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Here, I will review recent developments in our understanding of ligand recognition and binding promiscuity within the SLC15 family, and discuss current models for prodrug recognition. © 2020 The Author(s).Little is known about the functional relationship of delaying second-line treatment initiation for HIV-positive patients and mortality, given a patient’s immune status. We included 7255 patients starting antiretroviral therapy between 2004-2017, from 9 South African cohorts, with virological failure and complete baseline data. We estimated the impact of switch time on the hazard of death using inverse probability of treatment weighting (IPTW) of marginal structural models. The non-linear relationship between month of switch and the 5-year survival probability, stratified by CD4 count at failure, was estimated with targeted maximum likelihood estimation (TMLE). We adjusted for measured time-varying confounding by CD4 count, viral load and visit frequency. 5-year mortality was estimated as 10.5% (2.2%; 18.8%) for immediate switch and as 26.6% (20.9%; 32.3%) for no switch (49.9% if CD4 count less then 100 cells/mm3). The hazard of death was estimated to be 0.40 (95%CI 0.33-0.48) times lower if everyone had been switched immediately compared to never. The shorter the delay in switching, the lower the hazard of death, e.g. delaying 30-60 days reduced the hazard 0.52 (0.41-0.65) times, and 60-120 days 0.56 (0.47-0.66) times. Early treatment switch is particularly important for patients with low CD4 counts at failure. © The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Processing of and responding to various signals is an essential cellular function that influences survival, homeostasis, development, and cell death. Extra- or intracellular signals are perceived via specific receptors and transduced in a particular signalling pathway that results in a precise response. Reversible post-translational redox modifications of cysteinyl and methionyl residues have been characterised in countless signal transduction pathways. Due to the low reactivity of most sulfur-containing amino acid side chains with hydrogen peroxide, for instance, and also to ensure specificity, redox signalling requires catalysis, just like phosphorylation signalling requires kinases and phosphatases. While reducing enzymes of both cysteinyl- and methionyl-derivates have been characterised in great detail before, the discovery and characterisation of MICAL proteins evinced the first examples of specific oxidases in signal transduction. This article provides an overview of the functions of MICAL proteins in the redox regulation of cellular functions. © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.The cellular mitochondrial population undergoes repeated cycles of fission and fusion to maintain its integrity, as well as overall cellular homeostasis. While equilibrium usually exists between the fission-fusion dynamics, their rates are influenced by organellar and cellular metabolic and pathogenic conditions. Under conditions of cellular stress, there is a disruption of this fission and fusion balance and mitochondria undergo either increased fusion, forming a hyperfused meshwork or excessive fission to counteract stress and remove damaged mitochondria via mitophagy. While some previous reports suggest that hyperfusion is initiated to ameliorate cellular stress, recent studies show its negative impact on cellular health in disease conditions. The exact mechanism of mitochondrial hyperfusion and its role in maintaining cellular health and homeostasis, however, remain unclear. In this review, we aim to highlight the different aspects of mitochondrial hyperfusion in either promoting or mitigating stress and also its role in immunity and diseases. © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.Few studies comprehensively investigated the association of two key kidney measures, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR), with cancer incidence. In 8,935 participants at the baseline (1996-98) from the Atherosclerosis Risk in Communities (ARIC) study, we quantified the associations of eGFR (based on creatinine and cystatin C) and ACR with cancer risk using Cox regression models adjusted for potential confounders. Due to changing guidelines for prostate cancer screening during the follow-up, we investigated overall cancer, overall non-prostate cancer, and site-specific cancer. During a median follow-up of 14.7 years, 2,030 incident cancer cases occurred. In demographically-adjusted model, low eGFR and high ACR were associated with cancer incidence (both overall and overall non-prostate cancer). These associations were attenuated after adjusting for other shared risk factors, with a significant association remaining only for ACR (≥103 compared to 5 mg/g) and overall non-prostate cancer. GSK2643943A clinical trial For site-specific cancer, only high ACR showed a significant association with lung and urinary tract cancers. Of these, the association between ACR and lung cancer appeared most robust in several sensitivity analyses. Kidney measures, particularly high ACR, were independently associated with cancer risk. The association between ACR and lung cancer was uniquely robust, warranting future studies to explore potential mechanisms. © The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.DNA is exposed to both endogenous and exogenous DNA damaging agents that chemically modify it. To counteract the deleterious effects exerted by DNA lesions, eukaryotic cells have evolved a network of cellular pathways, termed DNA damage response (DDR). The DDR comprises both mechanisms devoted to repair DNA lesions and signal transduction pathways that sense DNA damage and transduce this information to specific cellular targets. These targets, in turn, impact a wide range of cellular processes including DNA replication, DNA repair and cell cycle transitions. The importance of the DDR is highlighted by the fact that DDR inactivation is commonly found in cancer and causes many different human diseases. The protein kinases ATM and ATR, as well as their budding yeast orthologs Tel1 and Mec1, act as master regulators of the DDR. The initiating events in the DDR entail both DNA lesion recognition and assembly of protein complexes at the damaged DNA sites. Here, we review what is known about the early steps of the DDR.