DNA can experience “replication stress”, an important source of genome instability, induced by various external or endogenous impediments that slow down or stall DNA synthesis. While genome instability is largely documented to favor both tumor formation and heterogeneity, as well as drug resistance, conversely, excessive instability appears to suppress tumorigenesis and is associated with improved prognosis. These findings support the view that karyotypic diversity, necessary to adapt to selective pressures, may be limited in tumors so as to reduce the risk of excessive instability. This review aims to highlight the contribution of specialized DNA polymerases in limiting extreme genetic instability by allowing DNA replication to occur even in the presence of DNA damage, to either avoid broken forks or favor their repair after collapse. These mechanisms and their key regulators Rad18 and Polθ not only offer diversity and evolutionary advantage by increasing mutagenic events, but also provide cancer cells with a way to escape anti-cancer therapies that target replication forks. 相似文献
NiO nanostructure was synthesized using a simple co-precipitation method and was embedded on reduced graphene oxide surface via ultrasonication. Structural investigations were made through X-ray diffraction (XRD) and functional groups were confirmed by Fourier transform infrared spectroscopy (FTIR). XRD analysis revealed the grain size reduction with doping. Fourier transform infrared spectroscopy confirmed the presence of metal-oxygen bond in pristine and doped NiO nanostructure as well as the presence of carbon containing groups. Scanning electron microscopy (SEM) indicated that the particle size decreased when NiO nanostructure was doped with copper. BET surface area was found to increase almost up to 43 m2/g for Cu doped NiO nanostructure/rGO composite. Current-voltage measurements were performed using two probe method. UV–Visible spectroscopic profiles showed the blue and red shift for Cu doped NiO nanostructure and Cu doped NiO Nanostructure/rGO composite respectively. Rate constant for Cu doped NiO nanostructure/rGO composite found to increase 4.4 times than pristine NiO nanostructure. 相似文献
Targeting protein-protein interactions (PPIs) with small-molecule inhibitors has become a hotbed of modern drug development. In this review, we describe a new class of PPI inhibitors that block menin from binding to MLL proteins. Menin is encoded by the MEN1 tumor suppressor, but acts as an essential cofactor for MLL/KMT2A-rearranged leukemias. The most promising menin-MLL inhibitors belong to the thienopyrimidine class and have recently entered phase I/II clinical trials for treating acute leukemias characterized by MLL/KMT2A translocations or NPM1 mutations. As single agents, thienopyrimidine compounds eradicate leukemia in a xenograft models of primary leukemic cells belonging to the MLL-rearranged or NPM1-mutant subtypes. These compounds are well tolerated with few or no side effects, which is remarkable given the tumor-suppressor function of menin. The menin-MLL inhibitors highlight how leukemia patients could benefit from a targeted epigenetic therapy with novel PPI inhibitors obtained by directed chemical evolution. 相似文献
Vitamin A is an essential micronutrient whose deficiency is still a major health concern in many regions of the world. It plays an essential role in human growth and development, immunity, and vision, but may also help prevent several other chronic diseases. The total amount of vitamin A in the human diet often falls below the recommended dietary allowance of approximately 900–1000 g/day for a healthy adult. Moreover, a significant proportion of vitamin A may be degraded during food processing, storage, and distribution, thereby reducing its bioactivity. Finally, the vitamin A in some foods has a relatively low bioavailability, which further reduces its efficacy. The World Health Organization has recommended fortification of foods and beverages as a safe and cost-effective means of addressing vitamin A deficiency. However, there are several factors that must be overcome before effective fortified foods can be developed, including the low solubility, chemical stability, and bioavailability of this oil-soluble vitamin. Consequently, strategies are required to evenly disperse the vitamin throughout food matrices, to inhibit its chemical degradation, to avoid any adverse interactions with any other food components, to ensure the food is palatable, and to increase its bioavailability. In this review article, we discuss the chemical, physical, and nutritional attributes of vitamin A, its main dietary sources, the factors contributing to its current deficiency, and various strategies to address these deficiencies, including diet diversification, biofortification, and food fortification. 相似文献
This study presents a new systematic algorithm to optimize the durability of reinforced recycled aggregate concrete. The proposed algorithm integrates machine learning with a new version of the firefly algorithm called chaotic based firefly algorithm (CFA) to evolve a rational and efficient predictive model. The CFA optimizer is augmented with chaotic maps and Lévy flight to improve the firefly performance in forecasting the chloride penetrability of strengthened recycled aggregate concrete (RAC). A comprehensive and credible database of distinctive chloride migration coefficient results is used to establish the developed algorithm. A dataset composite of nine effective parameters, including concrete components and fundamental characteristics of recycled aggregate (RA), is used as input to predict the migration coefficient of strengthened RAC as output. k-fold cross validation algorithm is utilized to validate the hybrid algorithm. Three numerical benchmark analyses are applied to prove the superiority and applicability of the CFA algorithm in predicting chloride penetrability. Results show that the developed CFA approach significantly outperforms the firefly algorithm on almost tested functions and demonstrates powerful prediction. In addition, the proposed strategy can be an active tool to recognize the contradictions in the experimental results and can be especially beneficial for assessing the chloride resistance of RAC. 相似文献
The effect of Co, Pd and Pt ultrathin films on the kinetics of the formation of Ni-silicide by reactive diffusion is investigated. 50 nm Ni/1 nm X/ 50 nm Ni (X?=?Co, Pd, Pt) deposited on Si(100) substrates are studied using in-situ and ex-situ measurements by X-ray diffraction (XRD). The presence of Co, Pd or Pt thin films in between the Ni layers delays the formation of the metal rich phase compared to the pure Ni/Si system and thus these films act as diffusion barriers. A simultaneous silicide formation (δ-Ni2Si and NiSi phases) different from the classic sequential formation is found during the consumption of the top Ni layer for which Ni has to diffuse through the barrier. A model for the simultaneous growth in the presence of a barrier is developed, and simulation of the kinetics measured by XRD is used to determine the permeability of the different barriers. Atom probe tomography (APT) of the Ni/Pd/Ni system shows that the Pd layer is located between the Ni top layer and δ-Ni2Si during the silicide growth, in accordance with a silicide formation controlled by Ni diffusion through the Pd layer. The effect of the barrier on the silicide formation and properties is discussed.
Materials with magneto-electric (ME) properties are of great importance because of their demand in electronic industries. Three dimensional nano-particles of the ME-composites having the general formula (1-x)CoCr0.3Fe1.7O4(CCFO)+(x)BaTiO3(BTO) (x = 0.0, 0.2, 0.4, 0.6, 0.8 and 1.0) were obtained by comprising the piezoelectric-BTO and piezomagnetic-CCFO phases. The individual phases of CCFO and BTO were synthesized separately by ultrasonic irradiation assisted sonochemical and sol-gel routs. X-ray diffraction patterns (XRD) confirmed the well-crystalline nature of both the phases. BTO and CCFO phases were under tensile strain as confirmed by the variation in lattice constants with varying proportion of BTO and CCFO. An energy-dispersive X-ray spectroscopy spectrum confirmed the phase purity of the samples and stoichiometric concentration of elements. Magnetic properties were investigated by M ? H loop measurements and dielectric properties by using RF impedance analyzer. Dielectric constant increased with the increasing percentage of BTO. The maximum value of ME coefficient (24.7 mV/cm?Oe) is observed for the 60%CCFO+40%BTO sample. The obtained results were discussed in the light of grain size, strain and the basic properties of the individual phases. The prepared materials can be applicable in electronic devices where high magneto-electric coefficient is desirable. 相似文献
Coeliac disease (CD) and Type 1 diabetes mellitus (T1DM) are immune-mediated diseases. Emerging evidence suggests that dysbiosis in the gut microbiome plays a role in the pathogenesis of both diseases and may also be associated with the development of neuropathy. The primary goal in this cross-sectional pilot study was to identify whether there are distinct gut microbiota alterations in children with CD (n = 19), T1DM (n = 18) and both CD and T1DM (n = 9) compared to healthy controls (n = 12). Our second goal was to explore the relationship between neuropathy (corneal nerve fiber damage) and the gut microbiome composition. Microbiota composition was determined by 16S rRNA gene sequencing. Corneal confocal microscopy was used to determine nerve fiber damage. There was a significant difference in the overall microbial diversity between the four groups with healthy controls having a greater microbial diversity as compared to the patients. The abundance of pathogenic proteobacteria Shigella and E. coli were significantly higher in CD patients. Differential abundance analysis showed that several bacterial amplicon sequence variants (ASVs) distinguished CD from T1DM. The tissue transglutaminase antibody correlated significantly with a decrease in gut microbial diversity. Furthermore, the Bacteroidetes phylum, specifically the genus Parabacteroides was significantly correlated with corneal nerve fiber loss in the subjects with neuropathic damage belonging to the diseased groups. We conclude that disease-specific gut microbial features traceable down to the ASV level distinguish children with CD from T1DM and specific gut microbial signatures may be associated with small fiber neuropathy. Further research on the mechanisms linking altered microbial diversity with neuropathy are warranted. 相似文献
Magnetic Resonance Materials in Physics, Biology and Medicine - Quantitative analysis in MRI is challenging due to variabilities in intensity distributions across patients, acquisitions and... 相似文献