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'Ethnic Group', the State and the Politics of Representation
This paper explores the notion of 'ethnic group' focussing, in particular, on attempts to transform the concept into an empirical indicator in population censuses. The latter is seen to be riven with difficulties, not least the fact that such measures tend to be attempting to address two conflicting agendas - one requiring an ascriptive, the other a subjective, measure. Illustrating the core arguments with the decennial census in Britain, the paper explores the contested political terrain underpinning the introduction of such a question, and then demonstrates that the construction of an 'ethnic group' indicator takes the form of a complex dialectical process involving negotiation and re-negotiation on the part of a myriad of social actors and structural forces at macro-, meso- and micro-levels. Finally, it reflects on broader concerns arising from the reification of the measure, not least its material effects in the context of debates and policies on 'multiculturalism'. © 2013 Copyright Taylor and Francis Group, LLC.
Tau depletion in human neurons mitigates Aβ-driven toxicity.
Alzheimer's disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unexplored. In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neurons in vitro in co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC-derived cortical neurons. We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. Finally, tau depletion protected neurons from adverse effects by mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration. Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt-/- mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.
Two sample Mendelian Randomisation using an outcome from a multilevel model of disease progression.
Identifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time-for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying causal relationships between one exposure and one outcome in observational data whilst avoiding bias due to confounding is two sample Mendelian Randomisation (2SMR). We consider a multivariate approach to 2SMR using a multilevel model for disease progression to estimate the causal effect an exposure has on the intercept and slope. We carry out a simulation study comparing a naïve univariate 2SMR approach to a multivariate 2SMR approach with one exposure that effects both the intercept and slope of an outcome that changes linearly with time since diagnosis. The simulation study results, across six different scenarios, for both approaches were similar with no evidence against a non-zero bias and appropriate coverage of the 95% confidence intervals (for intercept 93.4-96.2% and the slope 94.5-96.0%). The multivariate approach gives a better joint coverage of both the intercept and slope effects. We also apply our method to two Parkinson's cohorts to examine the effect body mass index has on disease progression. There was no strong evidence that BMI affects disease progression, however the confidence intervals for both intercept and slope were wide.
Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.
The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Maternal iron deficiency perturbs embryonic cardiovascular development in mice.
Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.
Iron-Deficiency Anemia Results in Transcriptional and Metabolic Remodeling in the Heart Toward a Glycolytic Phenotype.
Iron deficiency is the most prevalent micronutrient disorder globally. When severe, iron deficiency leads to anemia, which can be deleterious to cardiac function. Given the central role of iron and oxygen in cardiac biology, multiple pathways are expected to be altered in iron-deficiency anemia, and identifying these requires an unbiased approach. To investigate these changes, gene expression and metabolism were studied in mice weaned onto an iron-deficient diet for 6 weeks. Whole-exome transcriptomics (RNAseq) identified over 1,500 differentially expressed genes (DEGs), of which 22% were upregulated and 78% were downregulated in the iron-deficient group, relative to control animals on an iron-adjusted diet. The major biological pathways affected were oxidative phosphorylation and pyruvate metabolism, as well as cardiac contraction and responses related to environmental stress. Cardiac metabolism was studied functionally using in vitro and in vivo methodologies. Spectrometric measurement of the activity of the four electron transport chain complexes in total cardiac lysates showed that the activities of Complexes I and IV were reduced in the hearts of iron-deficient animals. Pyruvate metabolism was assessed in vivo using hyperpolarized 13C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate. Hearts from iron-deficient and anemic animals showed significantly decreased flux through pyruvate dehydrogenase and increased lactic acid production, consistent with tissue hypoxia and induction of genes coding for glycolytic enzymes and H+-monocarboxylate transport-4. Our results show that iron-deficiency anemia results in a metabolic remodeling toward a glycolytic, lactic acid-producing phenotype, a hallmark of hypoxia.
Cardiomyocyte Na+/H+ Exchanger-1 Activity Is Reduced in Hypoxia.
Fully-activated Na+/H+ exchanger-1 (NHE1) generates the cardiomyocyte's largest trans-membrane extrusion of H+ ions for an equimolar influx of Na+ ions. This has the desirable effect of clearing excess intracellular acidity, but comes at a large energetic premium because the exchanged Na+ ions must ultimately be extruded by the sodium pump, a process that consumes the majority of the heart's non-contractile ATP. We hypothesize that the state of NHE1 activation depends on metabolic resources, which become limiting in periods of myocardial hypoxia. To test this functionally, NHE1 activity was measured in response to in vitro and in vivo hypoxic treatments. NHE1 flux was interrogated as a function of intracellular pH by fluorescence imaging of rodent ventricular myocytes loaded with pH-sensitive dyes BCECF or cSNARF1. Anoxic superfusates promptly inhibited NHE1, tracking the time-course of mitochondrial depolarization. Mass spectrometry of NHE1 immuno-precipitated from Langendorff-perfused anoxic hearts identified Tyr-581 dephosphorylation and Tyr-561 phosphorylation. The latter residue is part of the domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane lipid that becomes depleted under metabolic inhibition. Tyr-561 phosphorylation is expected to electrostatically weaken this activatory interaction. To test if a period of hypoxia produces a persistent inhibition of NHE1, measurements under normoxia were performed on myocytes that had been incubated in 2% O2 for 4 h. NHE1 activity remained inhibited, but the effect was ablated in the presence of Dasatinib, an inhibitor of Abl/Src-family tyrosine kinases. Chronic tissue hypoxia in vivo, attained in a mouse model of anemic hypoxia, also resulted in persistently slower NHE1. In summary, we show that NHE1 responds to oxygen, a physiologically-relevant metabolic regulator, ostensibly to divert ATP for contraction. We describe a novel mechanism of NHE1 inhibition that may be relevant in cardiac disorders featuring altered oxygen metabolism, such as myocardial ischemia and reperfusion injury.
Systematic review and meta-analysis of prolactin and iron deficiency in peripartum cardiomyopathy.
OBJECTIVES: We conducted a systematic review and meta-analysis of studies that compared levels of molecular biomarkers in women with peripartum cardiomyopathy (PPCM) to those in healthy pregnant and postpartum women to: (1) assess the evidence for prolactin (PRL) metabolism in PPCM, (2) ascertain the evidence for biomarkers of iron deficiency in PPCM, (3) identify other biomarkers associated with PPCM. METHODS: We searched Medline, Embase, Cumulated Index to Nursing and Allied Health Literature (CINAHL) and the Global Health Library from inception without language restriction for studies that compared biomarkers levels in PPCM cases to healthy controls. Pooled standardised mean difference (SMD) was generated using a random effects model for the difference in levels of biomarkers. RESULTS: Two studies assessed the association of PRL with PPCM, and reported that PPCM cases have higher levels of total PRL. No studies investigated iron metabolism in PPCM. Other biomarkers associated with PPCM included serum levels of natriuretic peptides (SMD=3.77, 95% CI 0.71 to 6.82), albumin (SMD=-0.67, 95% CI -1.01 to -0.32), C-reactive protein (SMD=1.67, 95% CI 0.22 to 3.12), selenium (SMD=-0.73, 95% CI -1.58 to 0.12), cardiac troponins (SMD=1.06, 95% CI 0.33 to 1.80), creatinine (SMD=0.51, 95% CI 0.33 to 0.69), white bloodcells (SMD=0.44, 95 % CI 0.07 to 0.82), haemoglobin (SMD=-0.45, 95% CI -0.64 to-0.26). CONCLUSIONS: More robust molecular studies are needed to explore the association between prolactin and PPCM in human subjects and to determine the extent to which iron deficiency (with or without anaemia) contributes to the risk of PPCM.
Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells.
Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours.
Compartment-based reconstruction of acquisition-weighted 31P cardiac MRSI reduces sensitivity to cardiac motion and scan planning
Motivation:31P magnetic resonance spectroscopic imaging (31P MRSI) is a powerful technique for investigating the metabolic effects of treatments for heart failure in vivo, allowing a better understanding of their mechanism of action in patient cohorts. Unfortunately, cardiac 31P MRSI is fundamentally limited by low SNR, which leads to compromises in acquisition, such as no cardiac or respiratory gating or low spatial resolution, in order to achieve reasonable scan times. Spectroscopy with linear algebra modeling (SLAM) reconstruction may be able to address these challenges and therefore improve repeatability by incorporating a segmented localizer into the reconstruction.Methods: Six healthy volunteers were scanned twice in a test–retest procedure to allow quantification of repeatability. Each scan consisted of anatomical localizers and two acquisition-weighted (AW) 31P MRSI acquisitions, which were acquired with and without cardiac gating. Five patients with heart failure with a preserved ejection fraction were then scanned with the same 31P MRSI sequence without cardiac gating. All 31P MRSI datasets were reconstructed with both conventional Fourier transform (FT)-based reconstruction and SLAM reconstruction, which were compared statistically. The effect of shifting the 31P MRSI acquisition field of view was also investigated.Results: In the healthy volunteer cohort, the spectral fit of the SLAM reconstructions had significantly improved Cramer–Rao lower bounds (CRLBs) compared to the FT-based reconstruction of non-cardiac gated data, as well as improved coefficients of variability and repeatability. The SLAM reconstruction found a significant difference in the PCr/ATP ratio between the healthy volunteer and patient cohorts, which the FT-based reconstruction did not find. Furthermore, the SLAM reconstruction was less influenced by the placement of the field of view (FOV) of the 31P MRSI acquisition in post hoc analysis.Discussion: The experimental benefits of the SLAM reconstruction for AW data were demonstrated by the improvements in fit confidence and repeatability seen in the healthy volunteer cohort and post hoc FOV analysis. The benefit of SLAM reconstruction of AW data for clinical studies was then illustrated by the patient cohort, which suggested improved sensitivity to clinically significant changes in the PCr/ATP ratio.
Printed smart devices for anti-counterfeiting allowing precise identification with household equipment.
Counterfeiting has become a serious global problem, causing worldwide losses and disrupting the normal order of society. Physical unclonable functions are promising hardware-based cryptographic primitives, especially those generated by chemical processes showing a massive challenge-response pair space. However, current chemical-based physical unclonable function devices typically require complex fabrication processes or sophisticated characterization methods with only binary (bit) keys, limiting their practical applications and security properties. Here, we report a flexible laser printing method to synthesize unclonable electronics with high randomness, uniqueness, and repeatability. Hexadecimal resistive keys and binary optical keys can be obtained by the challenge with an ohmmeter and an optical microscope. These readout methods not only make the identification process available to general end users without professional expertise, but also guarantee device complexity and data capacity. An adopted open-source deep learning model guarantees precise identification with high reliability. The electrodes and connection wires are directly printed during laser writing, which allows electronics with different structures to be realized through free design. Meanwhile, the electronics exhibit excellent mechanical and thermal stability. The high physical unclonable function performance and the widely accessible readout methods, together with the flexibility and stability, make this synthesis strategy extremely attractive for practical applications.
Enhanced Antimalarial and Antisequestration Activity of Methoxybenzenesulfonate-Modified Biopolymers and Nanoparticles for Tackling Severe Malaria.
Severe malaria is a life-threatening condition that is associated with a high mortality. Severe Plasmodium falciparum infections are mediated primarily by high parasitemia and binding of infected red blood cells (iRBCs) to the blood vessel endothelial layer, a process known as sequestration. Here, we show that including the 5-amino-2-methoxybenzenesulfonate (AMBS) chemical modification in soluble biopolymers (polyglutamic acid and heparin) and poly(acrylic acid)-exposing nanoparticles serves as a universal tool to introduce a potent parasite invasion inhibitory function in these materials. Importantly, the modification did not add or eliminated (for heparin) undesired anticoagulation activity. The materials protected RBCs from invasion by various parasite strains, employing both major entry pathways. Two further P. falciparum strains, which either expose ligands for chondroitin sulfate A (CSA) or intercellular adhesion molecule 1 (ICAM-1) on iRBCs, were tested in antisequestration assays due to their relevance in placental and cerebral malaria, respectively. Antisequestration activity was found to be more efficacious with nanoparticles vs gold-standard soluble biopolymers (CSA and heparin) against both strains, when tested on receptor-coated dishes. The nanoparticles also efficiently inhibited and reversed the sequestration of iRBCs on endothelial cells. First, the materials described herein have the potential to reduce the parasite burden by acting at the key multiplication stage of reinvasion. Second, the antisequestration ability could help remove iRBCs from the blood vessel endothelium, which could otherwise cause vessel obstruction, which in turn can lead to multiple organ failure in severe malaria infections. This approach represents a further step toward creation of adjunctive therapies for this devastating condition to reduce morbidity and mortality.
Magnetically driven formation of 3D freestanding soft bioscaffolds.
3D soft bioscaffolds have great promise in tissue engineering, biohybrid robotics, and organ-on-a-chip engineering applications. Though emerging three-dimensional (3D) printing techniques offer versatility for assembling soft biomaterials, challenges persist in overcoming the deformation or collapse of delicate 3D structures during fabrication, especially for overhanging or thin features. This study introduces a magnet-assisted fabrication strategy that uses a magnetic field to trigger shape morphing and provide remote temporary support, enabling the straightforward creation of soft bioscaffolds with overhangs and thin-walled structures in 3D. We demonstrate the versatility and effectiveness of our strategy through the fabrication of bioscaffolds that replicate the complex 3D topology of branching vascular systems. Furthermore, we engineered hydrogel-based bioscaffolds to support biohybrid soft actuators capable of walking motion triggered by cardiomyocytes. This approach opens new possibilities for shaping hydrogel materials into complex 3D morphologies, which will further empower a broad range of biomedical applications.
Layer 6b controls brain state via apical dendrites and the higher-order thalamocortical system.
The deepest layer of the cortex (layer 6b [L6b]) contains relatively few neurons, but it is the only cortical layer responsive to the potent wake-promoting neuropeptide orexin/hypocretin. Can these few neurons significantly influence brain state? Here, we show that L6b-photoactivation causes a surprisingly robust enhancement of attention-associated high-gamma oscillations and population spiking while abolishing slow waves in sleep-deprived mice. To explain this powerful impact on brain state, we investigated L6b's synaptic output using optogenetics, electrophysiology, and monoCaTChR ex vivo. We found powerful output in the higher-order thalamus and apical dendrites of L5 pyramidal neurons, via L1a and L5a, as well as in superior colliculus and L6 interneurons. L6b subpopulations with distinct morphologies and short- and long-term plasticities project to these diverse targets. The L1a-targeting subpopulation triggered powerful NMDA-receptor-dependent spikes that elicited burst firing in L5. We conclude that orexin/hypocretin-activated cortical neurons form a multifaceted, fine-tuned circuit for the sustained control of the higher-order thalamocortical system.