Topological optimization and fatigue life prediction of a single pad externally adjustable fluid film bearing.

This work focuses on the prediction and comparison of the fatigue life of topologically optimized pads in an externally adjustable fluid film (EAFF) bearing. It integrates one-way/two-way fluid-structure interaction analysis, topological optimization (TO), and design modifications of the pad of an externally adjustable fluid film bearing. The major goal is to create an optimum pad design that minimizes weight and maintains structural integrity, and then to predict and compare the fatigue life of these alternative designs. The outcomes of the present study are as follows: (i) Two-way FSI results show a decrease of 65.64% in hydrodynamic fluid film pressure when compared to one-way FSI results because they take into account modifications in the fluid region's geometry caused by pad deformation; (ii) even though the maximum pad deformation in optimized pad geometry (Type-4) resulting from oil film pressure is relatively small (0.0036551 mm), the influence of pad deformation on the fluid domain due to hydrodynamic fluid film pressure cannot be understated; and (iii) when comparing the TO technique's results with fatigue life results, four elongated holes in the radial direction (Type-4) are most appropriate.

Multiple impact effects of helium-driven shocks on thin fiber-metal laminates.

Fiber Metal Laminates (FMLs) have garnered considerable attention and are increasingly being utilized in the development of protective armors for explosion and ballistic scenarios. While most research has focused on assessing the response of FMLs to single impacts, real battlefield situations often require shielding structures to endure multiple impacts. Thus, this study revolves around the creation of hybrid FMLs designed for shock shielding purposes. The primary focus is on how these laminates withstand repetitive impacts from high-intensity shock waves, aiming to pinpoint the optimal sequence that offers the highest resistance against multiple shock impacts. To establish effective shielding, a multi-layered FML configuration is employed. This configuration incorporates AA6061-T6 facing plates, ballistic-grade synthetic materials like aramid/epoxy ply, and ultra-high molecular weight polyethylene (UHMWPE)/epoxy ply. Additionally, a paperboard/epoxy lamina is introduced to induce functional grading based on layerwise shock impedance mismatches. Shock impact experiments are conducted using a shock tube equipped with helium as the driver gas. Critical shock parameters, including Mach Number, positive impulse, and peak overpressure, are meticulously evaluated. For validation purposes, a numerical model is employed to project the damage profile as a function of radial distance across different laminate sequences. The study unveils that ply deformations are strongly influenced by the arrangement of core layers, particularly the positions of the paperboard and UHMWPE layers within the core structure. To contextualize the findings, the shock impact results obtained from this study are compared with those from prior experiments that employed nitrogen-driven shocks.

Fiber metal laminates for high strain rate applications with layerwise shock impedance tuning.

Novel materials such as fiber-metal laminates (FMLs) have demonstrated significant potential in a variety of applications. They must contend with problems such fatigue, creep, high-speed projectile impact, and deformation at high strain rates while in use. When employed as structural materials in aircraft, especially when exposed to shock wave impact and high velocity impact, fiber-metal laminates' high strain rate characteristics become crucial. Shock impedance matching is a revolutionary approach used for shock-tuning the separate layers. The novelty of the current work is in developing custom shielding laminates, with in-depth analysis on the response of the shock impedance tuning of individual layers on the laminate behaviour at high strain rates. In the current study, five stackups of FMLs comprising metallic (AA 6061-T6) and fiber-reinforced polymer (FRP) plies, were formulated, incorporating shock impedance matching. The fiber-polymer plies used in the FMLs include ultra-high molecular weight polyethylene (UHMWPE), p-aramid for supplementing the impact resistance. Transmission loss functions (TL) estimated from the impedance tube experiments were used to indicate the shock tuning of the various laminates. The laminates underwent testing using a Split Hopkinson Pressure Bar (SHPB) apparatus to determine their properties at high strain rates ([Formula: see text] to [Formula: see text]). The variation in the Shock Energy (SE) absorbed by the laminates at various strain rates was analyzed as a function of the corresponding Transmission Loss employing regression. The dynamic stress-strain curves showed an increase in shock energy absorption at higher strain rates. The sequence SSP-IV and SSP-II showed the highest values of energy absorption as well as Transmission Loss.

Fate-Regulating Circuits in Viruses: From Discovery to New Therapy Targets.

Current antivirals effectively target diverse viruses at various stages of their life cycles. Nevertheless, curative therapy has remained elusive for important pathogens, such as human immunodeficiency virus type 1 (HIV-1) and herpesviruses, in large part due to viral latency and the evolution of resistance to existing therapies. Here, we review the discovery of viral master circuits: virus-encoded autoregulatory gene networks that autonomously control viral expression programs (i.e., between active, latent, and abortive fates). These circuits offer the opportunity for a new class of antivirals that could lead to intrinsic combination-antiviral therapies within a single molecule-evolutionary escape from such circuit-disrupting antivirals would require simultaneous evolution of both the viral cis regulatory element (e.g., the DNA-binding site) and the trans element (e.g., the transcription factor) in order for the virus to recapitulate a circuit that would not be disrupted. We review the architectures of these fate-regulating master circuits in HIV-1 and the human herpesvirus cytomegalovirus along with potential circuit-disruption strategies that may ultimately enable escape-resistant antiviral therapies.

Long-term growth data of Escherichia coli at a single-cell level.

Long-term, single-cell measurement of bacterial growth is extremely valuable information, particularly in the study of homeostatic aspects such as cell-size and growth rate control. Such measurement has recently become possible due to the development of microfluidic technology. Here we present data from single-cell measurements of Escherichia coli growth over 70 generations obtained for three different growth conditions. The data were recorded every minute, and contain time course data of cell length and fluorescent intensity of constitutively expressed yellow fluorescent protein.

A noisy linear map underlies oscillations in cell size and gene expression in bacteria.

During bacterial growth, a cell approximately doubles in size before division, after which it splits into two daughter cells. This process is subjected to the inherent perturbations of cellular noise and thus requires regulation for cell-size homeostasis. The mechanisms underlying the control and dynamics of cell size remain poorly understood owing to the difficulty in sizing individual bacteria over long periods of time in a high-throughput manner. Here we measure and analyse long-term, single-cell growth and division across different Escherichia coli strains and growth conditions. We show that a subset of cells in a population exhibit transient oscillations in cell size with periods that stretch across several (more than ten) generations. Our analysis reveals that a simple law governing cell-size control-a noisy linear map-explains the origins of these cell-size oscillations across all strains. This noisy linear map implements a negative feedback on cell-size control: a cell with a larger initial size tends to divide earlier, whereas one with a smaller initial size tends to divide later. Combining simulations of cell growth and division with experimental data, we demonstrate that this noisy linear map generates transient oscillations, not just in cell size, but also in constitutive gene expression. Our work provides new insights into the dynamics of bacterial cell-size regulation with implications for the physiological processes involved.

A hardwired HIV latency program.

Biological circuits can be controlled by two general schemes: environmental sensing or autonomous programs. For viruses such as HIV, the prevailing hypothesis is that latent infection is controlled by cellular state (i.e., environment), with latency simply an epiphenomenon of infected cells transitioning from an activated to resting state. However, we find that HIV expression persists despite the activated-to-resting cellular transition. Mathematical modeling indicates that HIV's Tat positive-feedback circuitry enables this persistence and strongly controls latency. To overcome the inherent crosstalk between viral circuitry and cellular activation and to directly test this hypothesis, we synthetically decouple viral dependence on cellular environment from viral transcription. These circuits enable control of viral transcription without cellular activation and show that Tat feedback is sufficient to regulate latency independent of cellular activation. Overall, synthetic reconstruction demonstrates that a largely autonomous, viral-encoded program underlies HIV latency­potentially explaining why cell-targeted latency-reversing agents exhibit incomplete penetrance.

Programmed Allee effect in bacteria causes a tradeoff between population spread and survival.

Dispersal is necessary for spread into new habitats, but it has also been shown to inhibit spread. Theoretical studies have suggested that the presence of a strong Allee effect may account for these counterintuitive observations. Experimental demonstration of this notion is lacking due to the difficulty in quantitative analysis of such phenomena in a natural setting. We engineered Escherichia coli to exhibit a strong Allee effect and examined how the Allee effect would affect the spread of the engineered bacteria. We showed that the Allee effect led to a biphasic dependence of bacterial spread on the dispersal rate: spread is promoted for intermediate dispersal rates but inhibited at low or high dispersal rates. The shape of this dependence is contingent upon the initial density of the source population. Moreover, the Allee effect led to a tradeoff between effectiveness of population spread and survival: increasing the number of target patches during dispersal allows more effective spread, but it simultaneously increases the risk of failing to invade or of going extinct. We also observed that total population growth is transiently maximized at an intermediate number of target patches. Finally, we demonstrate that fluctuations in cell growth may contribute to the paradoxical relationship between dispersal and spread. Our results provide direct experimental evidence that the Allee effect can explain the apparently paradoxical effects of dispersal on spread and have implications for guiding the spread of cooperative organisms.

Generic metric to quantify quorum sensing activation dynamics.

Quorum sensing (QS) enables bacteria to sense and respond to changes in their population density. It plays a critical role in controlling different biological functions, including bioluminescence and bacterial virulence. It has also been widely adapted to program robust dynamics in one or multiple cellular populations. While QS systems across bacteria all appear to function similarly-as density-dependent control systems-there is tremendous diversity among these systems in terms of signaling components and network architectures. This diversity hampers efforts to quantify the general control properties of QS. For a specific QS module, it remains unclear how to most effectively characterize its regulatory properties in a manner that allows quantitative predictions of the activation dynamics of the target gene. Using simple kinetic models, here we show that the dominant temporal dynamics of QS-controlled target activation can be captured by a generic metric, 'sensing potential', defined at a single time point. We validate these predictions using synthetic QS circuits in Escherichia coli. Our work provides a computational framework and experimental methodology to characterize diverse natural QS systems and provides a concise yet quantitative criterion for selecting or optimizing a QS system for synthetic biology applications.

Mayer-Rokitansky-Kuster-Hauser syndrome type II: A rare case.

Mayer-Rokitansky-Kuster-Hauser (MRKH) is a malformation complex comprising absent vagina and absent or rudimentary uterus. MRKH syndrome may be attributed to an initial affection of the intermediate mesoderm consequently leading (by the end of the 4(th) week of fetal life) to an alteration of the blastema of the cervicothoracicsomites and the pronephricducts. These latter subsequently induce the differentiation of the mesonephric and then the Wolffian and Mullerian ducts. There are very sparse such cases reported. We present a case of type II MRKH or Mullerian renal cervical somite association (i.e., Mullerian duct aplasia, renal dysplasia, and cervical somite anomalies).

Optimality and robustness in quorum sensing (QS)-mediated regulation of a costly public good enzyme.

Bacteria secrete a variety of public good exoproducts into their environment. These exoproducts are typically produced under the control of quorum sensing (QS), a signaling mechanism by which bacteria sense and respond to changes in their density. QS seems to provide an advantageous strategy to regulate these costly but beneficial exoproducts: it delays production until sufficiently high cell density, when the overall benefit of exoproducts outweighs cost of their production. This notion raises several fundamental questions about QS as a general control strategy adopted by bacteria. How much delay is advantageous? Under what conditions does QS-mediated regulation become advantageous? How does this advantage depend on the kinetic properties of QS? How robust is a given QS system to the stochastic events that occur over bacterial lifecycles? To quantitatively address these questions, we engineered a gene circuit in Escherichia coli to control the synthesis and secretion of a costly but beneficial exoenzyme. We show that exoenzyme production is overall advantageous only if initiated at a sufficiently high density. This property sets the potential advantage for QS-mediated regulation when the initial density is low and the growth cycle is sufficiently long compared with the exoenzyme response time. This advantage of QS-mediated regulation is robust to varying initial cell densities and growth durations, and it is particularly striking when bacteria face uncertainty, such as from stochastic dispersal during their lifecycle. We show, however, that, for QS to be optimal, its kinetic properties must be appropriately tuned; this property has implications for antibacterial treatments that target QS.

Programming stress-induced altruistic death in engineered bacteria.

Programmed death is often associated with a bacterial stress response. This behavior appears paradoxical, as it offers no benefit to the individual. This paradox can be explained if the death is 'altruistic': the killing of some cells can benefit the survivors through release of 'public goods'. However, the conditions where bacterial programmed death becomes advantageous have not been unambiguously demonstrated experimentally. Here, we determined such conditions by engineering tunable, stress-induced altruistic death in the bacterium Escherichia coli. Using a mathematical model, we predicted the existence of an optimal programmed death rate that maximizes population growth under stress. We further predicted that altruistic death could generate the 'Eagle effect', a counter-intuitive phenomenon where bacteria appear to grow better when treated with higher antibiotic concentrations. In support of these modeling insights, we experimentally demonstrated both the optimality in programmed death rate and the Eagle effect using our engineered system. Our findings fill a critical conceptual gap in the analysis of the evolution of bacterial programmed death, and have implications for a design of antibiotic treatment.

Engineering multicellular systems by cell-cell communication.

Synthetic biology encompasses the design of new biological parts and systems as well as the modulation of existing biological networks to generate novel functions. In recent years, increasing emphasis has been placed on the engineering of population-level behaviors using cell-cell communication. From the engineering perspective, cell-cell communication serves as a versatile regulatory module that enables coordination among cells in and between populations and facilitates the generation of reliable dynamics. In addition to exploring biological 'design principles' via the construction of increasingly complex dynamics, communication-based synthetic systems can be used as well-defined model systems to study ecological and social interactions such as competition, cooperation, and predation. Here we discuss the dynamic properties of cell-cell communication modules, how they can be engineered for synthetic circuit design, and applications of these systems.

Optimal tuning of bacterial sensing potential.

Through production and sensing of small signal molecules, quorum sensing (QS) enables bacteria to detect changes in their density and regulate their functions accordingly. QS systems are tremendously diverse in terms of their specific sensory components, the biochemical and transport properties of signaling molecules, their target functions and the context in which QS-mediated functions are activated. Cutting across this diversity, however, the central architecture of QS systems is universal; it comprises signal synthesis, secretion, degradation and detection. We are thus able to derive a general metric for QS 'sensing potential' based on this 'core' module. The sensing potential quantifies the ability of a single bacterium to sense the dimensions of its microenvironment. This simple metric captures the dominant activation properties of diverse QS systems, giving a concise description of the sensing characteristics. As such, it provides a convenient quantitative framework to study the phenotypic effects of QS characteristics. As an example, we show how QS characteristics uniquely determine the scenarios in which regulation of a typical QS-controlled function, such as exoenzyme secretion, becomes advantageous.

Decoding biological principles using gene circuits.

A major flavor of synthetic biology is the creation of artificial gene circuits to perform user-defined tasks. One aspect of this area is to realize ever-increasingly more complicated circuit behavior. Such efforts have led to the identification and evaluation of design strategies that enable robust control of dynamics in single cells and in cell populations. On the other hand, there is increasing emphasis on using artificial systems programmed by simple circuits to explore fundamental biological questions of broad significance.

In situ Microrheological Determination of Neutrophil Stiffening Following Adhesion in a Model Capillary.

There has been considerable debate on the relative importance of biochemical stimuli and mechanical deformation in neutrophil adhesion in lung capillaries, a process observed following bacterial infection in the body. In contrast to venules, where the vessel diameter is larger than the leukocyte diameter (6-9 microm) and the adhesion process is better understood, in lung capillaries the vessel diameter (2-8 microm) is smaller than the leukocyte diameter. In this study, a micropipette was used as a model for the alveolar capillary microcirculation, allowing the effects of adhesion molecules (ICAM-1) on cell mechanical properties to be observed while applying a mechanical deformation. The microrheology technique that tracks the thermal motion of granules within neutrophils was used to extract the local intracellular viscoelastic moduli. Small regional differences in rheology were found, with the central body region being significantly stiffer than the leading end cap region. When cells were exposed to ICAM-1, the regional differences were preserved, but the viscoelastic moduli were moderately increased in all regions. These results are consistent with the literature on leukocyte sequestration and provide insight into the regional rheological effects of deformation and adhesion molecules on neutrophils.