Instability of supersymmetric microstate geometries

We investigate the classical stability of supersymmetric, asymptotically flat, microstate geometries with five non-compact dimensions. Such geometries admit an "evanescent ergosurface": a timelike hypersurface of infinite redshift. On such a surface, there are null geodesics with zero energy relative to infinity. These geodesics are stably trapped in the potential well near the ergosurface. We present a heuristic argument indicating that this feature is likely to lead to a nonlinear instability of these solutions. We argue that the precursor of such an instability can be seen in the behaviour of linear perturbations: nonlinear stability would require that all linear perturbations decay sufficiently rapidly but the stable trapping implies that some linear perturbation decay very slowly. We study this in detail for the most symmetric microstate geometries. By constructing quasinormal modes of these geometries we show that generic linear perturbations decay slower than any inverse power of time.This work was supported by European Research Council grant ERC-2011-StG279363-HiDGR.This is the final version of the article. It first appeared from Springer via https://doi.org/10.1007/JHEP10(2016)03

Evidence Associated with the Use of Oxazolidinones for the Treatment of Skin and Skin Structure Infections: A Retrospective Study

INTRODUCTION: Skin and skin structure infections are an increasing cause of hospitalization. Although mortality is relatively low, skin and skin structure infections are associated with prolonged hospital length of stay and high costs. Oxazolidinones have been suggested as a tool to treat infected patients in the ambulatory setting in order to decrease hospital length of stay. We wanted to address the evidence associated with the use of oxazolidinones in the treatment of skin and skin structure infections. MATERIAL AND METHODS: In this observational retrospective study we analyzed the anonymized diagnosis related group coded information from the Portuguese database for hospital admissions, that included all adult patients with a diagnosis of oxazolidinone use and a SSSI, discharged between 2010 and 2015. RESULTS: During the study period, a total of 5518 patients had a diagnosis of oxazolidinone treatment. We selected 483 of those who were also diagnosed with a skin and skin structure infections. Their mean age was 64.9 years and 62.7% were male. The median hospital length of stay was 27 days (Inter quartile range 13 - 56) and the mortality rate was 12.6%. The prevalence of secondary anemia and of thrombocytopenia in the whole group treated with oxazolidinones was 2.5% and 3%, respectively. DISCUSSION: Despite the high bioavailability of oxazolidinones, we were not able to find evidence that its use was associated with a decrease of mortality or hospital length of stay (due to early discharge) of patients with skin and skin structure infections. CONCLUSION: In this study we were not able to find evidence that oxazolidinones had any clinically significant benefit. A structured approach, including antibiotics with favorable pharmacokinetic and safety profile as well as a carefully planned ambulatory follow up may be needed.info:eu-repo/semantics/publishedVersio

An instability of higher-dimensional rotating black holes

We present the first example of a linearized gravitational instability of an asymptotically flat vacuum black hole. We study perturbations of a Myers-Perry black hole with equal angular momenta in an odd number of dimensions. We find no evidence of any instability in five or seven dimensions, but in nine dimensions, for sufficiently rapid rotation, we find perturbations that grow exponentially in time. The onset of instability is associated with the appearance of time-independent perturbations which generically break all but one of the rotational symmetries. This is interpreted as evidence for the existence of a new 70-parameter family of black hole solutions with only a single rotational symmetry. We also present results for the Gregory-Laflamme instability of rotating black strings, demonstrating that rotation makes black strings more unstable.Comment: 38 pages, 13 figure

New formulation of an old drug in hypertension treatment: the sustained release of captopril from cyclodextrin nanoparticles

Captopril (CAP) was the first angiotensin I-converting enzyme (ACE) inhibitor to be developed and is widely used in hypertension treatment. On the other hand, cyclodextrins (CDs) are cyclic oligosaccharides whose cone-shaped cavity allows formation of noncovalent inclusion complexes with appropriately sized guest molecules, thus modifying guest physical, chemical, and biological properties. Herein, the physicochemical characterization and in vivo ACE inhibition evaluation of seven CAP/CD complexes are reported. The inclusion complexes were prepared by spray-drying, freeze-drying, kneading, or lyophilization methods and characterized by nuclear magnetic resonance, Fourier-transformed infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy techniques. In vivo assays compared CAP and CAP/CD complex administration (0.5 mg kg−1 or 0.09 mg kg−1, n = 4–7) to evaluate the ACE inhibition by continuous infusion of angiotensin I (30 ng 50 μL−1 min−1) in conscious Wistar rats. The physicochemical analysis demonstrated complete amorphization and complexation between CAP and CDs, indicating the substitution of water molecules inside the CD cavity with CAP. During the infusion of angiotensin I, the administration of all CAP/CD complexes induced a reduction in mean arterial pressure similar to that observed upon CAP administration. The nanoparticles obtained by the kneading method (CAP/α-CD:KM) showed a potent and long-lasting inhibitory activity (∼22 hours) on the angiotensin I pressor effect. The results suggest that the inclusion complex of CAP and α-CD can function as a novel antihypertensive formulation that may improve therapeutic use of CAP by reducing its oral dose administration to once per day, thus providing better quality of life for almost 25% of the world’s population who suffer from hypertension

No time to rest: How the effects of climate change on nest decay threaten the conservation of apes in the wild

Since 1994, IUCN Red List assessments apply globally acknowledged standards to assess species distribution, abundance and trends. The extinction risk of a species has a major impact on conservation science and international funding mechanisms. Great ape species are listed as Endangered or Critically Endangered. Their populations are often assessed using their unique habit of constructing sleeping platforms, called nests. As nests rather than apes are counted, it is necessary to know the time it takes for nests to disappear to convert nest counts into ape numbers. However, nest decomposition is highly variable across sites and time and the factors involved are poorly understood. Here, we used 1,511 bonobo (Pan paniscus) nests and 15 years of climatic data (2003–2018) from the research site LuiKotale, Democratic Republic of the Congo, to investigate the effects of climate change and behavioural factors on nest decay time, using a Bayesian gamma survival model. We also tested the logistic regression method, a recommended time-efficient option for estimating nest decay time. Our climatic data showed a decreasing trend in precipitation across the 15 years of study. We found bonobo nests to have longer decay times in recent years. While the number of storms was the main factor driving nest decay time, nest construction type and tree species used were also important. We also found evidence for bonobo nesting behaviour being adapted to climatic conditions, namely strengthening the nest structure in response to unpredictable, harsh precipitation. By highlighting methodological caveats, we show that logistic regression is effective in estimating nest decay time under certain conditions. Our study reveals the impact of climate change on nest decay time in a tropical remote area. Failure to account for these changes would invalidate biomonitoring estimates of global significance, and subsequently jeopardize the conservation of great apes in the wild

Ultraspinning instability: the missing link

We study linearized perturbations of Myers-Perry black holes in d=7, with two of the three angular momenta set to be equal, and show that instabilities always appear before extremality. Analogous results are expected for all higher odd d. We determine numerically the stationary perturbations that mark the onset of instability for the modes that preserve the isometries of the background. The onset is continuously connected between the previously studied sectors of solutions with a single angular momentum and solutions with all angular momenta equal. This shows that the near-extremality instabilities are of the same nature as the ultraspinning instability of d>5 singly-spinning solutions, for which the angular momentum is unbounded. Our results raise the question of whether there are any extremal Myers-Perry black holes which are stable in d>5.Comment: 19 pages. 1 figur

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

Rituximab in refractory Vogt–Koyanagi–Harada disease

IntroductionVogt–Koyanagi–Harada (VKH) prognosis depends on early recognition and treatment; chronic disease may be developed when either delayed or inadequate treatment is performed, whereas other cases despite correct treatment are refractory to different drugs and also become chronic. We report a case of refractory VKH controlled with rituximab treatment.Case reportA 41-year-old female with painful visual loss and headache was examined. (VA 0.4 in RE and hand movements (HM) in LE). Retinal examination demonstrated multiple serous retinal detachments in both eyes. High-dose oral steroids were started, followed by progressive tapering of prednisone. New acute anterior and posterior relapses were achieved, and other immunommodulators were progressively added—new high-dose steroid treatment, adalimumab, cyclosporine, and methotrexate—but patient had new anterior and posterior recurrences associated with tinnitus and headache. Thus, an infusion of 1 g of rituximab was administered after 15 months follow-up; the VA was 0.2 in RE and counting fingers in LE. Three additional doses of 1 g each were administered 1, 6, and 16 months later. We have achieved a final VA after 34 months follow-up of 0.2 in RE and HM in LE, with definitive control of inflammation, without acute relapses since rituximab was administered.ConclusionAfter searching PubMed/Medline, this is the first report of VKH disease treated with rituximab. Additional studies are warranted to confirm the efficacy of this new approach for inflammatory control in refractory cases of VKH disease

The Mechanisms of Codon Reassignments in Mitochondrial Genetic Codes

Many cases of non-standard genetic codes are known in mitochondrial genomes. We carry out analysis of phylogeny and codon usage of organisms for which the complete mitochondrial genome is available, and we determine the most likely mechanism for codon reassignment in each case. Reassignment events can be classified according to the gain-loss framework. The gain represents the appearance of a new tRNA for the reassigned codon or the change of an existing tRNA such that it gains the ability to pair with the codon. The loss represents the deletion of a tRNA or the change in a tRNA so that it no longer translates the codon. One possible mechanism is Codon Disappearance, where the codon disappears from the genome prior to the gain and loss events. In the alternative mechanisms the codon does not disappear. In the Unassigned Codon mechanism, the loss occurs first, whereas in the Ambiguous Intermediate mechanism, the gain occurs first. Codon usage analysis gives clear evidence of cases where the codon disappeared at the point of the reassignment and also cases where it did not disappear. Codon disappearance is the probable explanation for stop to sense reassignments and a small number of reassignments of sense codons. However, the majority of sense to sense reassignments cannot be explained by codon disappearance. In the latter cases, by analysis of the presence or absence of tRNAs in the genome and of the changes in tRNA sequences, it is sometimes possible to distinguish between the Unassigned Codon and Ambiguous Intermediate mechanisms. We emphasize that not all reassignments follow the same scenario and that it is necessary to consider the details of each case carefully.Comment: 53 pages (45 pages, including 4 figures + 8 pages of supplementary information). To appear in J.Mol.Evo

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel