Topological Yang-Mills Theory with Two Fermionic Charges. A Superfield Approach on K\"ahler Manifolds

The four-dimensional topological Yang-Mills theory with two anticommuting charges is naturally formulated on K\"ahler manifolds. By using a superspace approach we clarify the structure of the Faddeev-Popov sector and determine the total action. This enables us to perform perturbation theory around any given instanton configuration by manifestly maintaining all the symmetries of the topological theory. The superspace formulation is very useful for recognizing a trivial observable (i.e. having vanishing correlation functions only) as the highest component of a gauge invariant superfield. As an example of non-trivial observables we construct the complete solution to the simultaneous cohomology problem of both fermionic charges. We also show how this solution has to be used in order to make Donaldson's interpretation possible.Comment: 41 pages, LaTeX. Section about Donaldson cohomology revised and completed. To be published in Nucl. Phys.

'Caught Between a Rock and a Hard Place': Anti-discrimination Legislation in the Liberal State and the Fate of the Australian Disability Discrimination Act

This article offers a critical analysis of some of the practical implications for disabled people of the Disability Discrimination Act of 1992. Specifically, it raises questions about politics and the role of the law as an instrument of social change?taking greater account of the interests of disabled people?on the one hand, and of the reliance of the social model of disability on a strategy based upon legal rights on the other. The article also suggests that the constraining effects of Australia's constitutional protections of rights and its federal system of government hinder the mildly progressive elements of the Disability Discrimination Act. To illustrate this, the paper employs empirical evidence to suggest that these effects have been exacerbated by the passage of the Human Rights Legislation Amendment Act in 1999

On the Behavior of the Effective QCD Coupling alpha_tau(s) at Low Scales

The hadronic decays of the tau lepton can be used to determine the effective charge alpha_tau(m^2_tau') for a hypothetical tau-lepton with mass in the range 0 < m_tau' < m_tau. This definition provides a fundamental definition of the QCD coupling at low mass scales. We study the behavior of alpha_tau at low mass scales directly from first principles and without any renormalization-scheme dependence by looking at the experimental data from the OPAL Collaboration. The results are consistent with the freezing of the physical coupling at mass scales s = m^2_tau' of order 1 GeV^2 with a magnitude alpha_tau ~ 0.9 +/- 0.1.Comment: 15 pages, 4 figures, submitted to Physical Review D, added references, some text added, no results nor figures change

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A small molecule modulator of prion protein increases human mesenchymal stem cell lifespan, ex vivo expansion, and engraftment to bone marrow in NOD/SCID mice

Human mesenchymal stem cells (hMSCs) have been shown to have potential in regenerative approaches in bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSCs lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Cellular prion protein (PrP) has been shown to enhance proliferation and promote self-renewal of hematopoietic, mammary gland, and neural stem cells. Here we show, for the first time, that expression of PrP decreased in hMSC following ex vivo expansion. When PrP expression was knocked down, hMSC showed significant reduction in proliferation and differentiation. In contrast, hMSC expanded in the presence of small molecule 3/689, a modulator of PrP expression, showed retention of PrP expression with ex vivo expansion and extended lifespan up to 10 population doublings. Moreover, cultures produced a 300-fold increase in the number of cells generated. These cells showed a 10-fold increase in engraftment levels in bone marrow 5 weeks post-transplant. hMSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression, in line with data obtained by gene expression profiling. Moreover, upregulation of superoxide dismutase-2 (SOD2) was also observed in hMSC expanded in the presence of 3/689. The increase in SOD2 was dependent on PrP expression and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target for chemical intervention in stem cell regenerative medicine