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At least 1,621 records · Page 90

Price equation captures the role of drug interactions and collateral effects in the evolution of multidrug resistance

Bacterial adaptation to antibiotic combinations depends on the joint inhibitory effects of the two drugs (drug interaction [DI]) and how resistance to one drug impacts resistance to the other (collateral effects [CE]). Here we model these evolutionary dynamics on two-dimensional phenotype spaces that leverage scaling relations between the drug-response surfaces of drug-sensitive (ancestral) and drug-resistant (mutant) populations. We show that evolved resistance to the component drugs – and in turn, the adaptation of growth rate – is governed by a Price equation whose covariance terms encode geometric features of both the two-drug-response surface (DI) in ancestral cells and the correlations between resistance levels to those drugs (CE). Within this framework, mean evolutionary trajectories reduce to a type of weighted gradient dynamics, with the drug interaction dictating the shape of the underlying landscape and the collateral effects constraining the motion on those landscapes. We also demonstrate how constraints on available mutational pathways can be incorporated into the framework, adding a third key driver of evolution. Our results clarify the complex relationship between drug interactions and collateral effects in multidrug environments and illustrate how specific dosage combinations can shift the weighting of these two effects, leading to different and temporally explicit selective outcomes.

Gjini, Erida↗

Mechanism of the cadherin–catenin F-actin catch bond interaction

Mechanotransduction at cell–cell adhesions is crucial for the structural integrity, organization, and morphogenesis of epithelia. At cell–cell junctions, ternary E-cadherin/β-catenin/αE-catenin complexes sense and transmit mechanical load by binding to F-actin. The interaction with F-actin, described as a two-state catch bond, is weak in solution but is strengthened by applied force due to force-dependent transitions between weak and strong actin-binding states. Here, we provide direct evidence from optical trapping experiments that the catch bond property principally resides in the αE-catenin actin-binding domain (ABD). Consistent with our previously proposed model, the deletion of the first helix of the five-helix ABD bundle enables stable interactions with F-actin under minimal load that are well described by a single-state slip bond, even when αE-catenin is complexed with β-catenin and E-cadherin. Our data argue for a conserved catch bond mechanism for adhesion proteins with structurally similar ABDs. We also demonstrate that a stably bound ABD strengthens load-dependent binding interactions between a neighboring complex and F-actin, but the presence of the other αE-catenin domains weakens this effect. These results provide mechanistic insight to the cooperative binding of the cadherin–catenin complex to F-actin, which regulate dynamic cytoskeletal linkages in epithelial tissues.

59 BASIC BIOLOGICAL SCIENCES↗

Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase

β-Lactam antibiotics are the most important and widely used antibacterial agents across the world. However, the widespread dissemination of β-lactamases among pathogenic bacteria limits the efficacy of β-lactam antibiotics. This has created a major public health crisis. The use of β-lactamase inhibitors has proven useful in restoring the activity of β-lactam antibiotics, yet, effective clinically approved inhibitors against class B metallo-β-lactamases are not available. L1, a class B3 enzyme expressed by Stenotrophomonas maltophilia , is a significant contributor to the β-lactam resistance displayed by this opportunistic pathogen. Structurally, L1 is a tetramer with two elongated loops, α3-β7 and β12-α5, present around the active site of each monomer. Residues in these two loops influence substrate/inhibitor binding. To study how the conformational changes of the elongated loops affect the active site in each monomer, enhanced sampling molecular dynamics simulations were performed, Markov State Models were built, and convolutional variational autoencoder-based deep learning was applied. The key identified residues (D150a, H151, P225, Y227, and R236) were mutated and the activity of the generated L1 variants was evaluated in cell-based experiments. The results demonstrate that there are extremely significant gating interactions between α3-β7 and β12-α5 loops. Taken together, the gating interactions with the conformational changes of the key residues play an important role in the structural remodeling of the active site. These observations offer insights into the potential for novel drug development exploiting these gating interactions.

59 BASIC BIOLOGICAL SCIENCES↗

Nonlinear interactions of electromagnetic waves with a thermally generated cesium plasma.

The interaction of a large‐amplitude disturbing wave with a thermally generated, highly ionized cesium plasma has been investigated using a small‐amplitude sensing wave as a probe. The subsequent interaction between the disturbing and sensing waves is related to the plasma electron temperature. The plasma was contained in a magnetic field of 500–1000 G and had an electron plasma frequency near 10 GHz and an electron gyromagnetic frequency around 2 GHz. The sensing wave was a 10 GHz plane wave of approximately 1.5 mW input power and the disturbing wave was 7.5 GHz plane wave of about 1.2 W peak power. Measurements of the sensing‐wave transmitted power were made using standard microwave techniques. A notch filter in the sensing‐wave receiving circuit reduced the scattered disturbing‐wave interference to an immeasurably low level. Langmuir probes were used to detect disturbing‐wave modulation and to measure plasma temperatures and densities. Measurements of the interaction were correlated with a solution of the Boltzmann transport equation for a perturbed Maxwellian distribution function with binary Coulomb collisions.

Jack G Hewitt, Jr↗

Interactive display/graphics systems for remote sensor data analysis

A color-television display system and interactive graphics equipment on-line to an IBM 360/44 computer are used to develop a variety of interactive displays which aid in analyzing remote sensor data. These interactive displays are used to: (1) analyze data from a multispectral scanner; (2) develop automatic pattern recognition systems based on multispectral scanner measurements; and (3) analyze data from non-imaging sensors such as the infrared radiometer and microwave scatterometer.

Eppler, W. G.↗

Meteoroid-bumper interactions program

An investigation has been made of the interaction of meteoroids with shielded structures. The interaction has been simulated by the impact of Lexan cylinders onto lead shields in order to provide the vaporous debris believed to be created by meteoroid impact on a space vehicle. Shock compression data for Lexan was determined. This, in combination with the known shock compression data for the lead shield, has permitted the definition of the initial high pressure states in the impacted projectile and shield. The debris from such impact events has been permitted to interact with aluminum main walls. The walls were chosen to be sufficiently large to be effectively infinite in diameter compared to the loaded area. The thickness of the wall and the spacing from the shield were varied to determine the effect of these parameters. In addition, the effect of having a body of water behind the wall has been assessed. Measurements of the stagnation pressure in the debris cloud have been made and correlated with the response of the main wall.

Gough, P. S.↗

Interactive graphics system for IBM 1800 computer

A FORTRAN compatible software system that has been developed to provide an interactive graphics capability for the IBM 1800 computer is described. The interactive graphics hardware consists of a Hewlett-Packard 1300A cathode ray tube, Sanders photopen, digital to analog converters, pulse counter, and necessary interface. The hardware is available from IBM as several related RPQ's. The software developed permits the application programmer to use IBM 1800 FORTRAN to develop a display on the cathode ray tube which consists of one or more independent units called pictures. The software permits a great deal of flexibility in the manipulation of these pictures and allows the programmer to use the photopen to interact with the displayed data and make decisions based on information returned by the photopen.

Carleton, T. P.↗

Thermal conductivity and resonant multipole interactions

The influence of multipole interactions on exchanges of rotational energy in molecular collisions was investigated by means of a simple two-state impact parameter approximation. The calculations are restricted to linear molecules and to dipole and quadrupole fields. The effects of such exchanges on the thermal conductivity of gases and of gaseous mixtures was investigated, after correcting the kinetic theory of mixtures to include exchanges between unlike molecules. It was found that dipole-quadrupole and quadrupole-quadrupole interactions may have a significant effect for molecules with low moments of inertia. In particular, quadrupole interactions are important in the hydrogen isotopes, and the calculated corrections for H2 are consistent with recent experimental work by Harris. The theory seems capable of accounting for the anomalies observed in HF + DF and HCl + DCl mixtures in terms of multipolar accidental resonances.

Nyeland, C.↗

Interaction between an upstream facing wall jet and a supersonic stream

The flow field resulting from the interaction of an upstream facing wall jet with a supersonic counterflowing stream has been investigated. A flow field model and the main parameters governing the phenomena were determined from quantitative and qualitative experimental observations. Experimental results for different ranges of the main parameters are presented. A theoretical analysis was performed to describe the flow field in the mixing region between the two counterflowing streams. The results obtained by applying a locally similar solution compare favorably with the experimentally measured values. Large values of jet penetration were obtained with a high subsonic or low supersonic jet; large interaction forces are characteristics of higher supersonic injections. For the case of large penetration the cooling effectiveness presented as a function of the main parameters indicates the possibility of interacting cooling applications.

Piva, R.↗

Interactive display/graphics systems for remote sensor data analysis.

Using a color-television display system and interactive graphics equipment on-line to an IBM 360/44 computer, investigators at the Manned Spacecraft Center have developed a variety of interactive displays which aid in analyzing remote sensor data. This paper describes how such interactive displays are used to: (1) analyze data from a multispectral scanner, (2) develop automatic pattern recognition systems based on multispectral scanner measurements, and (3) analyze data from nonimaging sensors such as the infrared radiometer and microwave scatterometer.

Eppler, W. G.↗

Structure and orientations of solar-wind interaction fronts - Pioneer 6.

An analysis is given of five stream-stream interaction events observed in the Pioneer 6 plasma and field data. That the time profiles of all the parameters are consistent among the events and with previous descriptions given in the literature substantiates the notion of a common interaction type. The velocity variations in four of the events tend to lie in planes approximately parallel to the corotation spiral; thus it is implied that the events are reasonably stationary in time in the corotating frame. The data are interpreted in terms of a corotating interaction front, which is a ridge of high pressure parallel to a corotating spiral. The increased pressure is due to radial compression of the streams. The east-west (zonal) flow directions also occur in the front and are shown to be produced by the zonal pressure gradient of the pressure ridge.

Siscoe, G. L.↗

Nonlinear interaction of resonant plasma oscillations.

Using the water-bag model of an electron plasma the nonlinear interaction of two plasma wave pulses (each of sufficiently narrow wave-number spectrum) is discussed. It is shown that for the special case of a resonant (zero group velocity) pulse interacting with a nonresonant pulse, the interaction produces an effective slowing down of the group velocity of the nonresonant pulse. An application of this theory to the explanation of the apparent resonances at fractions of the plasma frequency observed in the ionosphere is discussed.

Lewak, G. J.↗

Observation of a quadrupole interaction for cubic imperfections exhibiting a dynamic Jahn-Teller effect.

The observation and interpretation of weak EPR transitions, identified as 'forbidden' transitions, establish the existence of a new type of quadrupole interaction for cubic-symmetry imperfections. This interaction is simply a consequence of the ground-vibronic-state degeneracy. The signs as well as the magnitudes of the quadrupole-coupling coefficients are determined experimentally. These data agree well with the predictions of crystal field theory modified to account for a weak-to-moderate vibronic interaction (i.e., a dynamic Jahn-Teller effect).

Herrington, J. R.↗

Shock wave-turbulent boundary layer interactions in rectangular channels.

Interaction regions created by the impingement of full span, externally generated, shock waves on a nozzle wall boundary layer were investigated. Incident shock strength was varied to produce unseparated, incipient, and fully separated flow fields. Significant departures from two-dimensionality were observed over the entire range of shock strengths tested and were identified with sidewall and corner boundary layer effects. However, comparisons of present centerline results with published two-dimensional data, obtained under similar test conditions and geometrical constraints, showed excellent agreement (e.g., incipient separation pressure levels, wall pressure distributions, free-interaction, and scale of the interaction region). This raises some question concerning the degree of two-dimensionality achieved in these previous investigations.

Reda, D. C.↗

Methods for reducing blade passing frequency noise generated by rotor-wake - stator interaction

A theoretical model for the generation of blade-passage noise caused by the interaction of rotor wakes with the downstream stator blades in a fan stage has been compiled. This model has combined a description of the rotor wake based on existing experimental correlations with an existing theory for the response of the stator blades to those wakes. This model of the interaction-caused blade-passage noise has been used to examine some effects of blade geometry and flow conditions on the noise generated. A set of significant parameters has been identified to reduce this interaction-caused blade-passage frequency noise. A redesign of an existing fan with the use of these concepts has produced a theoretical noise reduction of more than 7 decibels.

Dittmar, J. H.↗

Analysis and Simulation of the Mariner Mars 1971 Scan Platform: Spacecraft Dynamic Interaction

The equations of motion are developed which describe the dynamic interaction between the spacecraft bus and the movable appendages about a single axis. The effect is evaluated of the dynamic interaction on the attitude control subsystem with computer simulations, and design recommendations to reduce the impact of this interaction on future attitude control subsystems are presented.

Schumacher, L.↗

Small Interactive Image Processing System (SMIPS) system description

The Small Interactive Image Processing System (SMIPS) operates under control of the IBM-OS/MVT operating system and uses an IBM-2250 model 1 display unit as interactive graphic device. The input language in the form of character strings or attentions from keys and light pen is interpreted and causes processing of built-in image processing functions as well as execution of a variable number of application programs kept on a private disk file. A description of design considerations is given and characteristics, structure and logic flow of SMIPS are summarized. Data management and graphic programming techniques used for the interactive manipulation and display of digital pictures are also discussed.

Moik, J. G.↗

Calculation of free turbulent mixing by interaction approach.

The applicability of Bradshaw's interaction hypothesis to two-dimensional free shear flows was investigated. According to it, flows with velocity extrema may be considered to consist of several interacting layers. The hypothesis leads to a new expression for the shear stress which removes the usual restriction that shear stress vanishes at the velocity extremum. The approach is based on kinetic energy and the length scale equations. The compressible flow equations are simplified by restriction to low Mach numbers, and the range of their applicability is discussed. The empirical functions of the turbulence model are found here to be correlated with the spreading rate of the shear layer. The analysis demonstrates that the interaction hypothesis is a workable concept.

Morel, T.↗