Homological algebra of twisted quiver bundles

Several important cases of vector bundles with extra structure (such as Higgs bundles and triples) may be regarded as examples of twisted representations of a finite quiver in the category of sheaves of modules on a variety/manifold/ringed space. We show that the category of such representations is an abelian category with enough injectives by constructing an explicit injective resolution. Using this explicit resolution, we find a long exact sequence that computes the Ext groups in this new category in terms of the Ext groups in the old category. The quiver formulation is directly reflected in the form of the long exact sequence. We also show that under suitable circumstances, the Ext groups are isomorphic to certain hypercohomology groups.Comment: 20 pages; v2: substantially revised version; v3: minor clarifications and correction

Dimer models and cluster categories of Grassmannians

We associate a dimer algebra A to a Postnikov diagram D (in a disk) corresponding to a cluster of minors in the cluster structure of the Grassmannian Gr(k, n). We show that A is isomorphic to the endomorphism algebra of a corresponding Cohen-Macaulay module T over the algebra B used to categorify the cluster structure of Gr(k, n) by Jensen-King-Su. It follows that B can be realised as the boundary algebra of A, that is, the subalgebra eAe for an idempotent e corresponding to the boundary of the disk. The construction and proof uses an interpretation of the diagram D, with its associated plabic graph and dual quiver (with faces), as a dimer model with boundary. We also discuss the general surface case, in particular computing boundary algebras associated to the annulus

In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells

The brain is the most complex organ in the body, controlling our highest functions, as well as regulating myriad processes which incorporate the entire physiological system. The effects of prospective therapeutic entities on the brain and central nervous system (CNS) may potentially cause significant injury, hence, CNS toxicity testing forms part of the “core battery” of safety pharmacology studies. Drug-induced seizure is a major reason for compound attrition during drug development. Currently, the rat ex vivo hippocampal slice assay is the standard option for seizure-liability studies, followed by primary rodent cultures. These models can respond to diverse agents and predict seizure outcome, yet controversy over the relevance, efficacy, and cost of these animal-based methods has led to interest in the development of human-derived models. Existing platforms often utilize rodents, and so lack human receptors and other drug targets, which may produce misleading data, with difficulties in inter-species extrapolation. Current electrophysiological approaches are typically used in a low-throughput capacity and network function may be overlooked. Human-derived induced pluripotent stem cells (iPSCs) are a promising avenue for neurotoxicity testing, increasingly utilized in drug screening and disease modeling. Furthermore, the combination of iPSC-derived models with functional techniques such as multi-electrode array (MEA) analysis can provide information on neuronal network function, with increased sensitivity to neurotoxic effects which disrupt different pathways. The use of an in vitro human iPSC-derived neural model for neurotoxicity studies, combined with high-throughput techniques such as MEA recordings, could be a suitable addition to existing pre-clinical seizure-liability testing strategies

A functorial construction of moduli of sheaves

We show how natural functors from the category of coherent sheaves on a projective scheme to categories of Kronecker modules can be used to construct moduli spaces of semistable sheaves. This construction simplifies or clarifies technical aspects of existing constructions and yields new simpler definitions of theta functions, about which more complete results can be proved.Comment: 52 pp. Dedicated to the memory of Joseph Le Potier. To appear in Inventiones Mathematicae. Slight change in the definition of the Kronecker algebra in Secs 1 (p3) and 2.2 (p6), with corresponding small alterations elsewhere, to make the constructions work for non-reduced schemes. Section 6.5 rewritten. Remark 2.6 and new references adde

Flow and retreat of the Late Quaternary Pine Island-Thwaites palaeo-ice stream, West Antarctica

Multibeam swath bathymetry and sub-bottom profiler data are used to establish constraints on the flow and retreat history of a major palaeo-ice stream that carried the combined discharge from the parts of the West Antarctic Ice Sheet now occupied by the Pine Island and Thwaites glacier basins. Sets of highly elongated bedforms show that, at the last glacial maximum, the route of the Pine Island-Thwaites palaeo-ice stream arced north-northeast following a prominent cross-shelf trough. In this area, the grounding line advanced to within similar to 68 km of, and probably reached, the shelf edge. Minimum ice thickness is estimated at 715 m on the outer shelf, and we estimate a minimum ice discharge of similar to 108 km(3) yr(-1) assuming velocities similar to today's Pine Island glacier (similar to 2.5 km yr(-1)). Additional bed forms observed in a trough northwest of Pine Island Bay likely formed via diachronous ice flows across the outer shelf and demonstrate switching ice stream behavior. The "style" of ice retreat is also evident in five grounding zone wedges, which suggest episodic deglaciation characterized by halts in grounding line migration up-trough. Stillstands occurred in association with changes in ice bed gradient, and phases of inferred rapid retreat correlate to higher bed slopes, supporting theoretical studies that show bed geometry as a control on ice margin recession. However, estimates that individual wedges could have formed within several centuries still imply a relatively rapid overall retreat. Our findings show that the ice stream channeled a substantial fraction of West Antarctica's discharge in the past, just as the Pine Island and Thwaites glaciers do today

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

\u27Struggling with Language\u27 : Indigenous movements for Linguistic Security and the Politics of Local Community

In this article, I explore the relationship between linguistic diversity and political power. Specifically, I outline some of the ways that linguistic diversity has served as a barrier to the centralization of power, thus constraining, for example, the political practice of empire-formation. A brief historical example of this dynamic is presented in the case of Spanish colonialism of the 16th-century. The article proceeds then to demonstrate how linguistic diversity remains tied to struggles against forms of domination. I argue that in contemporary indigenous movements for linguistic security, the languages themselves are not merely conceived of as the object of the political struggle, but also as the means to preserve a space for local action and deliberation – a ‘politics of local community’. I show that linguistic diversity and the devolution of political power to the local level are in a mutually reinforcing relationship. Finally, I consider the implications of this thesis for liberal theorizing on language rights, arguing that such theory cannot fully come to terms with this political-strategic dimension of language struggles

Monitoring indirect impact of COVID-19 pandemic on services for cardiovascular diseases in the UK.

OBJECTIVE: To monitor hospital activity for presentation, diagnosis and treatment of cardiovascular diseases during the COVID-19) pandemic to inform on indirect effects. METHODS: Retrospective serial cross-sectional study in nine UK hospitals using hospital activity data from 28 October 2019 (pre-COVID-19) to 10 May 2020 (pre-easing of lockdown) and for the same weeks during 2018-2019. We analysed aggregate data for selected cardiovascular diseases before and during the epidemic. We produced an online visualisation tool to enable near real-time monitoring of trends. RESULTS: Across nine hospitals, total admissions and emergency department (ED) attendances decreased after lockdown (23 March 2020) by 57.9% (57.1%-58.6%) and 52.9% (52.2%-53.5%), respectively, compared with the previous year. Activity for cardiac, cerebrovascular and other vascular conditions started to decline 1-2 weeks before lockdown and fell by 31%-88% after lockdown, with the greatest reductions observed for coronary artery bypass grafts, carotid endarterectomy, aortic aneurysm repair and peripheral arterial disease procedures. Compared with before the first UK COVID-19 (31 January 2020), activity declined across diseases and specialties between the first case and lockdown (total ED attendances relative reduction (RR) 0.94, 0.93-0.95; total hospital admissions RR 0.96, 0.95-0.97) and after lockdown (attendances RR 0.63, 0.62-0.64; admissions RR 0.59, 0.57-0.60). There was limited recovery towards usual levels of some activities from mid-April 2020. CONCLUSIONS: Substantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently