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"RICHARD, B. M"
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How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell
ATP hydrolysis is required for the synthesis, transport and polymerization of monomers for macromolecules as well as for the assembly of the latter into cellular structures. Other cellular processes not directly related to synthesis of biomass, such as maintenance of membrane potential and cellular shape, also require ATP. The unicellular flagellated parasite
Trypanosoma brucei
has a complex digenetic life cycle. The primary energy source for this parasite in its bloodstream form (BSF) is glucose, which is abundant in the host’s bloodstream. Here, we made a detailed estimation of the energy budget during the BSF cell cycle. As glycolysis is the source of most produced ATP, we calculated that a single parasite produces 6.0 x 10
11
molecules of ATP/cell cycle. Total biomass production (which involves biomass maintenance and duplication) accounts for ~63% of the total energy budget, while the total biomass duplication accounts for the remaining ~37% of the ATP consumption, with in both cases translation being the most expensive process. These values allowed us to estimate a theoretical
Y
ATP
of 10.1 (g biomass)/mole ATP and a theoretical
Y
A
T
P
m
a
x
of 28.6 (g biomass)/mole ATP. Flagellar motility, variant surface glycoprotein recycling, transport and maintenance of transmembrane potential account for less than 30% of the consumed ATP. Finally, there is still ~5.5% available in the budget that is being used for other cellular processes of as yet unknown cost. These data put a new perspective on the assumptions about the relative energetic weight of the processes a BSF trypanosome undergoes during its cell cycle.
Journal Article
Doctor Strange, supreme sorcerer : afterlife. Volume 13, 1994-1997
\"A new look for Doctor Strange - but will it be his last? The Sorcerer Supreme has a youthful appearance, yet he's still taking care of business - including Nightmare's hunt for an heir! But long hair and dark glasses don't suit a man as urbane as Stephen Strange. It's time for a dapper new wardrobe and a new source of power: catastrophe magic! Which is fitting, given what archfoe Baron Mordo has in store. Mordo has had a profound impact on Strange's life - and now the villain is plotting his death! Plus: In an award-winnign classic, discover what disturbs Stephen! And a particularly Strange Tale unites the Sorcerer Supreme with the Thing and Human Torch!\" -- Page 4 of cover.
Book
Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling
The adult stem cell marker Lgr5 and its relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. We find that conditional deletion of both genes in the mouse gut impairs Wnt target gene expression and results in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition. Mass spectrometry demonstrates that Lgr4 and Lgr5 associate with the Frizzled/Lrp Wnt receptor complex. Each of the four R-spondins, secreted Wnt pathway agonists, can bind to Lgr4, -5 and -6. In HEK293 cells, RSPO1 enhances canonical WNT signals initiated by WNT3A. Removal of LGR4 does not affect WNT3A signalling, but abrogates the RSPO1-mediated signal enhancement, a phenomenon rescued by re-expression of LGR4, -5 or -6. Genetic deletion of
Lgr4
/
5
in mouse intestinal crypt cultures phenocopies withdrawal of Rspo1 and can be rescued by Wnt pathway activation. Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues.
Regeneration by R-spondins
The adult stem-cell marker Lgr5 and its family members encode orphan seven-transmembrane receptors that are similar to the receptors for the hormones FSH, LH and TSH, but their ligand and molecular function have been elusive. In experiments on intestinal epithelial crypt cells, binding of Lgr5 homologues to R-spondins — a family of secreted proteins linked to the Wnt signalling pathway — is shown to trigger downstream canonical Wnt signals through associated Frizzled–Lrp5/6 complexes. This work suggests that R-spondins have regenerative activity in tissues that express Lgr5 homologues.
Journal Article
This idea is brilliant : lost, overlooked, and underappreciated scientific concepts everyone should know
Presents essays responding to a question about what scientific term or concept ought to be more widely known, written by such authors as Jared Diamond, Richard Thaler, Richard Dawkins, Lisa Randall, Steven Pinker, and Carlo Roveri.
BOOK
Correction: How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell
[This corrects the article DOI: 10.1371/journal.ppat.1011522.].[This corrects the article DOI: 10.1371/journal.ppat.1011522.].
Journal Article
A New Approach to Examine Cell–Antibody Avidity with Surface Plasmon Resonance Imaging
In recent years, avidity has emerged as a critical parameter in antibody design, yet most current analytical instruments are limited to measuring affinity alone. This study aims to evaluate the capabilities and advantages of a novel surface plasmon resonance imaging instrument, CellVysion, designed to quantify cell–antibody avidity using a continuous antibody density gradient. A key feature of this approach is the identification of a “tipping point”—the specific ligand density, measured in µRIUs, at which cells remain bound to the sensor surface under defined shear flow conditions. In this paper, we present the technical principles and application of this method, demonstrating how avidity can be quantitatively assessed across different antibody–cell line combinations.
Journal Article
An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection
Trypanosoma cruzi is a hemoflagellated parasite causing Chagas disease, which affects 6–8 million people in the Americas. More than one hundred years after the description of this disease, the available drugs for treating the T . cruzi infection remain largely unsatisfactory. Chloroquinoline and arylamidine moieties are separately found in various compounds reported for their anti-trypanosoma activities. In this work we evaluate the anti- T . cruzi activity of a collection of 26 “chimeric” molecules combining choroquinoline and amidine structures. In a first screening using epimastigote forms of the parasite as a proxy for the clinically relevant stages, we selected the compound 7-chloro-4-[4-(4,5-dihydro-1H-imidazol-2-yl)phenoxy]quinoline (named here as A6 ) that performed better as an anti- T . cruzi compound (IC 50 of 2.2 ± 0.3 μM) and showed a low toxicity for the mammalian cell CHO-K 1 (CC 50 of 137.9 ± 17.3 μM). We initially investigated the mechanism of death associated to the selected compound. The A6 did not trigger phosphatidylserine exposure or plasma membrane permeabilization. Further investigation led us to observe that under short-term incubations (until 6 hours), no alterations of mitochondrial function were observed. However, at longer incubation times (4 days), A6 was able to decrease the intracellular Ca 2+ , to diminish the intracellular ATP levels, and to collapse mitochondrial inner membrane potential. After analysing the cell cycle, we found as well that A6 produced an arrest in the S phase that impairs the parasite proliferation. Finally, A6 was effective against the infective forms of the parasite during the infection of the mammalian host cells at a nanomolar concentration (IC 50(tryps) = 26.7 ± 3.7 nM), exhibiting a selectivity index ( SI ) of 5,170. Our data suggest that A6 is a promising hit against T . cruzi .
Journal Article
IgG Subclass Determines Suppression Versus Enhancement of Humoral Alloimmunity to Kell RBC Antigens in Mice
It has long been appreciated that immunoglobulins are not just the effector endpoint of humoral immunity, but rather have a complex role in regulating antibody responses themselves. Donor derived anti-RhD IgG has been used for over 50 years as an immunoprophylactic to prevent maternal alloimmunization to RhD. Although anti-RhD has dramatically decreased rates of hemolytic disease of the fetus and newborn (for the RhD alloantigen), anti-RhD also fails in some cases, and can even paradoxically enhance immune responses in some circumstances. Attempts to generate a monoclonal anti-RhD have largely failed, with some monoclonals suppressing less than donor derived anti-RhD and others enhancing immunity. These difficulties likely result, in part, because the mechanism of anti-RhD remains unclear. However, substantial evidence exists to reject the common explanations of simple clearance of RhD + RBCs or masking of antigen. Donor derived anti-RhD is a mixture of 4 different IgG subtypes. To the best of our knowledge an analysis of the role different IgG subtypes play in immunoregulation has not been carried out; and, only IgG1 and IgG3 have been tested as monoclonals. Multiple attempts to elicit alloimmune responses to human RhD epitopes in mice have failed. To circumvent this limitation, we utilize a tractable animal model of RBC alloimmunization using the human Kell glycoprotein as an antigen to test the effect of IgG subtype on immunoregulation by antibodies to RBC alloantigens. We report that the ability of an anti-RBC IgG to enhance, suppress (at the level of IgM responses), or have no effect is a function of the IgG subclass in this model system.
Journal Article