Analogous Resistance Research Articles

GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites.

Efforts to control the global malaria health crisis are undermined by antimalarial resistance. Identifying mechanisms of resistance will uncover the underlying biology of the Plasmodium falciparum malaria parasites that allow evasion of our most promising therapeutics and may reveal new drug targets. We utilized fosmidomycin (FSM) as a chemical inhibitor of plastidial isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway. We have thus identified an unusual metabolic regulation scheme in the malaria parasite through the essential glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Two parallel genetic screens converged on independent but functionally analogous resistance alleles in GAPDH. Metabolic profiling of FSM-resistant gapdh mutant parasites indicates that neither of these mutations disrupt overall glycolytic output. While FSM-resistant GAPDH variant proteins are catalytically active, they have reduced assembly into the homotetrameric state favored by wild-type GAPDH. Disrupted oligomerization of FSM-resistant GAPDH variant proteins is accompanied by altered enzymatic cooperativity and reduced susceptibility to inhibition by free heme. Together, our data identifies a new genetic biomarker of FSM-resistance and reveals the central role of GAPDH in MEP pathway control and antimalarial sensitivity.

Low-cost lumped parameter modelling of hydrogen storage in solid-state materials

A low-cost lumped parameter model (LPM) is developed to simulate hydrogen storage in solid-state materials. The proposed LPM is a zero-dimensional model based on an analogous transient thermal resistance network that considers the whole storage system as a resistor–capacitor (RC) circuit with a current source. Combined with the mass conservation, sorption kinetics, and equation of state, the LPM is capable of predicting key thermofluidic quantities of the storage system, such as the storage bed temperature and pressure, hydrogen fraction and flowrate, and storage tank temperature. To test the applicability of the LPM, chemisorptive (Mg and LaNi5) and physisorptive (activated carbon) solid-state materials are simulated for adsorption and desorption processes. For both material types, LPM achieves predictive accuracies comparable to three-dimensional computational fluid dynamics (CFD) simulations, especially for hydrogen fraction and storage times (with maximum errors less than 9.6%), for a fraction of the computational cost (23,734 times lower memory requirement and 126 times faster calculation time). In addition, several formulations of the bed thermal resistance are proposed and discussed in terms of their impact on the accuracy of the LPM predictions. For slender cylindrical tanks, an equivalent annulus formula achieves the best balance of simplicity and accuracy.

Modeling Current-Voltage Charateristics of Proteorhodopsin and Bacteriorhodopsin: Towards an Optoelectronics Based on Proteins.

Current-voltage characteristics of metal-protein-metal structures made of proteorhodopsin and bacteriorhodopsin are modeled by using a percolation-like approach. Starting from the tertiary structure pertaining to the single protein, an analogous resistance network is created. Charge transfer inside the network is described as a sequential tunneling mechanism and the current is calculated for each value of the given voltage. The theory is validated with available experiments, in dark and light. The role of the tertiary structure of the single protein and of the mechanisms responsible for the photo-activity is discussed.

From Complicit Citizens to Potential Prey: State Imaginaries and Subjectivities in US War Resistance

The movements against the Vietnam and Iraq wars gave rise to analogous resistance efforts, in the form of draft resistance and counter-recruitment, respectively. Despite their many similarities, the draft resistance and counter-recruitment movements emerged in distinct historical eras marked by very different ‘state imaginaries’ or assumptions about the nature of the state and people’s relation to it. Drawing on original archival work, this paper excavates these state imaginaries and examines how they conditioned activists’ subjectivities in each era. More specifically, this paper argues that the 1960s were marked by an imaginary of the state based on consent, which positioned draft resisters as complicit citizens and engendered a sense of personal responsibility for the war. This state imaginary was displaced in the neoliberal era by an imaginary of the state as an alien and invasive force, which positioned counter-recruitment activists (or their children) as potential prey and impelled efforts at self-defense.

The FonSIX6 gene acts as an avirulence effector in the Fusarium oxysporum f. sp. niveum - watermelon pathosystem.

When infecting a host plant, the fungus Fusarium oxysporum secretes several effector proteins into the xylem tissue to promote virulence. However, in a host plant with an innate immune system involving analogous resistance proteins, the fungus effector proteins may trigger resistance, rather than promoting virulence. Identity of the effector genes of Fusarium oxysporum f. sp. niveum (Fon) races that affect watermelon (Citrullus lanatus) are currently unknown. In this study, the SIX6 (secreted in xylem protein 6) gene was identified in Fon races 0 and 1 but not in the more virulent Fon race 2. Disrupting the FonSIX6 gene in Fon race 1 did not affect the sporulation or growth rate of the fungus but significantly enhanced Fon virulence in watermelon, suggesting that the mutant ΔFon1SIX6 protein allowed evasion of R protein-mediated host resistance. Complementation of the wild-type race 2 (which lacks FonSIX6) with FonSIX6 reduced its virulence. These results provide evidence supporting the hypothesis that FonSIX6 is an avirulence gene. The identification of FonSix6 as an avirulence factor may be a first step in understanding the mechanisms of Fon virulence and resistance in watermelon and further elucidating the role of Six6 in Fusarium-plant interactions.

Development and Characterization of a Differentiated Thyroid Cancer Cell Line Resistant to VEGFR-Targeted Kinase Inhibitors

Vascular endothelial growth factor-targeted kinase inhibitors have emerged as highly promising therapies for radioiodine-refractory metastatic differentiated thyroid cancer. Unfortunately, drug resistance uniformly develops, limiting their therapeutic efficacies and thereby constituting a major clinical problem. To study acquired drug resistance and elucidate underlying mechanisms in this setting, BHP2-7 human differentiated thyroid cancer cells were subjected to prolonged continuous in vitro selection with 18 μM pazopanib, a clinically relevant concentration; acquisition of pazopanib resistance was serially assessed, with the resulting resistant cells thereafter subcloned and characterized to assess potential mechanisms of acquired pazopanib resistance. Stable 2- to 4-fold in vitro pazopanib resistance emerged in response to pazopanib selection associated with similar in vitro growth characteristics but with markedly more aggressive in vivo xenograft growth. Selected cells were cross-resistant to sunitinib and to a lesser extent sorafenib but not to MAPK kinase (MEK1/2) inhibition by GSK1120212. Genotyping demonstrated acquisition of a novel activating KRAS codon 13 GGC to GTT (glycine to valine) mutation, consistent with the observed resistance to upstream vascular endothelial growth factor receptor inhibition yet sensitivity to downstream MAPK kinase (MEK1/2) inhibition. Selection of thyroid cancer cells with clinically utilized therapeutics can lead to acquired drug resistance and altered in vivo xenograft behavior that can recapitulate analogous drug resistance observed in patients. This approach has the potential to lead to insights into acquired treatment-related drug resistance in thyroid cancers that can be subjected to subsequent validation in serially collected patient samples and that has the potential to yield preemptive and responsive approaches to dealing with this important clinical problem.

Thermoelectric Power Generator Design for Maximum Power: It’s All About ZT

There is a significant amount of literature that discusses thermoelectric power generator (TEG) design, but much of it overly simplifies the design space and therefore the results have limited use in designing real-life systems. This paper develops a more comprehensive model of the thermal and electrical interactions of a TEG in a system with known hot-side and cold-side thermal resistances and corresponding constant system temperature differential. Two design scenarios are investigated for common TEG system applications. In one method, the power from a TEG is maximized for a given electrical load, simulating a case where the TEG is electrically in series with a known load such as a fan. In the second design scenario, the power from a TEG is maximized for a given electrical load resistance ratio, n (the ratio between the external load resistance and the internal TEG resistance), simulating an application where the TEG is electrically in series with a load-matching converter. An interesting conclusion from this work is that, in the first design scenario, the electrical load resistance ratio, n, that maximizes TEG power occurs at \( \sqrt {1 + ZT} \) (where ZT is the thermoelectric figure of merit) instead of 1 as reported previously in literature. Equally interesting is that, if you define an analogous thermal resistance ratio, m′ (representing the ratio between the TEG thermal resistance at open-circuit conditions and the system thermal resistance), the maximum power in both design scenarios occurs at \( \sqrt {1 + ZT} \) instead of the commonly cited value of 1. Furthermore, results are presented for real-life designs that incorporate electrical and thermal losses common to realistic TEG systems such as electrical contact resistance and thermal bypass around the TEG due to sealing.

Lysine‐Dependent Binding of OspE to the C‐terminus of Factor H Mediates Complement Resistance in Borrelia burgdorferi

Serum resistance of Borrelia burgdorferi strains belonging to the B. afzelii and B. burgdorferi sensu stricto genospecies is dependent on binding of complement inhibitor factor H. We recently reported that factor H binding by B. burgdorferi is due to inducible expression of several approximately 20 kDa plasmid‐encoded, surface‐exposed lipoproteins related to OspE (e.g. ErpA, ErpP and P21). In addition, a second class of factor H‐binding proteins of approximately 27–35 kDa has been described. The OspE‐related lipoproteins are dramatically induced by B. burgdorferi during transmission from its tick vector into the mammalian host. The induction of OspE‐related lipoproteins during mammalian infection may play a key a role in the borrelial evasion of the host's immune system. The goal of the present study was to define the factor H‐binding regions of OspE‐related proteins using mutagenesis, peptide mapping and surface plasmon resonance analysis (Biacore). The combined studies revealed that the C‐terminal regions of both human and mouse factor H (SCRs 18–20) specifically bind to OspE‐related lipoproteins. We also found FHR‐1, whose C‐terminal SCRs 3–5 are homologous to SCRs 18–20 of factor H, to bind to OspE. Peptide mapping revealed five putative regions (designated I‐V) in OspE that could directly interact with factor H. Deleting the C‐terminal 15 amino acid residues from region V of P21 abolished its ability to bind factor H. At the same time, however, synthetic peptides corresponding to the C‐termini of OspE, P21 and ErpP did not inhibit factor H binding to OspE. Thus, the C‐terminal‐binding region V appears to be necessary but not sufficient for factor H binding. When a more specific mutation strategy was employed, where single amino acid residues in peptides spanning over the factor H‐binding regions were mutated to alanines, we observed that lysines in the factor H‐binding regions of OspE were required for factor H binding. The combined data have revealed that key lysine residues in OspE‐related lipoproteins and ionic interactions are crucial for factor H interactions. Furthermore, binding of OspE to the C‐termini of both mouse and human factor H suggests that Borrelia spirochetes utilize analogous complement resistance mechanisms in both rodents and man. In Borrelia garinii strains, which in in vitro analyses have been found to be sensitive to complement killing, differences in the OspE sequences as well as in the expression of factor H‐binding proteins may account for their susceptibility to serum lysis.

A structural homologue of colipase in black mamba venom revealed by NMR floating disulphide bridge analysis

The solution structure of mamba intestinal toxin 1 (MIT1), isolated from Dendroaspis polylepis polylepis venom, has been determined. This molecule is a cysteine-rich polypeptide exhibiting no recognised family membership. Resistance to MIT1 to classical specific endoproteases produced contradictory NMR and biochemical information concerning disulphide-bridge topology. We have used distance restraints allowing ambiguous partners between S atoms in combination with NMR-derived structural information, to correctly determine the disulphide-bridge topology. The resultant solution structure of MIT1, determined to a resolution of 0.5 Å, reveals an unexpectedly similar global fold with respect to colipase, a protein involved in fatty acid digestion. Colipase exhibits an analogous resistance to endoprotease activity, indicating for the first time the possible topological origins of this biochemical property. The biochemical and structural homology permitted us to propose a mechanically related digestive function for MIT1 and provides novel information concerning snake venom protein evolution.

The identification of engineering system parameters

A procedure enabling the identification of the mass/inertia, damping and stiffness matrices for mechanical systems or the analogous inductance, resistance and capacitance matrices for electrical, fluid or thermal systems from measured results is developed. Analytical constraints that are mandatory are defined. Illustrative examples are provided.

DNA probes for studying streptothricin resistance evolution in enteric bacteria

Probes for the detection of streptothricin resistance genes have been derived from recombinant plasmids. These include the streptothricin resistance gene probe sat 1/2 derived from Tn 1826 and specific for both the sat-1 determinant of Tn 1825 and the sat-2 determinant of Tn 1826, and the probe sat D derived from and specific for the sat-1 determinant of transposon Tn 1825. A third streptothricin resistance gene probe, sat 3, represents the streptothricin resistance determinant sat-3 of the IncQ R plasmid pIE639. Hybridization studies did not reveal any sequence homology between sat-3 and the transposon-localized sat-1 and sat-2 determinants. Moreover, non of the different sat-determinants isolated from plasmids of gram negative bacteria hybridized with the analogous resistance determinant of Streptomyces noursei, which had been cloned and named nat by Krügel et al. (Gene, 1988, 62, 209-214). The sat 1/2 probe in combination with the sat D probe proved to be suitable for the identification and the differentiation of sat-1 and sat-2 determinants in different genetic environments. Streptothricin resistance genes related to those present on transposons Tn 1825 and Tn 1826 have been detected by hybridization with the probe sat 1/2 on plasmids isolated a long time ago before the application of streptothricins. The sat-3 determinant appears to be exclusively associated with the IncQ plasmid pIE639.

A cell membrane alteration specifically induced by SV40 transformation

Transformation of mouse 3T3 cells by SV40 results in a specific membrane modification which renders cells resistant to the killing action of the lipophilic antibiotic Amphotericin B. This alteration is under genetic cellular control and is specific for SV40 transformation since transformation with polyoma or mouse sarcoma viruses does not confer resistance to the antibiotic. Analogous resistance is induced by SV40 transformation of primary human fibroblast cells. The acquired resistance is not due to decreased binding of Amphotericin B and is partially reversed if cells are grown in the presence of cholesterol. The results are interpreted as a specific change of sterol structure of the membrane or the loss of a minor cholesterol fraction responsible for the killing action of the antibiotic.

Periodic Fluid Flow Through Circular Orifices

The results of an experimental investigation of both the linear and nonlinear analogous acoustic resistance and inductance of circular orifices with water and 10 centistoke Dow Corning Silicone fluid are presented. Experimental determinations of the end corrections for resistance and inductance are in good agreement with the classical end correction as given by Rayleigh for inductance. A series of determinations of the criterion for the onset of nonlinearity in resistance and inductance, together with photographs of the fluid flow patterns developed, are presented. A characteristic of one of the fluid flow patterns is correlated with the onset of nonlinearity.

Periodic Fluid Flow Through Circular Tubes

Some aspects of the periodic flow of an incompressible fluid through a circular tube of large length to diameter ratio have been studied. Expressions for the analogous acoustic resistance and inductance of the tube are presented. An experimental investigation of the resistance and inductance is described in which the tube dimensions, the viscosity of the fluid, and the frequency of the periodic motion are varied over a wide range. The experimental results are found to be in good agreement with the predictions of the hydro-dynamical theory.

The Correlation of Non-Linear Resistance, Flow Resistance, and Differential Resistance for Sharp-Edged Circular Orifices

According to Sivian's analysis of the acoustic resistance of small orifices a close correlation should exist between three kinds of measurable resistance in small orifices. If the losses are mainly due to the kinetic energy acquired by the air in the orifice the non-linear acoustic resistance RN, the analogous flow resistance RF, and the analogous differential resistance RD, are related thus: RN = 12RF, RD = 2RF. The non-linear acoustic resistance RN of orifices of 0.375 cm and 0.50 cm diameter has been obtained from plane wave transmission loss measurements made in a three-inch tube equipped with a ρc termination. Orifice thicknesses were varied from 0.05 to 1.25 cm. In this manner RN was measurable at incident pressures greater than that required to cause a deviation from constancy in the transmission loss. It was found that, in the non-linear region, the sound pressure of the wave transmitted by the orifice depends on the square of the incident sound pressure. This relation has been verified for incident sound pressure levels ranging from 115 to 160 decibels, and for frequencies from 238 to 800 c.p.s. (All levels considered were well into Region 4 of Ingaard's “phase diagrams.”) Analogous flow resistance measurements have been made on the same orifices for average particle velocities from 100 to 1,600 cm/sec. The analogous flow resistance was found to be given, within ± 30 percent, by a formula derived by Sivian from kinetic energy considerations. In most cases RN was found to be 25 percent greater than RF/2, and essentially independent of frequency over the range considered. For this comparison RN is taken at a peak orifice particle velocity equal to the orifice average velocity at which RF is measured. The differential resistance RD is the small signal acoustic resistance measured with a superimposed unidirectional flow. RD has been found to be approximately equal 2RF.

THE ADJUSTMENT OF MISCLOSURES

The adjustment of misclosures in slope traverses by the method of least squares is effected by solving a system of simultaneous equations which may be written by inspection of the traverse diagram. These equations can be solved by measurements of currents in an analogous electrical resistance network. This paper is devoted mainly to the development of the electrical analogy.