4,368 research outputs found
Indestructibility of Vopenka's Principle
We show that Vopenka's Principle and Vopenka cardinals are indestructible
under reverse Easton forcing iterations of increasingly directed-closed partial
orders, without the need for any preparatory forcing. As a consequence, we are
able to prove the relative consistency of these large cardinal axioms with a
variety of statements known to be independent of ZFC, such as the generalised
continuum hypothesis, the existence of a definable well-order of the universe,
and the existence of morasses at many cardinals.Comment: 15 pages, submitted to Israel Journal of Mathematic
The early X-ray afterglows of optically bright and dark Gamma-Ray Bursts
A systematical study on the early X-ray afterglows of both optically bright
and dark gamma-ray bursts (B-GRBs and D-GRBs) observed by Swift has been
presented. Our sample includes 25 GRBs. Among them 13 are B-GRBs and 12 are
D-GRBs. Our results show that the distributions of the X-ray afterglow fluxes
(), the gamma-ray fluxes (), and the ratio ()
for both the D-GRBs and B-GRBs are similar. The differences of these
distributions for the two kinds of GRBs should be statistical fluctuation.
These results indicate that the progenitors of the two kinds of GRBs are the
same population. Their total energy explosions are comparable. The suppression
of the optical emissions from D-GRBs should results from circumburst but not
their central engine.Comment: 10 pages, 3 figures, 1 table; accepted by ChJA
The prosequence of procaricain forms an α-helical domain that prevents access to the substrate-binding cleft
AbstractBackground Cysteine proteases are involved in a variety of cellular processes including cartilage degradation in arthritis, the progression of Alzheimer's disease and cancer invasion: these enzymes are therefore of immense biological importance. Caricain is the most basic of the cysteine proteases found in the latex of Carica papaya. It is a member of the papain superfamily and is homologous to other plant and animal cysteine proteases. Caricain is naturally expressed as an inactive zymogen called procaricain. The inactive form of the protease contains an inhibitory proregion which consists of an additional 106 N-terminal amino acids; the proregion is removed upon activation.Results The crystal structure of procaricain has been refined to 3.2 å resolution; the final model consists of three non-crystallographically related molecules. The proregion of caricain forms a separate globular domain which binds to the C-terminal domain of mature caricain. The proregion also contains an extended polypeptide chain which runs through the substrate-binding cleft, in the opposite direction to that of the substrate, and connects to the N terminus of the mature region. The mature region does not undergo any conformational change on activation.Conclusions We conclude that the rate-limiting step in the in vitro activation of procaricain is the dissociation of the prodomain, which is then followed by proteolytic cleavage of the extended polypeptide chain of the proregion. The prodomain provides a stable scaffold which may facilitate the folding of the C-terminal lobe of procaricain
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Gametogenesis in Malaria Parasites Is Mediated by the cGMP-Dependent Protein Kinase
Malaria parasite transmission requires differentiation of male and female gametocytes into gametes within a mosquito following a blood meal. A mosquito-derived molecule, xanthurenic acid (XA), can trigger gametogenesis, but the signalling events controlling this process in the human malaria parasite Plasmodium falciparum remain unknown. A role for cGMP was revealed by our observation that zaprinast (an inhibitor of phosphodiesterases that hydrolyse cGMP) stimulates gametogenesis in the absence of XA. Using cGMP-dependent protein kinase (PKG) inhibitors in conjunction with transgenic parasites expressing an inhibitor-insensitive mutant PKG enzyme, we demonstrate that PKG is essential for XA- and zaprinast-induced gametogenesis. Furthermore, we show that intracellular calcium (Ca2+) is required for differentiation and acts downstream of or in parallel with PKG activation. This work defines a key role for PKG in gametogenesis, elucidates the hierarchy of signalling events governing this process in P. falciparum, and demonstrates the feasibility of selective inhibition of a crucial regulator of the malaria parasite life cycle
Sex steroids do not affect shigatoxin cytotoxicity on human renal tubular or glomerular cells
BACKGROUND: The greater susceptibility of children to renal injury in post-diarrheal hemolytic-uremic syndrome (HUS) may be related, at least in part, to heightened renal cell sensitivity to the cytotoxic effect of Shiga toxin (Stx), the putative mediator of kidney damage in HUS. We hypothesized that sexual maturation, which coincides with a falling incidence of HUS, may induce a relatively Stx-resistant state in the renal cells. METHODS: Cultured human glomerular endothelial (HGEN), human glomerular visceral epithelial (HGEC) and human proximal tubule (HPT) cells were exposed to Stx-1 after pre-incubation with progesterone, β-estradiol or testosterone followed by determination of cytotoxicity. RESULTS: Under basal conditions, Stx-1 potently and dose-dependently killed HPT and HGEC, but had relatively little effect on HGEN. Pre-incubation for 1, 2 or 7 days with physiologic or pharmacologic concentrations of progesterone, β-estradiol or testosterone had no effect on Stx-1 cytotoxicity dose-response on any cell type. In addition, no steroid altered Gb3 expression (Stx receptor) by any cell type at any time point. CONCLUSION: These data do not support the notion that hormonal changes associated with puberty induce an Stx-resistant state within kidney cells
Lithium in the Intermediate-Age Open Cluster, NGC 3680
High-dispersion spectra centered on the Li 6708 A line have been obtained for
70 potential members of the open cluster NGC 3680, with an emphasis on stars in
the turnoff region. A measurable Li abundance has been derived for 53 stars, 39
of which have radial velocities and proper motions consistent with cluster
membership. After being transferred to common temperature and abundance scales,
previous Li estimates have been combined to generate a sample of 49 members, 40
of which bracket the cluster Li-dip. Spectroscopic elemental analysis of 8
giants and 5 turnoff stars produces [Fe/H] = -0.17 +/- 0.07 (sd) and -0.07 +/-
0.02 (sd), respectively. We also report measurements of Ca, Si and Ni which are
consistent with scaled-solar ratios within the errors. Adopting [Fe/H] = -0.08
(Sect. 3.6), Y^2 isochrone comparisons lead to an age of 1.75 +/- 0.10 Gyr and
an apparent modulus of (m-M) = 10.30 +/- 0.15 for the cluster, placing the
center of the Li-dip at 1.35 +/- 0.03 solar masses. Among the giants, 5 of 9
cluster members are now known to have measurable Li with A(Li) near 1.0. A
combined sample of dwarfs in the Hyades and Praesepe is used to delineate the
Li-dip profile at 0.7 Gyr and [Fe/H] = +0.15, establishing its center at 1.42
+/- 0.02 solar masses and noting the possible existence of secondary dip on its
red boundary. When evolved to the typical age of the clusters NGC 752, IC 4651
and NGC 3680, the Hyades/Praesepe Li-dip profile reproduces the observed
morphology of the combined Li-dip within the CMD's of the intermediate-age
clusters while implying a metallicity dependence for the central mass of the
Li-dip given by Mass = (1.38 +/-0.04) + (0.4 +/- 0.2)[Fe/H]. The implications
of the similarity of the Li-dichotomy among giants in NGC 752 and IC 4651 and
the disagreement with the pattern among NGC 3680 giants are discussed.Comment: Latex ms. is 56 pages, including 10 figures and 4 tables. Accepted
for the Astronomical Journa
Biomarkers of apoptosis
Within the era of molecularly targeted anticancer agents, it has become increasingly important to provide proof of mechanism as early on as possible in the drug development cycle, especially in the clinic. Selective activation of apoptosis is often cited as one of the major goals of cancer chemotherapy. Thus, the present minireview focuses on a discussion of the pros and cons of a variety of methodological approaches to detect different components of the apoptotic cascade as potential biomarkers of programmed cell death. The bulk of the discussion centres on serological assays utilising the technique of ELISA, since here there is an obvious advantage of sampling multiple time points. Potential biomarkers of apoptosis including circulating tumour cells, cytokeratins and DNA nucleosomes are discussed at length. However, accepting that a single biomarker may not have the power to predict proof of concept and patient outcome, it is clear that in the future more emphasis will be placed on technologies that can analyse panels of biomarkers in small volumes of samples. To this end the increased throughput afforded by multiplex ELISA technologies is discussed
Cryogenic germanium detectors for a weakly interactive massive particle (WIMP) dark-matter search
We are preparing an experimental search for weakly interacting massive particle (WIMP) dark matter using cryogenic germanium detectors. These detectors measure both the ionization and phonons produced by particle interactions in the substrate. The ionization measurement uses low drift fields, approximately equals 1 V/cm. The phonon measurement is made using neutron transmutation doped (NTD) germanium thermistors. Simultaneous detection of phonons and ionization allows us to discriminate between electron-recoil and nuclear-recoil events which gives a powerful method for isolating possible WIMP events (nuclear recoils) from background gamma ray events (electron recoils). Recent work on our understanding and optimization of these detectors will be presented
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