Somatic hypermutation (SHM) of immunoglobulin (
) genes plays a key role in antibody mediated immunity. SHM in B cells provides the molecular basis for affinity maturation of antibodies. In this way ...SHM is key in optimizing antibody dependent immune responses. SHM is initiated by targeting the Activation-Induced Cytidine Deaminase (AID) to rearranged V(D)J and switch regions of
genes. The mutation rate of this programmed mutagenesis is ~10
base pairs per generation, a million-fold higher than the non-AID targeted genome of B cells. AID is a processive enzyme that binds single-stranded DNA and deaminates cytosines in DNA. Cytosine deamination generates highly mutagenic deoxy-uracil (U) in the DNA of both strands of the
loci. Mutagenic processing of the U by the DNA damage response generates the entire spectrum of base substitutions characterizing SHM at and around the initial U lesion. Starting from the U as a primary lesion, currently five mutagenic DNA damage response pathways have been identified in generating a well-defined SHM spectrum of C/G transitions, C/G transversions, and A/T mutations around this initial lesion. These pathways include (1) replication opposite template U generates transitions at C/G, (2) UNG2-dependent translesion synthesis (TLS) generates transversions at C/G, (3) a hybrid pathway comprising non-canonical mismatch repair (ncMMR) and UNG2-dependent TLS generates transversions at C/G, (4) ncMMR generates mutations at A/T, and (5) UNG2- and PCNA Ubiquitination (PCNA-Ub)-dependent mutations at A/T. Furthermore, specific strand-biases of SHM spectra arise as a consequence of a biased AID targeting, ncMMR, and anti-mutagenic repriming. Here, we review mammalian SHM with special focus on the mutagenic DNA damage response pathways involved in processing AID induced Us, the origin of characteristic strand biases, and relevance of the cell cycle.
The prevalence of intermittent water supply in South Africa was investigated in this research study. Data on intermittent water supply in South Africa was collated by considering the following four ...sources: a targeted water services provider survey; published databases and related reports; open-access publications, such as online media articles; and field visits by the project team to selected areas. The data were spatially and temporally analysed to determine the prevalence of intermittent water supply. The population affected by intermittent water supply increased by ~26% between 2008 and 2017, which exceeds the population increase of ~12% over the same period. Moreover, 22 million people in South Africa were affected by intermittent water supply in 2017. Results from this study confirm an increased prevalence of intermittent water supply over time and show that 65 of the 231 municipalities in South Africa supplied water intermittently, 32 had continuous water supply and 134 had no data. Fundamentally, the outcomes highlight the widespread occurrence of intermittent water supply in South Africa, which is in line with the poor state of water services delivery in South Africa, as portrayed in the 2018 National Water and Sanitation Master Plan by the national Department of Water and Sanitation.
DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination activates an ...error-free pathway, elusive in mammals, enabling damage bypass by template switching. Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and template switching in vivo was unknown. Here we show that damage-induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance. Fork reversal in vivo also requires ZRANB3 translocase activity and its interaction with polyubiquitinated PCNA, pinpointing ZRANB3 as a key effector of error-free DNA damage tolerance. Mutations affecting fork reversal also induced unrestrained fork progression and chromosomal breakage, suggesting fork remodeling as a global fork slowing and protection mechanism. Targeting these fork protection systems represents a promising strategy to potentiate cancer chemotherapy.
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•Fork slowing and reversal upon damage require K63-linked PCNA polyubiquitination•ZRANB3 mediates fork slowing/reversal in vivo via binding to polyubiquitinated PCNA•ZRANB3 DNA translocase—not nuclease—activity mediates fork slowing and reversal•Mammalian error-free postreplication repair entails global fork slowing and reversal
Vujanovic et al. show that UBC13-mediated, K63-linked PCNA polyubiquitination mediates DNA damage-induced replication fork slowing and reversal, via recruitment to forks of ZRANB3 DNA translocase. These data link the postreplication repair pathway, yet elusive in mammals, to the regulation of fork progression and remodeling.
•We systematically review 114 studies on the residential end uses of water.•We develop a multi-level analysis to compare the outcomes available in the literature.•The study allows understanding the ...most investigated aspects of water end uses.•Features from different geographical and cultural regions of the world are explored.
A detailed characterization of residential water consumption is essential for ensuring urban water systems' capability to cope with changing water resources availability and water demands induced by growing population, urbanization, and climate change. Several studies have been conducted in the last decades to investigate the characteristics of residential water consumption with data at a sufficiently fine temporal resolution for grasping individual end uses of water. In this paper, we systematically review 114 studies to provide a comprehensive overview of the state-of-the-art research about water consumption at the end-use level. Specifically, we contribute with: (1) an in-depth discussion of the most relevant findings of each study, highlighting which water end-use characteristics were so far prioritized for investigation in different case studies and water demand modelling and management studies from around the world; and (2) a multi-level analysis to qualitatively and quantitatively compare the most common results available in the literature, i.e. daily per capita end-use water consumption, end-use parameter average values and statistical distributions, end-use daily profiles, end-use determinants, and considerations about efficiency and diffusion of water-saving end uses. Our findings can support water utilities, consumers, and researchers (1) in understanding which key aspects of water end uses were primarily investigated in the last decades; and (2) in exploring their main features considering different geographical, cultural, and socio-economic regions of the world.
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DNA damage tolerance (DDT) enables bypassing of DNA lesions during replication, thereby preventing fork stalling, replication stress, and secondary DNA damage related to fork stalling. Three modes of ...DDT have been documented: translesion synthesis (TLS), template switching (TS), and repriming. TLS and TS depend on site-specific PCNA K164 monoubiquitination and polyubiquitination, respectively. To investigate the role of DDT in maintaining hematopoietic stem cells (HSCs) and progenitors, we used PcnaK164R/K164R
mice as a unique DDT-defective mouse model. Analysis of the composition of HSCs and HSC-derived multipotent progenitors (MPPs) revealed a significantly reduced number of HSCs, likely owing to increased differentiation of HSCs toward myeloid/erythroid-associated MPP2s. This skewing came at the expense of the number of lymphoid-primed MPP4s, which appeared to be compensated for by increased MPP4 proliferation. Furthermore, defective DDT decreased the numbers of MPP-derived common lymphoid progenitor (CLP), common myeloid progenitor (CMP), megakaryocyte-erythroid progenitor (MEP), and granulocyte-macrophage progenitor (GMP) cells, accompanied by increased cell cycle arrest in CMPs. The HSC and MPP phenotypes are reminiscent of premature aging and stressed hematopoiesis, and indeed progressed with age and were exacerbated on cisplatin exposure. Bone marrow transplantations revealed a strong cell intrinsic defect of DDT-deficient HSCs in reconstituting lethally irradiated mice and a strong competitive disadvantage when cotransplanted with wild-type HSCs. These findings indicate a critical role of DDT in maintaining HSCs and progenitor cells, and in preventing premature aging.
Chromothripsis defines a genetic phenomenon where up to hundreds of clustered chromosomal rearrangements can arise in a single catastrophic event. The phenomenon is associated with cancer and ...congenital diseases. Most current models on the origin of chromothripsis suggest that prior to chromatin reshuffling numerous DNA double-strand breaks (DSBs) have to exist, i.e., chromosomal shattering precedes rearrangements. However, the preference of a DNA end to rearrange in a proximal accessible region led us to propose chromothripsis as the reaction product of successive chromatin rearrangements. We previously coined this process Alternative End Generation (AEG), where a single DSB with a repair-blocking end initiates a domino effect of rearrangements. Accordingly, chromothripsis is the end product of this domino reaction taking place in a single catastrophic event.
Water temperature is often monitored at water sources and treatment works; however, there is limited monitoring of the water temperature in the drinking water distribution system (DWDS), despite a ...known impact on physical, chemical and microbial reactions which impact water quality. A key parameter influencing drinking water temperature is soil temperature, which is influenced by the urban heat island effects. This paper provides critique and comprehensive summary of the current knowledge, policies and challenges regarding drinking water temperature research and presents the findings from a survey of international stakeholders. Knowledge gaps as well as challenges and opportunities for monitoring and research are identified. The conclusion of the study is that temperature in the DWDS is an emerging concern in various countries regardless of the water source and treatment, climate conditions, or network characteristics such as topology, pipe material or diameter. More research is needed, especially to determine (i) the effect of higher temperatures, (ii) a legislative limit on temperature and (iii) measures to comply with this limit.
AbstractThis research investigated relationships between the most notable characteristics of end-use events, namely, event duration, volume, and intensity, in order to categorize water use as being ...indoor or outdoor. Three classification models were developed, calibrated, and compared using more than 200,000 household end-use events that were recorded independently in Australia and South Africa. The three methods were also compared to a practice-based limit classification scheme. The classification model presented in this paper correctly apportions ∼81% of the indoor end-use event volumes and ∼98% of the outdoor end-use event volumes, thus reinforcing the value of basic smart water meter data sets as a source of useful information for water demand management.
Histone deacetylases (HDACs) counterbalance acetylation of lysine residues, a protein modification involved in numerous biological processes. Here, Hdac1 and Hdac2 conditional knock‐out alleles were ...used to study the function of class I Hdac1 and Hdac2 in cell cycle progression and haematopoietic differentiation. Combined deletion of Hdac1 and Hdac2, or inactivation of their deacetylase activity in primary or oncogenic‐transformed fibroblasts, results in a senescence‐like G1 cell cycle arrest, accompanied by up‐regulation of the cyclin‐dependent kinase inhibitor p21Cip. Notably, concomitant genetic inactivation of p53 or p21Cip indicates that Hdac1 and Hdac2 regulate p53–p21Cip‐independent pathways critical for maintaining cell cycle progression. In vivo, we show that Hdac1 and Hdac2 are not essential for liver homeostasis. In contrast, total levels of Hdac1 and Hdac2 in the haematopoietic system are critical for erythrocyte‐megakaryocyte differentiation. Dual inactivation of Hdac1 and Hdac2 results in apoptosis of megakaryocytes and thrombocytopenia. Together, these data indicate that Hdac1 and Hdac2 have overlapping functions in cell cycle regulation and haematopoiesis. In addition, this work provides insights into mechanism‐based toxicities observed in patients treated with HDAC inhibitors.
As the world increasingly faces water shortages, it is critical to develop realistic estimates of water consumption based on water-use activities rather than top-down imposed limits. This study ...quantifies the absolute basic consumption (ABC) of an individual, irrespective of water-use location or water source, with a focus on personal water-use activities rather than measured household consumption. A theoretical model to stochastically describe 21 personal water-use activities was developed, corresponding to lifestyle levels based upon Maslow's hierarchy of physiological needs. From this model, the expected value of ABC was 92 L/capita/day (LPCD) and includes restrictions on several everyday activities and thus would be better as a minimum target during stringent water restrictions. A more realistic expected value for non-wasteful, indoor-only water use was determined to be 175 LPCD. The results of this study serve as a useful benchmark to inform policy choices and efforts to conserve water without affecting health and wellbeing. HIGHLIGHTS It is important to quantify water consumption based on water-use activities and across all daily water-use locations.; The expected value of basic water consumption for a healthy urban lifestyle is 92 L/person/day, which includes restrictions on everyday activities.; A more realistic expected value for water consumption is 175 L/person/day across all water-use locations during a typical day.;
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