Pilot evaluation of risk assessment and enhanced protocols regarding contacts at an international professional golf event

Objectives The aim of this study was to assess whether a risk assessment and managed risk approach to contact tracing was practical and feasible at the Gran Canaria Lopesan Open 2021 and could inform further pilot work regarding disease transmission during elite sporting events. Methods This prospective cohort study included all international attendees. All participants required a minimum of one negative reverse transcriptase PCR (RT-PCR) test prior to travelling to each tournament. High-risk contacts were isolated for 10 days. Moderate-risk contacts received education regarding enhanced medical surveillance, had daily rapid antigen testing for 5 days, with RT-PCR day 5, mandated mask use and access to outside space for work purposes only. Low-risk contacts received rapid antigen testing every 48 hours and PCR testing on day 5. Results A total of 550 persons were accredited and were required to undergo RT-PCR testing before the event. Two of these tests were positive (0.36%). Of these, case 1 had 1 high, 23 moderate and 48 low-risk contacts. Case 2 did not have any significant travel history within 2 days of positive test and had one high-risk contact. There were no further positive tests on site in the wider cohort of attendees, from a total of 872 RT-PCR and 198 rapid antigen tests. Conclusions This pilot study showed it is practical, feasible and well accepted to provide enhanced (daily) virus testing and risk-mitigating measures at a professional golf event. Further study is required to assess the efficacy of these interventions; however, no transmission was found in this pilot study

Analysis of circulating protein aggregates as a route of investigation into neurodegenerative disorders.

Plasma proteome composition reflects the inflammatory and metabolic state of the organism and can be predictive of system-level and organ-specific pathologies. Circulating protein aggregates are enriched with neurofilament heavy chain-axonal proteins involved in brain aggregate formation and recently identified as biomarkers of the fatal neuromuscular disorder amyotrophic lateral sclerosis. Using unbiased proteomic methods, we have fully characterized the content in neuronal proteins of circulating protein aggregates from amyotrophic lateral sclerosis patients and healthy controls, with reference to brain protein aggregate composition. We also investigated circulating protein aggregate protein aggregation propensity, stability to proteolytic digestion and toxicity for neuronal and endothelial cell lines. Circulating protein aggregates separated by ultracentrifugation are visible as electron-dense macromolecular particles appearing as either large globular or as small filamentous formations. Analysis by mass spectrometry revealed that circulating protein aggregates obtained from patients are enriched with proteins involved in the proteasome system, possibly reflecting the underlying basis of dysregulated proteostasis seen in the disease, while those from healthy controls show enrichment of proteins involved in metabolism. Compared to the whole human proteome, proteins within circulating protein aggregates and brain aggregates show distinct chemical features of aggregation propensity, which appear dependent on the tissue or fluid of origin and not on the health status. Neurofilaments' two high-mass isoforms (460 and 268 kDa) showed a strong differential expression in amyotrophic lateral sclerosis compared to healthy control circulating protein aggregates, while aggregated neurofilament heavy chain was also partially resistant to enterokinase proteolysis in patients, demonstrated by immunoreactive bands at 171 and 31 kDa fragments not seen in digested healthy controls samples. Unbiased proteomics revealed that a total of 4973 proteins were commonly detected in circulating protein aggregates and brain, including 24 expressed from genes associated with amyotrophic lateral sclerosis. Interestingly, 285 circulating protein aggregate proteins (5.7%) were regulated (P < 0.05) and are present in biochemical pathways linked to disease pathogenesis and protein aggregation. Biologically, circulating protein aggregates from both patients and healthy controls had a more pronounced effect on the viability of hCMEC/D3 endothelial and PC12 neuronal cells compared to immunoglobulins extracted from the same plasma samples. Furthermore, circulating protein aggregates from patients exerted a more toxic effect than healthy control circulating protein aggregates on both cell lines at lower concentrations (P: 0.03, in both cases). This study demonstrates that circulating protein aggregates are significantly enriched with brain proteins which are representative of amyotrophic lateral sclerosis pathology and a potential source of biomarkers and therapeutic targets for this incurable disorder

Let Bengal be Heard: Dealing with Covid and Cyclone Amphan together

Reeling under the double burden of a biological and a natural disaster, West Bengal needs civil society mobilization in terms of both local and global synergy to rebuild the state and its economy. By acknowledging the lack of constitutional clarity regarding ‘disaster’ and hence the inherently conflicting centre-state relationship over disaster management, this paper argues that exclusive dependency on the government will yield no result at this hour. What is needed is a partnership between government and private initiatives and the civil society, especially the Bengal diaspora

Black Holes as Effective Geometries

Gravitational entropy arises in string theory via coarse graining over an underlying space of microstates. In this review we would like to address the question of how the classical black hole geometry itself arises as an effective or approximate description of a pure state, in a closed string theory, which semiclassical observers are unable to distinguish from the "naive" geometry. In cases with enough supersymmetry it has been possible to explicitly construct these microstates in spacetime, and understand how coarse-graining of non-singular, horizon-free objects can lead to an effective description as an extremal black hole. We discuss how these results arise for examples in Type II string theory on AdS_5 x S^5 and on AdS_3 x S^3 x T^4 that preserve 16 and 8 supercharges respectively. For such a picture of black holes as effective geometries to extend to cases with finite horizon area the scale of quantum effects in gravity would have to extend well beyond the vicinity of the singularities in the effective theory. By studying examples in M-theory on AdS_3 x S^2 x CY that preserve 4 supersymmetries we show how this can happen.Comment: Review based on lectures of JdB at CERN RTN Winter School and of VB at PIMS Summer School. 68 pages. Added reference

Kerr/CFT, dipole theories and nonrelativistic CFTs

We study solutions of type IIB supergravity which are SL(2,R) x SU(2) x U(1)^2 invariant deformations of AdS_3 x S^3 x K3 and take the form of products of self-dual spacelike warped AdS_3 and a deformed three-sphere. One of these backgrounds has been recently argued to be relevant for a derivation of Kerr/CFT from string theory, whereas the remaining ones are holographic duals of two-dimensional dipole theories and their S-duals. We show that each of these backgrounds is holographically dual to a deformation of the DLCQ of the D1-D5 CFT by a specific supersymmetric (1,2) operator, which we write down explicitly in terms of twist operators at the free orbifold point. The deforming operator is argued to be exactly marginal with respect to the zero-dimensional nonrelativistic conformal (or Schroedinger) group - which is simply SL(2,R)_L x U(1)_R. Moreover, in the supergravity limit of large N and strong coupling, no other single-trace operators are turned on. We thus propose that the field theory duals to the backgrounds of interest are nonrelativistic CFTs defined by adding the single Schroedinger-invariant (1,2) operator mentioned above to the original CFT action. Our analysis indicates that the rotating extremal black holes we study are best thought of as finite right-moving temperature (non-supersymmetric) states in the above-defined supersymmetric nonrelativistic CFT and hints towards a more general connection between Kerr/CFT and two-dimensional non-relativistic CFTs.Comment: 48+8 pages, 4 figures; minor corrections and references adde

Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma

Epigenetic mechanisms which play an essential role in normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC) are also responsible for some of the changes in the glioblastoma (GBM) genome. Here we develop a strategy to compare the epigenetic and transcriptional make-up of primary GBM cells (GIC) with patient-matched expanded potential stem cell (EPSC)-derived NSC (iNSC). Using a comparative analysis of the transcriptome of syngeneic GIC/iNSC pairs, we identify a glycosaminoglycan (GAG)-mediated mechanism of recruitment of regulatory T cells (Tregs) in GBM. Integrated analysis of the transcriptome and DNA methylome of GBM cells identifies druggable target genes and patient-specific prediction of drug response in primary GIC cultures, which is validated in 3D and in vivo models. Taken together, we provide a proof of principle that this experimental pipeline has the potential to identify patient-specific disease mechanisms and druggable targets in GBM

A bound on the entropy of supergravity?

We determine, in two independent ways, the number of BPS quantum states arising from supergravity degrees of freedom in a system with fixed total D4D0 charge. First, we count states generated by quantizing the spacetime degrees of freedom of 'entropyless' multicentered solutions consisting of anti-D0-branes bound to a D6-anti-D6 pair. Second, we determine the number of free supergravity excitations of the corresponding AdS_3 geometry with the same total charge. We find that, although these two approaches yield a priori different sets of states, the leading degeneracies in a large charge expansion are equal to each other and that, furthermore, the number of such states is parametrically smaller than that arising from the D4D0 black hole's entropy. This strongly suggests that supergravity alone is not sufficient to capture all degrees of freedom of large supersymmetric black holes. Comparing the free supergravity calculation to that of the D6-anti-D6-D0 system we find that the bound on the free spectrum imposed by the stringy exclusion principle (a unitarity bound in the dual CFT) seems to be captured in the dynamics of the fully interacting but classcial supergravity equations of motion.Comment: 33 pages, 5 figure

Widespread Expression of BORIS/CTCFL in Normal and Cancer Cells

BORIS (CTCFL) is the paralog of CTCF (CCCTC-binding factor; NM_006565), a ubiquitously expressed DNA-binding protein with diverse roles in gene expression and chromatin organisation. BORIS and CTCF have virtually identical zinc finger domains, yet display major differences in their respective C- and N-terminal regions. Unlike CTCF, BORIS expression has been reported only in the testis and certain malignancies, leading to its classification as a “cancer-testis” antigen. However, the expression pattern of BORIS is both a significant and unresolved question in the field of DNA binding proteins. Here, we identify BORIS in the cytoplasm and nucleus of a wide range of normal and cancer cells. We compare the localization of CTCF and BORIS in the nucleus and demonstrate enrichment of BORIS within the nucleolus, inside the nucleolin core structure and adjacent to fibrillarin in the dense fibrillar component. In contrast, CTCF is not enriched in the nucleolus. Live imaging of cells transiently transfected with GFP tagged BORIS confirmed the nucleolar accumulation of BORIS. While BORIS transcript levels are low compared to CTCF, its protein levels are readily detectable. These findings show that BORIS expression is more widespread than previously believed, and suggest a role for BORIS in nucleolar function

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Quantizing N=2 Multicenter Solutions

N=2 supergravity in four dimensions, or equivalently N=1 supergravity in five dimensions, has an interesting set of BPS solutions that each correspond to a number of charged centers. This set contains black holes, black rings and their bound states, as well as many smooth solutions. Moduli spaces of such solutions carry a natural symplectic form which we determine, and which allows us to study their quantization. By counting the resulting wavefunctions we come to an independent derivation of some of the wall-crossing formulae. Knowledge of the explicit form of these wavefunctions allows us to find quantum resolutions to some apparent classical paradoxes such as solutions with barely bound centers and those with an infinitely deep throat. We show that quantum effects seem to cap off the throat at a finite depth and we give an estimate for the corresponding mass gap in the dual CFT. This is an interesting example of a system where quantum effects cannot be neglected at macroscopic scales even though the curvature is everywhere small.Comment: 49 pages + appendice