDHL) is considered to be the isoenzyme of oxyglutarate dehydrogenase (OGDH) in the OGDH complex, which degrades glucose and glutamate. OGDHL was reported to reprogram glutamine metabolism to suppress HCC progression in an enzyme-activity-dependent manner. However, the potential subcellular localization and non-canonical function of OGDHL is poorly understood. We investigated the expression of OGDHL and its effect on HCC progression. By employing a variety of molecular biology techniques, we revealed the underlying mechanism of OGDHL-induced DNA damage in HCC cells in vitro and in vivo. AAV loaded with OGDHL exerts therapeutic effect on mouse HCC and prolongs survival time. OGDHL induces DNA damage in HCC cells in vitro and in vivo. We also observed that OGDHL possesses nuclear localization in HCC cells and OGDHL-induced DNA damage was independent of its enzymatic activity. Mechanistically, it was demonstrated that OGDHL binds to CDK4 in the nucleus to inhibit the phosphorylation of CDK4 by CAK, which in turn attenuates E2F1 signaling. Inhibition of E2F1 signaling downregulates pyrimidine and purine synthesis, thereby inducing DNA damage through dNTP depletion. We clarified the nuclear localization of OGDHL and its non-canonical function to induce DNA damage, which demonstrated that OGDHL may serve as a select potential therapeutic target for HCC.

Iron minerals in soil play an important role in controlling the migration of fluoroquinolones. In this study, batch experiments were carried out to investigate interactions in ciprofloxacin (CIP) adsorption to goethite, hematite, and magnetite at pH 6.0. Thermodynamics and the site energy distribution theory (SEDT) were adopted to clarify the complexation types. Using the adsorption results, pH‐dependent interactions were qualitatively elucidated. The thermodynamic data revealed the difference in adsorption mechanisms. With increasing sorbate loading, CIP adsorption to hematite and magnetite was endothermic, and both enthalpy change and entropy change decreased; however, CIP sorption to goethite showed opposite characteristics. The higher adsorption capacity and affinity of CIP to hematite and magnetite than those to goethite were caused by their higher site energy of the highest occurring frequency (E0*) and the temperature‐dependent average site energy, respectively. The E0*on the surface of goethite was about 17–19 kJ mol−1, where E0*values of hematite and magnetite were 20–26 kJ mol−1. When temperature increased from 289.15 to 308.15 K, the high‐ and low‐energy site densities for three iron minerals changed by −32 to 167% and by −36 to 223%, respectively. The different thermodynamic and SEDT results indicated that CIP adsorption mechanisms to goethite and hematite/magnetite were mainly outer‐ and inner‐sphere complexation, respectively. The findings of this study reveal the adsorption mechanisms and are helpful in evaluating the transport of antibiotics in soils containing typical iron minerals. Ciprofloxacin adsorption was exo‐/endo‐thermic to goethite/hematite and magnetite.ΔGincreased while ΔHand ΔSdecreased on minerals with ciprofloxacin concentration.The changes of high‐ and low‐energy adsorption sites with temperature were quantified.Heterogeneity and average of site energy were correlated with active site density.

To unravel the crucial components of natural organic matter that respond to the process of anthropogenic groundwater recharge (AGR) from different recharge water sources, dissolved organic matter (DOM) and base-extractable particulate organic matter (POM) in groundwater and surface water were analyzed using excitation–emission matrix spectroscopy coupled with parallel factor analysis (EEM–PARAFAC). The EEM and traditional spectral indices of samples show that the fluorescent intensity, molecular weight, and humification degree of the DOM were relatively higher than those of the POM, and the groundwater in the reclaimed water recharge area (RWRA) was more contaminated than in the south-to-north water recharge area (SNWRA). PARAFAC analysis indicates that the DOM was dominated by an allochthonous humic-like substance (C1), whereas the POM was dominated by tryptophan-like substances associated with microbial activity (C2). Partitioning of PARAFAC components between DOM and POM showed that the humic-like substances (C1 and C4) were more likely to be distributed into a dissolved phase compared to the protein-like substances (C2 and C3), which suggested the potential use of C1 and C4 as a tracking indicator. In particular, the clear gradient distributions along both the hydrogeological profile and different aquifer systems in terms of the concentration and composition of C1 also discriminated between the RWRA and SNWRA with regard to the effects of various AGRs on the groundwater. The association between C1 and water-quality indicators revealed by principal component analysis further indicated that refractory humic-like substances would track the environmental impacts of intentional AGR processes.

DNA polymerase β (Pol β) plays a critical role in DNA base excision repair (BER), which is involved in maintaining genomic stability and in the modulation of DNA demethylation. Numerous studies implicated deficiency of Pol β in the genomic instability and dysregulation of genes expression, leading to affecting initiation of cancer. However, the role of Pol β in cancer progression is still unclear. Here, we show that Pol β depresses migratory and invasive capabilities of both breast and lung carcinomas, which were evident in human breast and lung cancer cells, as well as in mouse xenograft tumors. On the molecular basis, overexpression of Pol β enhanced expression of CDH13, which show function on cell adhesion and migration. Knockdown of CDH13 restores the migratory, invasive capabilities and angiogenesis in tumor, which gets impaired by Pol β. According to the function of BER on modulation of DNA demethylation, our studies on CDH13 expression and the DNA methylation levels of CDH13 promoter suggested that Pol β promotes expression of CDH13 by augmenting DNA demethylation of CDH13 promoter. Our findings elucidated a novel possibility that Pol β impair cancer cell metastasis during cancer progression and shed light on the role of Pol β in cancer therapy.

The interaction between support and noble metal plays a crucial role in heterogeneous catalysis design. However, how to tune metal support interactions to optimize the activity still needs further exploration. CeO2was introduced to promote CO oxidation over Ir/TiO2by adjusting the interaction strength between iridium (Ir) and CeO2. The strong interaction between Ir and CeO2blocks CO adsorption and causes low CO oxidation activity. However, introducing CeO2on Ir/TiO2produces localized interaction between Ir and CeO2, which can tune the surface electronic state of Ir, so a “volcano curve” relationship between CO oxidation activity and electronic state is built. Limited amount of CeO2on Ir/TiO2(Ir/Ce0.2Ti) leads to CO complete oxidization at 22 °C, and a new pathway for CO oxidation was explored. The study demonstrates that the utilization of tuning interaction strength between active metal and support is a potential method to increase the catalytic activity.

Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3aknockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3ain kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3anull tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3aknockout mice is partially rescued by genetic ablation of Glis2and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest.

Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε (DGKE) that encodes the lipid kinase DGKε(Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Nat Genet45: 531–536, 2013; Ozaltin F, Li BH, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang CY, Chen P, Lu DM, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. J Am Soc Nephrol24: 377–384, 2013). DGKεis unrelated to the complement pathway, which suggests that unidentified pathogenic mechanisms independent of complement dysregulation may result in TMA. Studying Dgkeknockout mice may help to understand the pathogenesis of this disease, but no glomerular phenotype has been described in these animals so far. Here we report that Dgkenull mice present subclinical microscopic anomalies of the glomerular endothelium and basal membrane that worsen with age and develop glomerular capillary occlusion when exposed to nephrotoxic serum. We found that induction of cyclooxygenase-2 and of the proangiogenic prostaglandin E2are impaired in Dgkenull kidneys and are associated with reduced expression of the antithrombotic cell adhesion molecule platelet endothelial cell adhesion molecule-1/CD31 in the glomerular endothelium. Notably, prostaglandin E2supplementation was able to rescue motility defects of Dgkeknockdown cells in vitro and to restore angiogenesis in a test in vivo. Our results unveil an unexpected role of Dgkein the induction of cyclooxygenase-2 and in the regulation of glomerular prostanoids synthesis under stress.

The groundwater quality impacts associated with anthropogenic groundwater recharge (AGR) are of great concern for water management. However, the impacts of AGR on the molecular properties of dissolved organic matter (DOM) in aquifers are poorly understood. Herein, Fourier transform ion cyclotron resonance mass spectrometry was used to unravel the molecular characteristics of DOM in groundwaters from recharge areas by reclaimed water (RWRA) and natural water from South-to-North Water Diversion Project (SNWRA). Compared with RWRA groundwater, significantly fewer nitrogenous compounds, more sulfur-containing compounds, higher concentrations of NO3–N, and lower pH were observed in SNWRA groundwater, indicating the occurrence of deamination, sulfurization, and nitrification. The occurrence of these processes was further supported by transformations of more molecules related to nitrogen and sulfur in SNWRA groundwater relative to RWRA groundwater. The intensities of most common molecules in all samples were significantly correlated with the water quality indicators (e.g., Cl–and NO3–N) and fluorescent indicators (e.g., humic-like components (C1%)), indicating that those common molecules may have the potential to track the environmental impact of AGR on groundwater, especially these specific molecules having great mobility and being significantly correlated with other inert tracers like C1% and Cl–. This study is helpful to understand the environmental risks and regional applicability of AGR.

Hedgehog (Hh) is an evolutionary conserved signaling pathway that has important functions in kidney morphogenesis and adult organ maintenance. Recent work has shown that Hh signaling is reactivated in the kidney after injury and is an important mediator of progressive fibrosis. Pericytes and fibroblasts have been proposed to be the principal cells that respond to Hh ligands, and pharmacological attenuation of Hh signaling has been considered as a possible treatment for fibrosis, but the effect of Hh inhibition on tubular epithelial cells after kidney injury has not been reported. Using genetically modified mice in which tubule-derived hedgehog signaling is increased and mice in which this pathway is conditionally suppressed in pericytes that express the proteoglycan neuron glial protein 2 (NG2), we found that suppression of Hh signaling is associated with decreased macrophage infiltration and tubular proliferation but also increased tubular apoptosis, an effect that correlated with the reduction of tubular β-catenin activity. Collectively, our data suggest a complex function of hedgehog signaling after kidney injury in initiating both reparative and proproliferative, prosurvival processes.

A comparative study of two micro-blowing temperature cases has been performed to investigate the characteristics of drag reduction in a subsonic flat-plate flow (where the freestream Mach number is 0.7) by means of Direct Numerical Simulation (DNS). With minute amount of blowing gas injected from a 32×32 array of micro-holes arranged in a staggered pattern, the porosity of micro-holes is 23% and the blowing coefficient is 0.125%. The simulation results show that a drag reduction is achieved by micro-blowing, and a lower wall-friction drag can be obtained at a higher blowing temperature. The role of micro-blowing is to redistribute the total kinetic energy in the boundary layer, and the proportion of stream-wise kinetic energy decreases, resulting in the thickened boundary layer. Increasing micro-blowing temperature can accelerate this process and obtain an enhanced drag reduction. Moreover, an explanation of drag reduction by micro-blowing related to the micro-jet vortex clusters is proposed that these micro-jet vortex clusters firmly attached to the wall constitute a stable barrier, which is to prevent the direct contact between the stream-wise vortex and the wall. By Dynamic Mode Decomposition (DMD) from temporal/spatial aspects, it is revealed that small structures in the near-wall region play vital role in the change of turbulent scales. The high-frequency patterns are clearly strengthened, and the low-frequency patterns just maintain but are lifted up.

N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism, but its role in innate immunity-driven non-alcoholic fatty liver disease (NAFLD) and obesity is not known. Here, we show that myeloid lineage-restricted deletion of the m6A “writer” protein Methyltransferase Like 3 (METTL3) prevents age-related and diet-induced development of NAFLD and obesity in mice with improved inflammatory and metabolic phenotypes. Mechanistically, loss of METTL3 results in the differential expression of multiple mRNA transcripts marked with m6A, with a notable increase of DNA Damage Inducible Transcript 4 (DDIT4) mRNA level. In METTL3-deficient macrophages, there is a significant downregulation of mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4. Taken together, our findings identify the contribution of METTL3-mediated m6A modification of Ddit4mRNA to macrophage metabolic reprogramming in NAFLD and obesity.