Estimating Subnational Under-Five Mortality Rates Using a Spatio-Temporal Age-Period-Cohort Model

Producing subnational estimates of the under-five mortality rate (U5MR) is a vital goal for the United Nations to reduce inequalities in mortality and well-being across the globe. There is a great disparity in U5MR between high-income and Low-and-Middle Income Countries (LMICs). Current methods for modelling U5MR in LMICs use smoothing methods to reduce uncertainty in estimates caused by data sparsity. This paper includes cohort alongside age and period in a novel application of an Age-Period-Cohort model for U5MR. In this context, current methods only use age and period (and not cohort) for smoothing. With data from the Kenyan Demographic and Health Surveys (DHS) we use a Bayesian hierarchical model with terms to smooth over temporal and spatial components whilst fully accounting for the complex stratified, multi-staged cluster design of the DHS. Our results show that the use of cohort may be useful in the context of subnational estimates of U5MR. We validate our results at the subnational level by comparing our results against direct estimates.Comment: 16 pages, 6 Figures, 2 Table

The evolution of RNAs with multiple functions

Increasing numbers of transcripts have been reported to transmit both protein-coding and regulatory information. Apart from challenging our conception of the gene, this observation raises the question as to what extent this phenomenon occurs across the genome and how and why such dual encoding of function has evolved in the eukaryotic genome. To address this question, we consider the evolutionary path of genes in the earliest forms of life on Earth, where it is generally regarded that proteins evolved from a cellular machinery based entirely within RNA. This led to the domination of protein-coding genes in the genomes of microorganisms, although it is likely that RNA never lost its other capacities and functionalities, as evidenced by cis-acting riboswitches and UTRs. On the basis that the subsequent evolution of a more sophisticated regulatory architecture to provide higher levels of epigenetic control and accurate spatiotemporal expression in developmentally complex organisms is a complicated task, we hypothesize: (i) that mRNAs have been and remain subject to secondary selection to provide trans-acting regulatory capability in parallel with protein-coding functions; (ii) that some and perhaps many protein-coding loci, possibly as a consequence of gene duplication, have lost protein-coding functions en route to acquiring more sophisticated trans-regulatory functions; (iii) that many transcripts have become subject to secondary processing to release different products; and (iv) that novel proteins have emerged within loci that previously evolved functionality as regulatory RNAs. In support of the idea that there is a dynamic flux between different types of informational RNAs in both evolutionary and real time, we review recent observations that have arisen from transcriptomic surveys of complex eukaryotes and reconsider how these observations impact on the notion that apparently discrete loci may express transcripts with more than one function. In conclusion, we posit that many eukaryotic loci have evolved the capacity to transact a multitude of overlapping and potentially independent functions as both regulatory and protein-coding RNAs

Age Determination of Six Intermediate-age SMC Star Clusters with HST/ACS

We present a photometric analysis of the star clusters Lindsay 1, Kron 3, NGC339, NGC416, Lindsay 38, and NGC419 in the Small Magellanic Cloud (SMC), observed with the Hubble Space Telescope Advanced Camera for Surveys (ACS) in the F555W and F814W filters. Our color magnitude diagrams (CMDs) extend ~3.5 mag deeper than the main-sequence turnoff points, deeper than any previous data. Cluster ages were derived using three different isochrone models: Padova, Teramo, and Dartmouth, which are all available in the ACS photometric system. Fitting observed ridgelines for each cluster, we provide a homogeneous and unique set of low-metallicity, single-age fiducial isochrones. The cluster CMDs are best approximated by the Dartmouth isochrones for all clusters, except for NGC419 where the Padova isochrones provided the best fit. The CMD of NGC419 shows several main-sequence turn-offs, which belong to the cluster and to the SMC field. We thus derive an age range of 1.2-1.6 Gyr for NGC419. Interestingly, our intermediate-age star clusters have a metallicity spread of ~0.6 dex, which demonstrates that the SMC does not have a smooth, monotonic age-metallicity relation. We find an indication for centrally concentrated blue straggler star candidates in NGC416, while for the other clusters these are not present. Using the red clump magnitudes, we find that the closest cluster, NGC419 (~50kpc), and the farthest cluster, Lindsay 38 (~67kpc), have a relative distance of ~17kpc, which confirms the large depth of the SMC.Comment: 25 pages, 45 Figure

Ligand-engaged TCR is triggered by Lck not associated with CD8 coreceptor

Producción CientíficaThe earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction between TCR, CD8 and major histocompatibility complex (MHC)-peptide. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ–CD8 interactions require CD8–MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR-triggering event is induced by free Lck. The early signalling events that trigger initial T-cell receptor signalling are not clearly defined. Here the authors show that this occurs in two stages, the first between the CD8 coreceptor and CD3 requiring Lck association to CD8, while the second interaction requires binding of major histocompatibility molecules

Placing Joseph Banks in the North Pacific

The South Pacific was a fulcrum of Joseph Banks's maritime world and global networks. The North Pacific was a distance and intangible fringe. This article is concerned with how Banks should be ‘placed’ in the North Pacific. It tracks how Banks's activities have been delineated in terms of languages and categories of global and local, and centre and margin, and then considers the historical and geographical specifics apposite to his connection to the North Pacific. In this setting, ideas of place (as location and assignment) and capital (as a circulatory and everyday practice of exchange and opportunism) come into view and question the distinction between science and commerce in Banks historiography. The article considers a diverse group of non-Indigenous figures – explorers, traders, cartographers, scientists, collectors – operating in the North Pacific in the 1780s and 1790s whose initiatives and missives passed across Banks's desk, and assesses their place in Banks's archive by drawing on Peter Sloterdijk's ideas about the interiorising and exteriorising logic of capital.PostprintPeer reviewe

Diminished circadian and ultradian rhythms in pathological brain tissue in human in vivo

Chronobiological rhythms, such as the circadian rhythm, have long been linked to neurological disorders, but it is currently unknown how pathological processes affect the expression of biological rhythms in the brain. Here, we use the unique opportunity of long-term, continuous intracranially recorded EEG from 38 patients (totalling 6338 hours) to delineate circadian and ultradian rhythms in different brain regions. We show that functional circadian and ultradian rhythms are diminished in pathological tissue, independent of regional variations. We further demonstrate that these diminished rhythms are persistent in time, regardless of load or occurrence of pathological events. These findings provide the first evidence that brain pathology is functionally associated with persistently diminished chronobiological rhythms in vivo in humans, independent of regional variations or pathological events. Future work interacting with, and restoring, these modulatory chronobiological rhythms may allow for novel therapies

Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide-MHC

Recent work has demonstrated that nonstimulatory endogenous peptides can enhance T cell recognition of antigen, but MHCI- and MHCII-restricted systems have generated very different results. MHCII-restricted TCRs need to interact with the nonstimulatory peptide–MHC (pMHC), showing peptide specificity for activation enhancers or coagonists. In contrast, the MHCI-restricted cells studied to date show no such peptide specificity for coagonists, suggesting that CD8 binding to noncognate MHCI is more important. Here we show how this dichotomy can be resolved by varying CD8 and TCR binding to agonist and coagonists coupled with computer simulations, and we identify two distinct mechanisms by which CD8 influences the peptide specificity of coagonism. Mechanism 1 identifies the requirement of CD8 binding to noncognate ligand and suggests a direct relationship between the magnitude of coagonism and CD8 affinity for coagonist pMHCI. Mechanism 2 describes how the affinity of CD8 for agonist pMHCI changes the requirement for specific coagonist peptides. MHCs that bind CD8 strongly were tolerant of all or most peptides as coagonists, but weaker CD8-binding MHCs required stronger TCR binding to coagonist, limiting the potential coagonist peptides. These findings in MHCI systems also explain peptide-specific coagonism in MHCII-restricted cells, as CD4–MHCII interaction is generally weaker than CD8–MHCI.National Institutes of Health (U.S.). Pioneer Awar

Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide–MHC

Recent work has demonstrated that nonstimulatory endogenous peptides can enhance T cell recognition of antigen, but MHCI- and MHCII-restricted systems have generated very different results. MHCII-restricted TCRs need to interact with the nonstimulatory peptide–MHC (pMHC), showing peptide specificity for activation enhancers or coagonists. In contrast, the MHCI-restricted cells studied to date show no such peptide specificity for coagonists, suggesting that CD8 binding to noncognate MHCI is more important. Here we show how this dichotomy can be resolved by varying CD8 and TCR binding to agonist and coagonists coupled with computer simulations, and we identify two distinct mechanisms by which CD8 influences the peptide specificity of coagonism. Mechanism 1 identifies the requirement of CD8 binding to noncognate ligand and suggests a direct relationship between the magnitude of coagonism and CD8 affinity for coagonist pMHCI. Mechanism 2 describes how the affinity of CD8 for agonist pMHCI changes the requirement for specific coagonist peptides. MHCs that bind CD8 strongly were tolerant of all or most peptides as coagonists, but weaker CD8-binding MHCs required stronger TCR binding to coagonist, limiting the potential coagonist peptides. These findings in MHCI systems also explain peptide-specific coagonism in MHCII-restricted cells, as CD4–MHCII interaction is generally weaker than CD8–MHCI.National Institutes of Health (U.S.). Pioneer Awar