...loss of AID's C-terminal nuclear export signal, a mutation observed in immunodeficiency patients, leads to rapid degradation of the protein as it cannot be translocated back to the cytosol. ......the mutagenic activity of AID depends on its ability to overcome faithful uracil repair but also to remain in the nucleus of B cells. AID is preferentially recruited to the immunoglobulin locus by transcription, which takes place mostly during G1. ...its activity leads to localized mutagenesis when its presence in the cell nucleus can be tolerated.
The introduction of effective solid waste management strategies in developing countries should be considered for improving sustainability at global level. Many barriers should be overcome, concerning ...the introduction of environmental policies, effective investments, social inclusion and public awareness, which are significant issues in low-middle income countries. The Circular Economy could represent the answer for improving current solid waste management activities worldwide, since denote the principle of waste valorization and recycling for boosting developing economies. This paper is focused on this theme, analyzing main opportunities for improving the current state of solid waste management in developing big cities. The solid waste management of two countries are reviewed: Romania is the emerging country where Circular Economy is becoming a future objective due to economic aids and strength regulations which the European Union (EU) established for the nations forming parts the alliance; as a comparison, Bolivia is reported for evaluating main differences founded for developing recycling systems in a no-EU country. These two case studies could be of interest for highlighting main pros and cons of the participation into a wide organization like the EU for introducing in short terms Circular Economy principles. Moreover, a theoretical Circular Economy model for developing big cities in low-middle income countries is described within the study for effectively comparing which chances can spread for these countries as regard municipal solid waste exploitation. Despite the economic level, Romania and Bolivia are both facing with many solid waste management issues although in different magnitude. For the Romanian case study, it is visible how it cannot achieve the European goals for 2020 due the need of change in public recycling behavior. Bolivia, instead, represents the case where international aids and new investments are required, considering the informal sector into the formal management system as a real opportunity for improving local recycling rate. In conclusion, the comparison suggests how external supports led to implement the principles of the Circular Economy within a developing region. The model of Circular Economy proposed is recommended for developing big cities in order to advance a new form of safe employment, encouraging the activities that are still in action (i.e. informal sector) and boosting the principles of sustainable development.
•A circular economy model for developing countries was presented.•Solid waste management of Romania and Bolivia can be compared.•Municipal and “special” solid waste should be managed in an integrated manner.•Integrated regulations about solid waste are essential for developing countries.•The informal sector plays a key role on sustainable solid waste management.
Deamination of cytosine (C), 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) occurs spontaneously in mammalian DNA with several hundred deaminations occurring in each cell every day. The ...resulting potentially mutagenic mispairs of uracil (U), thymine (T) or 5-hydroxymethyluracil (hmU) with guanine (G) are substrates for repair by various DNA glycosylases. Here, we show that targeted inactivation of the mouse Smug1 DNA glycosylase gene is sufficient to ablate nearly all hmU-DNA excision activity as judged by assay of tissue extracts from knockout mice as well as by the resistance of their embryo fibroblasts to 5-hydroxymethyldeoxyuridine toxicity. Inactivation of Smug1 when combined with inactivation of the Ung uracil-DNA glycosylase gene leads to a loss of nearly all detectable uracil excision activity. Thus, SMUG1 is the dominant glycosylase responsible for hmU-excision in mice as well as the major UNG-backup for U-excision. Both Smug1-knockout and Smug1/Ung-double knockout mice breed normally and remain apparently healthy beyond 1 year of age. However, combined deficiency in SMUG1 and UNG exacerbates the cancer predisposition of Msh2(-/-) mice suggesting that when both base excision and mismatch repair pathways are defective, the mutagenic effects of spontaneous cytosine deamination are sufficient to increase cancer incidence but do not preclude mouse development.
Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered ...over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis. DOI:http://dx.doi.org/10.7554/eLife.00534.001.
DNA-RNA hybrids arise in all cell types, and are removed by multiple enzymes, including the trimeric ribonuclease, RNase H2. Mutations in human RNase H2 result in Aicardi-Goutières syndrome (AGS), an ...inflammatory brain disorder notable for being a Mendelian mimic of congenital viral infection. Previous studies have shown that several AGS-associated mutations of the RNase H2B subunit do not affect trimer stability or catalytic activity and are clustered on the surface of the complex, leading us to speculate that these mutations might impair important interactions of RNase H2 with so far unidentified proteins. In this study, we show that AGS mutations in this cluster impair the interaction of RNase H2 with several members of the CoREST chromatin-silencing complex that include the histone deacetylase HDAC2 and the demethylase KDM1A, the transcriptional regulators RCOR1 and GTFII-I as well as ZMYM3, an MYM-type zinc finger protein. We also show that the interaction is mediated by the zinc finger protein ZMYM3, suggesting that ZMYM3 acts as a novel type of scaffold protein coordinating interactions between deacetylase, demethylase and RNase H type enzymes, raising the question of whether coordination between histone modifications and the degradation of RNA-DNA hybrids may be required to prevent inflammation in humans.
High-affinity antibodies are generated by somatic hypermutation with nucleotide substitutions introduced into the IgV in a semirandom fashion, but with intrinsic mutational hotspots strategically ...located to optimize antibody affinity maturation. The process is dependent on activation-induced deaminase (AID), an enzyme that can deaminate deoxycytidine in DNA in vitro, where its activity is sensitive to the identity of the 5'-flanking nucleotide. As a critical test of whether such DNA deamination activity underpins antibody diversification and to gain insight into the extent to which the antibody mutation spectrum is dependent on the intrinsic substrate specificity of AID, we investigated whether it is possible to change the IgV mutation spectrum by altering AID's active site such that it prefers a pyrimidine (rather than a purine) flanking the targeted deoxycytidine. Consistent with the DNA deamination mechanism, B cells expressing the modified AID proteins yield altered IgV mutation spectra (exhibiting a purine-->pyrimidine shift in flanking nucleotide preference) and altered hotspots. However, AID-catalyzed deamination of IgV targets in vitro does not yield the same degree of hotspot dominance to that observed in vivo, indicating the importance of features beyond AID's active site and DNA local sequence environment in determining in vivo hotspot dominance.
The present work analyses aspects of the carbon footprint of a large wastewater treatment plant in central Italy. The plant mainly consists of a traditional activated sludge system along with an ...anaerobic digester providing a partial contribution of energy to the management. An integrated approach was adopted to evaluate the environmental sustainability of the treatment plant in terms of carbon footprint. For the assessment different sources of greenhouse gas emissions such as nitrous oxide and carbon dioxide were considered: effluent, production and transport of natural gas, energy consumption, boiler, co-generator, substrate and endogenous decays. According to the methodology adopted, energy consumption, production and transport of natural gas and N2O emissions from the effluent were found the most contributing sources of greenhouse gases. Based on this, these sources are suggested as the most relevant ones on which wastewater treatment plant managers should pay more attention when taking actions for carbon footprint mitigation. Considerations on the role of CO2 of biogenic origin (specifically the one in the biogas) in terms of sequestration options demonstrate that the analysis in this field should not be limited to the calculation and comment of non-fossil contributions to the overall balance.
Immunoglobulin (Ig) class switching is initiated by deamination of C-->U within the immunoglobulin heavy chain locus, catalyzed by activation-induced deaminase (AID). In the absence of uracil-DNA ...glycosylase (UNG) and the homologue of bacterial MutS (MSH)-2 mismatch recognition protein, the resultant U:G lesions are not processed into switching events but are fixed by replication allowing sites of AID-catalyzed deamination to be identified by the resulting C-->T mutations. We find that AID targets cytosines in both donor and acceptor switch regions (S regions) with the deamination domains initiating approximately 150 nucleotides 3' of the I exon start sites and extending over several kilobases (the IgH intronic enhancer is spared). Culturing B cells with interleukin 4 or interferon gamma specifically enhanced deamination around Sgamma1 and Sgamma2a, respectively. Mutation spectra suggest that, in the absence of UNG and MSH2, AID may occasionally act at the mu switch region in an apparently processive manner, but there is no marked preference for targeting of the transcribed versus nontranscribed strand (even in areas capable of R loop formation). The data are consistent with switch recombination being triggered by transcription-associated, strand-symmetric AID-mediated deamination at both donor and acceptor S regions with cytokines directing isotype specificity by potentiating AID recruitment to the relevant acceptor S region.
microRNA-155 (miR-155) is expressed by cells of the immune system after activation and has been shown to be required for antibody production after vaccination with attenuated
Salmonella. Here we show ...the intrinsic requirement for miR-155 in B cell responses to thymus-dependent and -independent antigens. B cells lacking miR-155 generated reduced extrafollicular and germinal center responses and failed to produce high-affinity IgG1 antibodies. Gene-expression profiling of activated B cells indicated that miR-155 regulates an array of genes with diverse function, many of which are predicted targets of miR-155. The transcription factor Pu.1 is validated as a direct target of miR155-mediated inhibition. When Pu.1 is overexpressed in wild-type B cells, fewer IgG1 cells are produced, indicating that loss of Pu.1 regulation is a contributing factor to the miR-155-deficient phenotype. Our results implicate post-transcriptional regulation of gene expression for establishing the terminal differentiation program of B cells.
Textile plays a crucial role in a circular economy and its traditional use needs to be replaced with sustainable ways. A circular economy gives repurpose and value to a resource in a continuous loop ...to be useful to its maximum extent at the end of stage life. Also, with the increase in population, consumption of resources, inflation, and environmental impacts are aggravated. Therefore, a literature review in this scenario which represents the solutions and the scope to incorporate circular economy with the clothes recovery is useful. The highlight of the review includes external hindrances such as consumer preferences, garment styles, and the need to involve indigenous productions in the regulations of the circular economy. In Swiss fashion firms, it’s harder to set circular economy principles as compared to Italy. Further, rich fashion brands do not generally favour the idea of a circular economy. However, a few young businesses, despite the complexities of each stage, are inclined more towards a circular economy. The overview of the current review gives various ideas, limitations, and the future perspective for the application of circular economy integrated with textile. Also, it gives an opportunity to assess and compare the circular economy hindrances and scope among different countries.