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A NICER view of the corona through time-dependent Comptonization of the quasi-periodic oscillations in nine black hole X-ray binaries
Get PDFWe present a systematic study of the evolution of the corona geometry in nine black hole X-ray binaries (BHXRBs) using archival data from Neutron Star Interior Composition Explorer (NICER). We identify 171 observations exhibiting quasi-periodic oscillations (QPOs) across various spectral states and model the time-averaged energy spectra of the source, as well as the energy-dependent rms and phase-lag spectra of the QPO, with the time-dependent Comptonization model vKompthdk. This allows us to simultaneously constrain the corona size and feedback fraction during outbursts. By using the power colour hue diagnostics, we identify different spectral states, and observe that the QPO frequency increases from 0.1 to 10 Hz in the low-hard and hard-intermediate states (LHS and HIMS), and remains approximately constant at 4–5 Hz in the soft-intermediate state (SIMS). The corona size shows significant evolution: the corona is large (– km) in the LHS, contracts rapidly to km in the HIMS, and exhibits a flare-like expansion near the HIMS-to-SIMS transition. In the SIMS and high-soft state (HSS), the corona becomes compact and stable (4000– 8000 km). The feedback fraction of the corona photons increases during the periods in which the corona contracts and decreases during the periods in which the corona expands, indicating a change of the disc–corona coupling. Our results are consistent with previous QPO-based studies using vKompthdk on some individual sources. This work, however, provides the first view of the coronal evolution across outbursts for a diverse BHXRB sample, offering critical insights into coronal behaviour as a function of the spectral state of the source
Deconvolution of small molecule pleiotropic effects during immunomodulation
Get PDFIschaemic heart disease is one of the leading causes of death worldwide, and is rapidly growing in prevalence. Despite improvements in response and treatment times, individuals who suffer from cardiac ischaemic injury are at risk of developing chronic heart failure. The development of regenerative therapeutics which harness endogenous recovery mechanisms to optimise repair of the injured heart after ischaemic injury are highly desired. One emerging mechanism via modulation of the immune response demonstrates great promise as a potential mediator of cardiac regeneration. The lymphatic system plays a significant immunomodulatory role in the transportation and clearance of immune cells. In the heart, the efficient clearance of immune cells post-ischaemic injury is linked to reduced fibrotic scarring and improved cardiac function, ultimately resulting in a more effective recovery after a myocardial infarction. This immune cell clearance is enhanced by lymphangiogenesis, which is the growth of new lymphatic vessels from pre-existing vasculature. This research has identified a small molecule, fingolimod, which induces lymphangiogenesis while also demonstrating previously reported pleiotropic effects upon both the lymphatic and immune system (i.e. T-lymphocyte sequestration in lymph nodes and T-lymphocyte migration inhibition).
The aim of this research was to deconvolute the potentially tissue-specific activity of fingolimod, to distinguish the mechanisms of action responsible for these immunomodulatory effects of interest. Phenotypic assays of lymphangiogenesis and T-lymphocyte migration were developed and optimised to aid this endeavour. Preliminary studies suggested that fingolimod’s metabolite, fingolimod phosphate is responsible for the immunomodulatory effects on both the lymphatic and immune system. Further pharmacological evaluation of fingolimod phosphate’s mechanisms of action demonstrated that these phenotypic effects were independent of fingolimod’s canonically associated sphingosine-1-phosphate receptors, but were dependent on another G-protein coupled receptor. The apelin receptor was identified as a target of interest, related to fingolimod’s lymphangiogenic effect. This observation was supported by CETSA, pharmacological inhibition studies, siRNA knockdown studies and downstream pathway analysis.
To further decipher fingolimod phosphate’s targets of phenotypic interest in an unbiased manner, fingolimod-derived chemical probes with a sustained functional effect were designed and synthesised, utilising photoaffinity labelling technology. A structurally similar but functionally inactive photoaffinity labelling probe was also synthesised and validated, with the intention of acting as a necessary negative control. There were significant attempts made to synthesise an iridium photocatalytic photoaffinity probe, to map fingolimod’s microenvironment, in addition to its direct targets. However, challenges in selectively modifying the sterically-hindered headgroup of fingolimod impeded this synthesis.
The validated photoaffinity probe was used to assess the direct targets of fingolimod in lymphatic endothelial cells. Proteomic analysis of probe-enriched proteins revealed novel interaction partners of fingolimod related to both its lymphangiogenic and migratory phenotypes. These findings also provided insight into the potential origins of fingolimod’s adverse side effects, as well as pleiotropic effects relating to other disease areas (i.e. diabetes, Alzheimer’s disease). These discoveries highlight the importance of target deconvolution in the development of effective therapeutics
The central sheaf of a Grothendieck category
No full textThe center Z(A) of an abelian category A is the endomorphism ring of the identity functor on that category. A localizing subcategory of a Grothendieck category C is said to be stable if it is stable under essential extensions. The set Lst(C) of stable localizing subcategories of C is partially ordered under reverse inclusion. We show L→Z(C/L) defines a sheaf of commutative rings on Lst(C) with respect to finite coverings. When C is assumed to be locally noetherian, we also show that the sheaf condition holds for arbitrary coverings
Developmental stage-specific responses to extreme climatic events and environmental variability in great tit nestlings
Get PDFClimate change poses a pervasive threat to many aspects of natural systems, and while impacts of changes in average conditions have been extensively studied, the effects of increased climate variability and extreme events on natural populations are less understood due to the challenges of studying these rare and unpredictable occurrences. Using 60 years of life-history data from over 83,000 individuals and historical daily climate records, we show that developmental stages in wild great tits (Parus major) differ in their sensitivity to extreme climatic events (ECEs). Exposure to extreme cold events during the first week of development is particularly detrimental to fledging mass, while extreme rain events have a stronger negative impact as nestlings grow older and their energetic requirements increase. Synergistic effects of ECEs and average climatic conditions can be particularly severe, exacerbating the challenges faced by these birds. Our findings indicate that combined exposure to extreme heat and heavy rainfall during early development is associated with a predicted reduction in fledging mass by up to 27%. Additionally, birth timing may further modulate these effects, since late-season broods exposed to frequent hot ECEs during early development are predicted to fledge nestlings up to 4.27 standard deviations (35%) lighter than broods laid earlier in the season. Moreover, phenotypic plasticity has enabled many similar populations to shift towards an overall earlier laying date, which may have increased susceptibility to cold extremes during development. However, our analyses suggest that the benefits of being part of an early-laid clutch within a season may, to some extent, offset the negative effects of extreme climate on fledging mass and apparent survival. In climate scenarios where ECEs are predicted to increase in frequency, duration and severity, these developmental stage-specific insights are important for understanding how climate change may be influencing wild avian populations
ID3 deficiency alters chromatin accessibility at DSB sites and enhances vulnerability to HDAC inhibition
Get PDFThe inhibitor of DNA‐binding 3 (ID3) plays a crucial role in DNA double‐strand break (DSB) repair. We previously reported that ID3 loss reduced chromatin accessibility at DNA repair gene promoters, yet its exact role in DNA repair via chromatin regulation remains elusive. Using the AID‐DIvA cell system with inducible DSBs, we show that ID3 directly regulates chromatin accessibility at DSB sites, as demonstrated by reduced chromatin accessibility and lower H3K27ac levels in ID3‐knockout (KO) cells. Loss of ID3 renders cells susceptible to histone deacetylase (HDAC) inhibition, particularly to the Class I HDAC inhibitor, leading to the accumulation of unrepaired DSBs and delayed cell cycle progression. Transcriptome and proteome analyses revealed that HDAC inhibition in ID3‐KO cells results in the downregulation of gene sets involved in the regulation of cell cycle and cell division. The synthetic lethality observed between ID3 loss and Class I HDAC inhibition underscores a novel therapeutic vulnerability in ID3‐deficient cancers, driven by compounded defects in chromatin remodeling, cell cycle, and DNA repair. Our study provides new insights into the relationship between chromatin regulation and genome stability, with implications for targeted cancer therapies
Insights into DNA repeat expansions among 900,000 biobank participants
Get PDFExpansions and contractions of tandem DNA repeats generate genetic variation in human populations and in human tissues. Some expanded repeats cause inherited disorders and some are also somatically unstable1, 2. Here we analysed DNA sequencing data from over 900,000 participants in the UK Biobank and the All of Us Research Program using computational approaches to recognize, measure and learn from DNA-repeat instability. Repeats at different loci exhibited widely variable tissue-specific propensities to mutate in the germline and blood. Common alleles of repeats in TCF4 and ADGRE2 exhibited high rates of length mosaicism in the blood, demonstrating that most human genomes contain repeat elements that expand as we age. Genome-wide association analyses of the extent of somatic expansion of unstable repeat alleles identified 29 loci at which inherited variants increased expansion of one or more DNA repeats in blood (P = 5 × 10−8 to 2.5 × 10−1,438). These genetic modifiers exhibited strong collective effects on repeat instability: at one repeat, somatic expansion rates varied fourfold between individuals with the highest and lowest 5% of polygenic scores. Modifier alleles at several DNA-repair genes exhibited opposite effects on the blood instability of the TCF4 repeat compared with other DNA repeats. Expanded repeats in the 5′ untranslated region of the glutaminase (GLS) gene associated with stage 5 chronic kidney disease (odds ratio (OR) = 14.0 (5.7–34.3, 95% confidence interval (CI))) and liver diseases (OR = 3.0 (1.5–5.9, 95% CI)). These results point to complex dynamics of DNA repeats in human populations and across the human lifespan
Approximating sparse matrices and their functions using matrix-vector products
No full textThe computation of a matrix function () is an important task in scientific computing appearing in machine learning, network analysis and the solution of partial differential equations. In this work, we use only matrix-vector products ↦ to approximate functions of sparse matrices and matrices with similar structures such as sparse matrices themselves or matrices that have a similar decay property as matrix functions. We show that when is a sparse matrix with an unknown sparsity pattern, techniques from compressed sensing can be used under natural assumptions. Moreover, if is a banded matrix then certain deterministic matrix-vector products can efficiently recover the large entries of (). We describe an algorithm for each of the two cases and give error analysis based on the decay bound for the entries of (). We finish with numerical experiments showing the accuracy of our algorithms
Implementing the BOOST (better outcomes for older people with spinal trouble) programme for older people with spinal stenosis
Get PDFSocial justice lawyering in post-apartheid South Africa: rules and ideals in everyday legal practice
Get PDFLaw has been central to successive state-making projects in South Africa. Most recently, the 1996 Constitution was said to mark a “break” from apartheid and its “wicked” system of law, providing both the tools and moral vision to forge a transformed society. Yet, thirty-one years after apartheid’s end, racialised patterns of inequality and poverty persist. For socio-legal scholars, this coexistence of a progressive rights regime with deepening inequality represents a “paradox” (Mnisi-Weeks, 2021).This thesis explores this paradox through a novel ethnographic analysis of lawyers who seek to advance social transformation in South Africa. Working within what I term the “access to justice (ATJ) legal field”, these lawyers provide clinical legal assistance to poor clients while pursuing strategic litigation aimed at broader systemic change. Their everyday work embodies the constitutional ideal of law as a means for both individual and societal improvement. Yet it also generates professional and moral dilemmas centred on tensions between a commitment to law as a system of rules; belief in law’s transformative moral potential; and self-conceptions as professionals who “help people.”Drawing on the concepts of “legalism” (Dresch and Scheele, 2015) and “legal culture” (Chanock, 2001; Mnisi-Weeks, 2021), the thesis analyses how these lawyers navigate such tensions and how they are shaped by the conditions of legal practice itself. This reveals a fundamental dynamic in South Africa’s project of law-based transformation: the struggle between lawyerly adherence to rules, at least partly anchored in the past; and the normative commitment to new legal ideals, oriented to remaking South Africa’s future. By examining this dynamic ethnographically, the thesis develops a grounded account of contemporary professional legal culture in the ATJ field. It argues that this culture – shaped by how lawyers negotiate rules and ideals – is central to understanding the possibilities and limits of law-based social change