1,235 research outputs found
Counterfactual reasoning and knowledge of possibilities
Williamson has argued against scepticism concerning our metaphysically modal knowledge, by arguing that standard patterns of suppositional reasoning to counterfactual conclusions provide reliable sources of correct ascriptions of possibility and necessity. The paper argues that, while Williamson’s claims relating to necessity may well be right, he has not provided adequate reasons for thinking that the familiar modes of counterfactual reasoning to which he points generalise to provide a decent route to ascriptions of possibility. The paper also explores another path to ascriptions of possibility that may be extracted from Williamson’s ideas, before briefly considering the general status of counterfactual reasoning in relation to our knowledge of possibilities
Recommended from our members
Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.
A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing
A validation of the Oswestry Spinal Risk Index
Purpose
The purpose of this study was to validate the Oswestry Spinal Risk Index (OSRI) in an external population. The OSRI predicts survival in patients with metastatic spinal cord compression (MSCC).
Methods
We analysed the data of 100 patients undergoing surgical intervention for MSCC at a tertiary spinal unit and recorded the primary tumour pathology and Karnofsky performance status to calculate the OSRI. Logistic regression models and survival plots were applied to the data in accordance with the original paper.
Results
Lower OSRI scores predicted longer survival. The OSRI score predicted survival accurately in 74% of cases (p = 0.004).
Conclusions
Our study has found that the OSRI is a significant predictor of survival at levels similar to those of the original authors and is a useful and simple tool in aiding complex decision making in patients presenting with MSC
Phase transitions and critical behavior of black branes in canonical ensemble
We study the thermodynamics and phase structure of asymptotically flat
non-dilatonic as well as dilatonic black branes in a cavity in arbitrary
dimensions (). We consider the canonical ensemble and so the charge inside
the cavity and the temperature at the wall are fixed. We analyze the stability
of the black brane equilibrium states and derive the phase structures. For the
zero charge case we find an analog of Hawking-Page phase transition for these
black branes in arbitrary dimensions. When the charge is non-zero, we find that
below a critical value of the charge, the phase diagram has a line of
first-order phase transition in a certain range of temperatures which ends up
at a second order phase transition point (critical point) as the charge attains
the critical value. We calculate the critical exponents at that critical point.
Although our discussion is mainly concerned with the non-dilatonic branes, we
show how it easily carries over to the dilatonic branes as well.Comment: 37 pages, 6 figures, the validity of using the effective action
discussed, references adde
Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling
Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.NWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]info:eu-repo/semantics/publishedVersio
Positional cloning of rp2 QTL associates the P450 genes CYP6Z1, CYP6Z3 and CYP6M7 with pyrethroid resistance in the malaria vector Anopheles funestus
Pyrethroid resistance in Anopheles funestus is threatening malaria control in Africa. Elucidation of underlying resistance mechanisms is crucial to improve the success of future control programs. A positional cloning approach was used to identify genes conferring resistance in the uncharacterised rp2 quantitative trait locus (QTL) previously detected in this vector using F6 advanced intercross lines (AIL). A 113 kb BAC clone spanning rp2 was identified and sequenced revealing a cluster of 15 P450 genes and one salivary protein gene (SG7-2). Contrary to A. gambiae, AfCYP6M1 is triplicated in A. funestus, while AgCYP6Z2 orthologue is absent. Five hundred and sixty-five new single nucleotide polymorphisms (SNPs)were identified for genetic mapping from rp2 P450s and other genes revealing high genetic polymorphisms with one SNP every 36 bp. A significant genotype/phenotype association was detected for rp2 P450s but not for a cluster of cuticular
protein genes previously associated with resistance in A. gambiae. QTL mapping using F6 AIL confirms the rp2 QTL with
an increase logarithm of odds score of 5. Multiplex gene expression profiling of 15 P450s and other genes around rp2
followed by individual validation using qRT–PCR indicated a significant overexpression in the resistant FUMOZ-R strain of the P450s AfCYP6Z1, AfCYP6Z3, AfCYP6M7 and the glutathione-s-transferase GSTe2 with respective fold change of 11.2,6.3, 5.5 and 2.8. Polymorphisms analysis of AfCYP6Z1 and AfCYP6Z3 identified amino acid changes potentially associated with resistance further indicating that these genes are controlling the pyrethroid resistance explained by the rp2 QTL. The characterisation of this rp2 QTL significantly improves our understanding of resistance mechanisms in A. funestus
Phase structure of black branes in grand canonical ensemble
This is a companion paper of our previous work [1] where we studied the
thermodynamics and phase structure of asymptotically flat black -branes in a
cavity in arbitrary dimensions in a canonical ensemble. In this work we
study the thermodynamics and phase structure of the same in a grand canonical
ensemble. Since the boundary data in two cases are different (for the grand
canonical ensemble boundary potential is fixed instead of the charge as in
canonical ensemble) the stability analysis and the phase structure in the two
cases are quite different. In particular, we find that there exists an analog
of one-variable analysis as in canonical ensemble, which gives the same
stability condition as the rather complicated known (but generalized from black
holes to the present case) two-variable analysis. When certain condition for
the fixed potential is satisfied, the phase structure of charged black
-branes is in some sense similar to that of the zero charge black -branes
in canonical ensemble up to a certain temperature. The new feature in the
present case is that above this temperature, unlike the zero-charge case, the
stable brane phase no longer exists and `hot flat space' is the stable phase
here. In the grand canonical ensemble there is an analog of Hawking-Page
transition, even for the charged black -brane, as opposed to the canonical
ensemble. Our study applies to non-dilatonic as well as dilatonic black
-branes in space-time dimensions.Comment: 32 pages, 2 figures, various points refined, discussion expanded,
references updated, typos corrected, published in JHEP 1105:091,201
Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.
AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to β subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only
Genomic Footprints of Selective Sweeps from Metabolic Resistance to Pyrethroids in African Malaria Vectors Are Driven by Scale up of Insecticide-Based Vector Control
Insecticide resistance in mosquito populations threatens recent successes in malaria prevention. Elucidating patterns of genetic structure in malaria vectors to predict the speed and direction of the spread of resistance is essential to get ahead of the `resistance curve' and to avert a public health catastrophe. Here, applying a combination of microsatellite analysis, whole genome sequencing and targeted sequencing of a resistance locus, we elucidated the continent-wide population structure of a major African malaria vector, Anopheles funestus. We identified a major selective sweep in a genomic region controlling cytochrome P450-based metabolic resistance conferring high resistance to pyrethroids. This selective sweep occurred since 2002, likely as a direct consequence of scaled up vector control as revealed by whole genome and fine-scale sequencing of pre- and post-intervention populations. Fine-scaled analysis of the pyrethroid resistance locus revealed that a resistanceassociated allele of the cytochrome P450 monooxygenase CYP6P9a has swept through southern Africa to near fixation, in contrast to high polymorphism levels before interventions, conferring high levels of pyrethroid resistance linked to control failure. Population structure analysis revealed a barrier to gene flow between southern Africa and other areas, which may prevent or slow the spread of the southern mechanism of pyrethroid resistance to other regions. By identifying a genetic signature of pyrethroid-based interventions, we have demonstrated the intense selective pressure that control interventions exert on mosquito populations. If this level of selection and spread of resistance continues unabated, our ability to control malaria with current interventions will be compromised
High energy emission from microquasars
The microquasar phenomenon is associated with the production of jets by X-ray
binaries and, as such, may be associated with the majority of such systems. In
this chapter we briefly outline the associations, definite, probable, possible,
and speculative, between such jets and X-ray, gamma-ray and particle emission.Comment: Contributing chapter to the book Cosmic Gamma-Ray Sources, K.S. Cheng
and G.E. Romero (eds.), to be published by Kluwer Academic Publishers,
Dordrecht, 2004. (19 pages
- …