127 research outputs found
Red blood cell invasion by Plasmodium vivax: Structural basis for DBP engagement of DARC
Plasmodium parasites use specialized ligands which bind to red blood cell (RBC) receptors during invasion. Defining the mechanism of receptor recognition is essential for the design of interventions against malaria. Here, we present the structural basis for Duffy antigen (DARC) engagement by P. vivax Duffy binding protein (DBP). We used NMR to map the core region of the DARC ectodomain contacted by the receptor binding domain of DBP (DBP-RII) and solved two distinct crystal structures of DBP-RII bound to this core region of DARC. Isothermal titration calorimetry studies show these structures are part of a multi-step binding pathway, and individual point mutations of residues contacting DARC result in a complete loss of RBC binding by DBP-RII. Two DBP-RII molecules sandwich either one or two DARC ectodomains, creating distinct heterotrimeric and heterotetrameric architectures. The DARC N-terminus forms an amphipathic helix upon DBP-RII binding. The studies reveal a receptor binding pocket in DBP and critical contacts in DARC, reveal novel targets for intervention, and suggest that targeting the critical DARC binding sites will lead to potent disruption of RBC engagement as complex assembly is dependent on DARC binding. These results allow for models to examine inter-species infection barriers, Plasmodium immune evasion mechanisms, P. knowlesi receptor-ligand specificity, and mechanisms of naturally acquired P. vivax immunity. The step-wise binding model identifies a possible mechanism by which signaling pathways could be activated during invasion. It is anticipated that the structural basis of DBP host-cell engagement will enable development of rational therapeutics targeting this interaction
Chaotic flow and efficient mixing in a micro-channel with a polymer solution
Microscopic flows are almost universally linear, laminar and stationary
because Reynolds number, , is usually very small. That impedes mixing in
micro-fluidic devices, which sometimes limits their performance. Here we show
that truly chaotic flow can be generated in a smooth micro-channel of a uniform
width at arbitrarily low , if a small amount of flexible polymers is added
to the working liquid. The chaotic flow regime is characterized by randomly
fluctuating three-dimensional velocity field and significant growth of the flow
resistance. Although the size of the polymer molecules extended in the flow may
become comparable with the micro-channel width, the flow behavior is fully
compatible with that in a table-top channel in the regime of elastic
turbulence. The chaotic flow leads to quite efficient mixing, which is almost
diffusion independent. For macromolecules, mixing time in this microscopic flow
can be three to four orders of magnitude shorter than due to molecular
diffusion.Comment: 8 pages,7 figure
Elastic turbulence in curvilinear flows of polymer solutions
Following our first report (A. Groisman and V. Steinberg, \sl Nature , 53 (2000)) we present an extended account of experimental observations of
elasticity induced turbulence in three different systems: a swirling flow
between two plates, a Couette-Taylor (CT) flow between two cylinders, and a
flow in a curvilinear channel (Dean flow). All three set-ups had high ratio of
width of the region available for flow to radius of curvature of the
streamlines. The experiments were carried out with dilute solutions of high
molecular weight polyacrylamide in concentrated sugar syrups. High polymer
relaxation time and solution viscosity ensured prevalence of non-linear elastic
effects over inertial non-linearity, and development of purely elastic
instabilities at low Reynolds number (Re) in all three flows. Above the elastic
instability threshold, flows in all three systems exhibit features of developed
turbulence. Those include: (i)randomly fluctuating fluid motion excited in a
broad range of spatial and temporal scales; (ii) significant increase in the
rates of momentum and mass transfer (compared to those expected for a steady
flow with a smooth velocity profile). Phenomenology, driving mechanisms, and
parameter dependence of the elastic turbulence are compared with those of the
conventional high Re hydrodynamic turbulence in Newtonian fluids.Comment: 23 pages, 26 figure
Nanomechanical detection of antibiotic-mucopeptide binding in a model for superbug drug resistance
The alarming growth of the antibiotic-resistant superbugs
methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant
Enterococcus (VRE) is driving the development of new technologies to
investigate antibiotics and their modes of action. We report the label-free
detection of vancomycin binding to bacterial cell wall precursor analogues
(mucopeptides) on cantilever arrays, with 10 nM sensitivity and at clinically
relevant concentrations in blood serum. Differential measurements quantified
binding constants for vancomycin-sensitive and vancomycin-resistant mucopeptide
analogues. Moreover, by systematically modifying the mucopeptide density we
gain new insights into the origin of surface stress. We propose that stress is
a product of a local chemical binding factor and a geometrical factor
describing the mechanical connectivity of regions affected by local binding in
terms of a percolation process. Our findings place BioMEMS devices in a new
class of percolative systems. The percolation concept will underpin the design
of devices and coatings to significantly lower the drug detection limit and may
also impact on our understanding of antibiotic drug action in bacteria.Comment: Comments: This paper consists of the main article (6 pages, 5
figures) plus Supplemental Material (6 pages, 3 figures). More details are
available at http://www.london-nano.co
PDGF-C Induces Maturation of Blood Vessels in a Model of Glioblastoma and Attenuates the Response to Anti-VEGF Treatment
Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). However, the survival benefit is usually short-lived as tumors escape anti-VEGF therapies. Here we tested the hypothesis that Platelet Derived Growth Factor-C (PDGF-C), an isoform of the PDGF family, affects GBM progression independent of VEGF pathway and hinders anti-VEGF therapy.We first showed that PDGF-C is present in human GBMs. Then, we overexpressed or downregulated PDGF-C in a human GBM cell line, U87MG, and grew them in cranial windows in nude mice to assess vessel structure and function using intravital microscopy. PDGF-C overexpressing tumors had smaller vessel diameters and lower vascular permeability compared to the parental or siRNA-transfected tumors. Furthermore, vessels in PDGF-C overexpressing tumors had more extensive coverage with NG2 positive perivascular cells and a thicker collagen IV basement membrane than the controls. Treatment with DC101, an anti-VEGFR-2 antibody, induced decreases in vessel density in the parental tumors, but had no effect on the PDGF-C overexpressing tumors.These results suggest that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization
Neptune to the Common-wealth of England (1652): the republican Britannia and the continuity of interests
In the seventeenth century, John Kerrigan reminds us, βmodels of empire did not always turn on monarchyβ. In this essay, I trace a vision of βNeptuneβs empireβ shared by royalists and republicans, binding English national interest to British overseas expansion. I take as my text a poem entitled βNeptune to the Common-wealth of Englandβ, prefixed to Marchamont Nedhamβs 1652 English translation of Mare Clausum (1635), John Seldenβs response to Mare Liberum (1609) by Hugo Grotius. This minor work is read alongside some equally obscure and more familiar texts in order to point up the ways in which it speaks to persistent cultural and political interests. I trace the afterlife of this verse, its critical reception and its unique status as a fragment that exemplifies the crossover between colonial republic and imperial monarchy at a crucial moment in British history, a moment that, with Brexit, remains resonant
BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications
Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs
BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications
Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs
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