Oxidative DNA damage is unavoidably and continuously generated by oxidant byproducts of normal cellular metabolism. The DNA damage repair genes, mutY and mutM, prevent G to T mutations caused by reactive oxygen species in Escherichia coli, but it has remained debatable whether deficiencies in their mammalian counterparts, Myh and Ogg1, are directly involved in tumorigenesis. Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas. Remarkably, subsequent analyses identified G to T mutations in 75% of the lung tumors at an activating hot spot, codon 12, of the K-ras oncogene, but none in their adjacent normal tissues. Moreover, malignant lung tumors were increased with combined heterozygosity of Msh2, a mismatch repair gene involved in oxidative DNA damage repair as well. Thus, oxidative DNA damage appears to play a causal role in tumorigenesis, and codon 12 of K-ras is likely to be an important downstream target in lung tumorigenesis. The multiple oxidative repair genes are required to prevent mutagenesis and tumor formation. The mice described here provide a valuable model for studying the mechanisms of oxidative DNA damage in tumorigenesis and investigating preventive or therapeutic approaches.

Highly selective adsorptive separation of olefin/paraffin through porous materials can produce high purity olefins in a much more energy-efficient way than the traditional cryogenic distillation. Here we report an ultramicroporous cobalt gallate metal–organic framework (Co-gallate) for the highly selective sieving separation of propylene/propane at ambient conditions. This material possesses optimal pore structure for the exact confinement of propylene molecules while excluding the slightly large propane molecules, as clearly demonstrated in the neutron diffraction crystal structure of Co-gallate⊃0.38C3D6. Its high separation performance has been confirmed by the gas sorption isotherms and column breakthrough experiments to produce the high purity of propylene (97.7%) with a high dynamic separation productivity of 36.4 cm3 cm–3 under ambient conditions. The gas adsorption measurement, pore size distribution, and crystallographic and modeling studies comprehensively support the high sieving C3H6/C3H8 separation in this MOF material. It is stable under different environments, providing its potential for the industrial propylene purification.

In eukaryotes, the nuclease activity of Rad27p (Fen1p) is thought to play a critical role in lagging-strand DNA replication by removing ribonucleotides present at the 5 ends of Okazaki fragments. Genetic analysis of Saccharomyces cerevisiae also has identified a role for Rad27p in mutation avoidance. rad27⌬ mutants display both a repeat tract instability phenotype and a high rate of forward mutations to canavanine resistance that result primarily from duplications of DNA sequences that are flanked by direct repeats. These observations suggested that Rad27p activities in DNA replication and repair could be altered by mutagenesis and specifically assayed. To test this idea, we analyzed two rad27 alleles, rad27-G67S and rad27-G240D, that were identified in a screen for mutants that displayed repeat tract instability and mutator phenotypes. In chromosome stability assays, rad27-G67S strains displayed a higher frequency of repeat tract instabilities relative to CAN1 duplication events; in contrast, the rad27-G240D strains displayed the opposite phenotype. In biochemical assays, rad27-G67Sp displayed a weak exonuclease activity but significant single-and double-flap endonuclease activities. In contrast, rad27-G240Dp displayed a significant double-flap endonuclease activity but was devoid of exonuclease activity and showed only a weak single-flap endonuclease activity. Based on these observations, we hypothesize that the rad27-G67S mutant phenotypes resulted largely from specific defects in nuclease function that are important for degrading bubble intermediates, which can lead to DNA slippage events. The rad27-G240D mutant phenotypes were more difficult to reconcile to a specific biochemical defect, suggesting a structural role for Rad27p in DNA replication and repair. Since the mutants provide the means to relate nuclease functions in vitro to genetic characteristics in vivo, they are valuable tools for further analyses of the diverse biological roles of Rad27p.

Separating acetylene from carbon dioxide is important but highly challenging owing to their similar physical properties and molecular dimensions. Herein, we report highly efficient electrostatically driven CO2/C2H2 separation in an ultramicroporous cadmium nitroprusside (Cd‐NP) with compact pore space and complementary electrostatic potential well fitting for CO2, thus enabling molecular quadrupole moment recognition of CO2 over C2H2. This material shows a high CO2/C2H2 uptake ratio of 6.0 as well as remarkable CO2/C2H2 selectivity of 85 under ambient conditions with modest CO2 heat of adsorption. Neutron powder diffraction experiments and molecular simulations revealed that the electrostatic potential compatibility between pore structure and CO2 allows it to be trapped in a head‐on orientation towards the Cd center, whereas the diffusion of C2H2 is electrostatically forbidden. Dynamic breakthrough experiments have validated the separation performance of this compound for CO2/C2H2 separation.

Physical separation of C 2 H 2 from CO 2 on metal−organic frameworks (MOFs) has received substantial research interest due to the advantages of simplicity, security, and energy efficiency. However, that C 2 H 2 and CO 2 exhibit very close physical properties makes their separation exceptionally challenging. Previous work appeared to mostly focused on introducing open metal sites that aims to enhance the C 2 H 2 affinity at desired sites, whereas the reticular manipulation of organic components has rarely been investigated. In this work, by reticulating preselected amino and hydroxy functionalities into isostructural ultramicroporous chiral MOFs Ni 2 (L-asp) 2 (bpy) (MOF-NH 2 ) and Ni 2 (L-mal) 2 (bpy) (MOF-OH)we targeted efficient C 2 H 2 uptake and C 2 H 2 /CO 2 separation, which outperforms most benchmark materials. Explicitly, MOF-OH adsorbs substantial amount of C 2 H 2 with record storage density of 0.81 g mL −1 at ambient conditions, which even exceeds the solid density of C 2 H 2 at 189 K. In addition, MOF-OH gave IAST selectivity of 25 toward equimolar mixture of C 2 H 2 /CO 2 , which is nearly twice higher than that of MOF-NH 2 . Notably, the adsorption enthalpies for C 2 H 2 at zero converge in both MOFs are remarkably low (17.5 kJ mol −1 for MOF-OH and 16.7 kJ mol −1 for MOF-NH 2 ), which to our knowledge are the lowest among efficient rigid C 2 H 2 sorbents. The efficiencies of both MOFs for the separation of C 2 H 2 /CO 2 are validated by multicycle breakthrough experiments. DFT calculations provide molecular-level insight over the adsorption/ separation mechanism. Moreover, MOF-OH can survive in boiling water for at least 1 week and can be easily scaled up to kilograms eco-friendly and economically, which is very crucial for potential industrial implementation.

Figure 4. a,b) Curves of breakthrough tests for an equimolar binary mixture of CO 2 /C 2 H 2 (a) and cycling tests of breakthrough tests the equimolar CO 2 /C 2 H 2 mixture (open symbols: C 2 H 2 , solid symbols: CO 2 ) (b) in a column packed with Cu-F-pymo at 298 K and 1 bar.

De novo mutations (DNMs) significantly contribute to sporadic diseases, particularly in neuropsychiatric disorders. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) provide effective methods for detecting DNMs and prioritizing candidate genes. However, it remains a challenge for scientists, clinicians, and biologists to conveniently access and analyse data regarding DNMs and candidate genes from scattered publications. To fill the unmet need, we integrated 580 799 DNMs, including 30 060 coding DNMs detected by WES/WGS from 23 951 individuals across 24 phenotypes and prioritized a list of candidate genes with different degrees of statistical evidence, including 346 genes with false discovery rates <0.05. We then developed a database called Gene4Denovo (http://www.genemed.tech/gene4denovo/), which allowed these genetic data to be conveniently catalogued, searched, browsed, and analysed. In addition, Gene4Denovo integrated data from >60 genomic sources to provide comprehensive variant-level and gene-level annotation and information regarding the DNMs and candidate genes. Furthermore, Gene4Denovo provides end-users with limited bioinformatics skills to analyse their own genetic data, perform comprehensive annotation, and prioritize candidate genes using custom parameters. In conclusion, Gene4Denovo conveniently allows for the accelerated interpretation of DNM pathogenicity and the clinical implication of DNMs in humans.

Biallelic germline mutations in the base excision repair enzyme gene MUTYH lead to multiple colorectal adenomas and carcinomas referred to as MUTYH-associated polyposis. MUTYH removes adenine misincorporated opposite the DNA oxidation product, 8-oxoguanine (OG), thereby preventing accumulation of G:C to T:A transversion mutations. The most common cancer-associated MUTYH variant proteins when expressed in bacteria exhibit reduced OG:A mismatch affinity and adenine removal activity. However, direct evaluation of OG:A mismatch repair efficiency in mammalian cells has not been assessed due to the lack of an appropriate assay. To address this, we developed a novel fluorescence-based assay of OG:A repair and measured the repair capacity of MUTYH-associated polyposis variants expressed in Mutyh-/- mouse embryonic fibroblasts (MEFs). The repair of a single site-specific synthetic lesion in a green fluorescent protein reporter leads to green fluorescent protein expression with co-expression of a red fluorescent protein serving as the transfection control. Cell lines that stably express the MUTYH-associated polyposis variants G382D and Y165C have significantly lower OG:A repair versus wild-type MEFs and MEFs expressing human wild-type MUTYH. The MUTYH allele that encodes the Q324H variant is found at a frequency above 40% in samples from different ethnic groups and has long been considered phenotypically silent but has recently been associated with increased cancer risk in several clinical studies. In vitro analysis of Q324H MUTYH expressed in insect cells showed that it has reduced enzyme activity similar to that of the known cancer variant G382D. Moreover, we find that OG:A repair in MEFs expressing Q324H was significantly lower than wild-type controls, establishing that Q324H is functionally impaired and providing further evidence that this common variant may lead to increased cancer risk.