49 research outputs found
Multi-omics integration reveals molecular networks and regulators of psoriasis.
BackgroundPsoriasis is a complex multi-factorial disease, involving both genetic susceptibilities and environmental triggers. Genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) have been carried out to identify genetic and epigenetic variants that are associated with psoriasis. However, these loci cannot fully explain the disease pathogenesis.MethodsTo achieve a comprehensive mechanistic understanding of psoriasis, we conducted a systems biology study, integrating multi-omics datasets including GWAS, EWAS, tissue-specific transcriptome, expression quantitative trait loci (eQTLs), gene networks, and biological pathways to identify the key genes, processes, and networks that are genetically and epigenetically associated with psoriasis risk.ResultsThis integrative genomics study identified both well-characterized (e.g., the IL17 pathway in both GWAS and EWAS) and novel biological processes (e.g., the branched chain amino acid catabolism process in GWAS and the platelet and coagulation pathway in EWAS) involved in psoriasis. Finally, by utilizing tissue-specific gene regulatory networks, we unraveled the interactions among the psoriasis-associated genes and pathways in a tissue-specific manner and detected potential key regulatory genes in the psoriasis networks.ConclusionsThe integration and convergence of multi-omics signals provide deeper and comprehensive insights into the biological mechanisms associated with psoriasis susceptibility
Single cell molecular alterations reveal target cells and pathways of concussive brain injury.
The complex neuropathology of traumatic brain injury (TBI) is difficult to dissect, given the convoluted cytoarchitecture of affected brain regions such as the hippocampus. Hippocampal dysfunction during TBI results in cognitive decline that may escalate to other neurological disorders, the molecular basis of which is hidden in the genomic programs of individual cells. Using the unbiased single cell sequencing method Drop-seq, we report that concussive TBI affects previously undefined cell populations, in addition to classical hippocampal cell types. TBI also impacts cell type-specific genes and pathways and alters gene co-expression across cell types, suggesting hidden pathogenic mechanisms and therapeutic target pathways. Modulating the thyroid hormone pathway as informed by the T4 transporter transthyretin Ttr mitigates TBI-associated genomic and behavioral abnormalities. Thus, single cell genomics provides unique information about how TBI impacts diverse hippocampal cell types, adding new insights into the pathogenic pathways amenable to therapeutics in TBI and related disorders
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Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes.
Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adipocyte RNA-sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function
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IDOL regulates systemic energy balance through control of neuronal VLDLR expression.
Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity
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Thyroid hormone T4 mitigates traumatic brain injury in mice by dynamically remodeling cell type specific genes, pathways, and networks in hippocampus and frontal cortex
The complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Thyroxine (T4) administration has been shown to prevent the cognitive impairments induced by mTBI in mice but the mechanism is poorly understood. To understand the underlying mechanism, we carried out a single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages in a mouse model of mTBI. We found that T4 treatment altered the proportions and transcriptomes of numerous cell types across tissues and timepoints, particularly oligodendrocytes, astrocytes, and microglia, which are crucial for injury repair. T4 also reversed the expression of mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, and Myo3a, as well as numerous pathways such as cell/energy/iron metabolism, immune response, nervous system, and cytoskeleton-related pathways. Cell-type specific network modeling revealed that T4 mitigated select mTBI-perturbed dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in oligodendrocytes. Cross cell-type ligand-receptor networks revealed the roles of App, Hmgb1, Fn1, and Tnf in mTBI, with the latter two ligands having been previously identified as TBI network hubs. mTBI and/or T4 signature genes were enriched for human genome-wide association study (GWAS) candidate genes for cognitive, psychiatric and neurodegenerative disorders related to mTBI. Our systems-level single cell analysis elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications as the mechanisms through which T4 mitigates cognitive dysfunction induced by mTBI
Whiteness and diasporic Irishness: nation, gender and class
Whiteness is often detached from the notion of diaspora in the recent flurry of interest in the phenomenon, yet it is a key feature of some of the largest and oldest displacements. This paper explores the specific contexts of white racial belonging and status over two centuries in two main destinations of the Irish diaspora, the USA and Britain. Its major contribution is a tracing of the untold story of ‘How the Irish became white in Britain’ to parallel and contrast with the much more fully developed narrative in the USA. It argues that, contrary to popular belief, the racialisation of the Irish in England did not fade away at the end of the nineteenth century but became transmuted in new forms which have continued to place the ‘white’ Irish outside the boundaries of the English nation. These have been strangely ignored by social scientists, who conflate Irishness and working-class identities in England without acknowledging the distinctive contribution of Irish backgrounds to constructions of class difference. Gender locates Irish women and men differently in relation to these class positions, for example allowing mothers to be blamed for the perpetuation of the underclass. Class and gender are also largely unrecognised dimensions of Irish ethnicity in the USA, where the presence of ‘poor white’ neighbourhoods continues to challenge the iconic story of Irish upward mobility. Irishness thus remains central to the construction of mainstream ‘white’ identities in both the USA and Britain into the twenty-first century
Liberal Neutrality and Charitable Purposes
Under UK charity law, organisations seeking charitable status must demonstrate, inter alia, that they will pursue a purpose the state deems ‘charitable’. Such purposes inevitably reflect conceptions of the good, thus it is argued here that the state, in granting charitable status, affirms the value of ideas about the good; it indicates that a set of conceptions of the good are worthy of special advantages that are not provided for the pursuit of other conceptions. The designation of charitable status appears to be at odds with liberal neutrality, which argues that the state should not pursue, promote or pass judgement on particular conceptions of the good. In short, there is a prima facie tension between the general liberal neutrality doctrine and charity law. Yet liberal neutralists have not addressed this policy area. This article surveys the grounds for reconciliation between some conceptions of liberal neutrality and the present charity law. ‘Neutrality of effect’ addresses some concerns but its implications for charity law are not in accord with the general practice and principles regarding charities. Barry's process of abstraction is argued to be untenable as a policy option for charities. The article concludes that in so far as one is neutralist, ‘neutrality of justification’ in the form of neutral goods provides the most plausible account of charity law. However, such an account entails alterations to the existing legislation that one may view as a failure to account for well-established, legitimate principles and traditions in charity law. </jats:p