Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response,Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.     

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases MUTYH and hOGG1 in Colorectal Cancer Patients

Oxidative stress, oxidative DNA damage and resulting mutations play a role in colorectal carcinogenesis. Impaired equilibrium between DNA damage formation, antioxidant status, and DNA repair capacity is responsible for the accumulation of genetic mutations and genomic instability. The lesion-specific DNA glycosylases, e.g., hOGG1 and MUTYH, initiate the repair of oxidative DNA damage. Hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome) with germline mutations causing a loss-of-function in base excision repair glycosylases, serve as straight forward evidence on the role of oxidative DNA damage and its repair. Altered or inhibited function of above glycosylases result in an accumulation of oxidative DNA damage and contribute to the adenoma-adenocarcinoma transition. Oxidative DNA damage, unless repaired, often gives rise G:C > T:A mutations in tumor suppressor genes and proto-oncogenes with subsequent occurrence of chromosomal copy-neutral loss of heterozygosity. For instance, G>T transversions in position c.34 of a KRAS gene serves as a pre-screening tool for MUTYH-associated polyposis diagnosis. Since sporadic colorectal cancer represents more complex and heterogenous disease, the situation is more complicated. In the present study we focused on the roles of base excision repair glycosylases (hOGG1, MUTYH) in colorectal cancer patients by investigating tumor and adjacent mucosa tissues. Although we found downregulation of both glycosylases and significantly lower expression of hOGG1 in tumor tissues, accompanied with G>T mutations in KRAS gene, oxidative DNA damage and its repair cannot solely explain the onset of sporadic colorectal cancer. In this respect, other factors (especially microenvironment) per se or in combination with oxidative DNA damage warrant further attention. Base excision repair characteristics determined in colorectal cancer tissues and their association with disease prognosis have been discussed as well.     

Modulation of Steroid and Triterpenoid Metabolism in Calendula officinalis Plants and Hairy Root Cultures Exposed to Cadmium Stress

The present study investigated the changes in the content of steroids and triterpenoids in C. officinalis hairy root cultures and plants exposed to cadmium stress. The observed effects included the content and composition of analyzed groups of compounds, particularly the proportions among individual sterols (e.g., stigmasterol-to-sitosterol ratio), their ester and glycoside conjugates. The total sterol content increased in roots (by 30%) and hairy root culture (by 44%), whereas it decreased in shoots (by 15%); moreover, these effects were inversely correlated with Cd-induced growth suppression. Metabolic alterations of sterols and their forms seemed to play a greater role in the response to Cd stress in roots than in shoots. The symptoms of the competition between general metabolites (sterols) and specialized metabolites (triterpenoids) were also observed, i.e., the increase of the sterol biosynthesis parallel to the decrease of the triterpenoid content in C. officinalis plant roots and hairy root culture, and the inverse phenomenon in shoots. The similarity of the metabolic modifications observed in the present study on C. officinalis plant roots and hairy roots confirmed the possibility of application of plant in vitro cultures in initial studies for physiological research on plant response to environmental stresses.     

First Report on Genome Editing via Ribonucleoprotein (RNP) in Castanea sativa Mill.

Castanea sativa is an important tree nut species worldwide, highly appreciated for its multifunctional role, in particular for timber and nut production. Nowadays, new strategies are needed to achieve plant resilience to diseases, climate change, higher yields, and nutritional quality. Among the new plant breeding techniques (NPBTs), the CRISPR/Cas9 system represents a powerful tool to improve plant breeding in a short time and inexpensive way. In addition, the CRISPR/Cas9 construct can be delivered into the cells in the form of ribonucleoproteins (RNPs), avoiding the integration of exogenous DNA (GMO-free) through protoplast technology that represents an interesting material for gene editing thanks to the highly permeable membrane to DNA. In the present study, we developed the first protoplast isolation protocol starting from European chestnut somatic embryos. The enzyme solution optimized for cell wall digestion contained 1% cellulase Onozuka R-10 and 0.5% macerozyme R-10. After incubation for 4 h at 25 °C in dark conditions, a yield of 4,500,000 protoplasts/mL was obtained (91% viable). The transfection capacity was evaluated using the GFP marker gene, and the percentage of transfected protoplasts was 51%, 72 h after the transfection event. The direct delivery of the purified RNP was then performed targeting the phytoene desaturase gene. Results revealed the expected target modification by the CRISPR/Cas9 RNP and the efficient protoplast editing.     

Enhanced and Differential Capture of Circulating Tumor Cells from Lung Cancer Patients by Microfluidic Assays Using Aptamer Cocktail

Collecting circulating tumor cells (CTCs) shed from solid tumor through a minimally invasive approach provides an opportunity to solve a long‐standing oncology problem, the real‐time monitoring of tumor state and analysis of tumor heterogeneity. However, efficient capture and detection of CTCs with diverse phenotypes is still challenging. In this work, a microfluidic assay is developed using the rationally‐designed aptamer cocktails with synergistic effect. Enhanced and differential capture of CTCs for nonsmall cell lung cancer (NSCLC) patients is achieved. It is also demonstrated that the overall consideration of CTC counts obtained by multiple aptamer combinations can provide more comprehensive information in treatment monitoring.     

Ultrahigh Energy Absorption Multifunctional Spinodal Nanoarchitectures

Nanolattices are promoted as next‐generation multifunctional high‐performance materials, but their mechanical response is limited to extreme strength yet brittleness, or extreme deformability but low strength and stiffness. Ideal impact protection systems require high‐stress plateaus over long deformation ranges to maximize energy absorption. Here, glassy carbon nanospinodals, i.e., nanoarchitectures with spinodal shell topology, combining ultrahigh energy absorption and exceptional strength and stiffness at low weight are presented. Noncatastrophic deformation up to 80% strain, and energy absorption up to one order of magnitude higher than for other nano‐, micro‐, macro‐architectures and solids, and state‐of‐the‐art impact protection structures are shown. At the same time, the strength and stiffness are on par with the most advanced yet brittle nanolattices, demonstrating true multifunctionality. Finite element simulations show that optimized shell thickness‐to‐curvature‐radius ratios suppress catastrophic failure by impeding propagation of dangerously oriented cracks. In contrast to most micro‐ and nano‐architected materials, spinodal architectures may be easily manufacturable on an industrial scale, and may become the next generation of superior cellular materials for structural applications.     

阴离子本体开环聚合反应挤出合成聚三氟丙基甲基硅氧烷

以同向紧啮合双螺杆挤出机为反应器,硅醇钠/乙酸乙酯(EA)为引发体系,通过三氟丙基甲基环三硅氧烷(F3)阴离子本体开环聚合,制备了聚三氟丙基甲基硅氧烷(PMTFPS)。采用红外光谱(FT-IR),核磁共振(1H-NMR)和凝胶渗透色谱(GPC)确认了聚合物的结构与分子量,用电离飞行时间质谱分析了副产物的组成。研究表明,提高反应温度和EA用量可使反应平衡点提前到达。而螺杆转速对反应的主要影响在于改变聚合反应时间。因此,控制适当反应条件,使反应在平衡点到来时间之前终止,可得到高分子量以及高收率的PMTFPS。所得产物的数均分子量为2.41×105,分子量分散指数为1.12,产率为90.5%。     

Business intelligence success: The roles of BI capabilities and decision environments

This study examines the role of the decision environment in how well business intelligence (BI) capabilities are leveraged to achieve BI success. We examine the decision environment in terms of the types of decisions made and the information processing needs of the organization. Our findings suggest that technological capabilities such as data quality, user access and the integration of BI with other systems are necessary for BI success, regardless of the decision environment. However, the decision environment does influence the relationship between BI success and capabilities, such as the extent to which BI supports flexibility and risk in decision making.