An interpretation of size-scale plasticity in geometrically confined systems

The mesoscopic constitutive behavior of face-centered cubic metals as a function of the system characteristic dimension recently has been investigated experimentally. Strong size effects have been identified in both polycrystalline submicron thin films and single crystal micro pillars. The size effect is manifested as an increase in strength and hardening rate as the system dimensions are decreased. In this article, we provide a mechanistic interpretation for the observed mesoscopic behavior. By performing 3D discrete dislocation dynamics simulations of grains representative of the system microstructure and associated characteristic dimensions, we show that the experimentally observed size effects can be qualitatively described. In these simulations, a constant density of dislocation sources per unit of grain boundary area is modeled by sources randomly distributed at grain boundaries. The source length (strength) is modeled by a Gaussian distribution, in which average and standard deviation is independent of the system characteristic dimension. The simulations reveal that two key concepts are at the root of the observed plasticity size effect. First, the onset of plasticity is governed by a dislocation nucleation-controlled process (sources of various length, i.e., strengths, in our model). Second, the hardening rate is controlled by source exhaustion, i.e., sources are active only once as a result of the limited dislocation mobility arising from size and boundary effects. The model postulated here improves our understanding of why "smaller is stronger" and provides predictive capabilities that should enhance the reliable design of devices in applications such as microelectronics and micro/nano-electro-mechanical systems.     

Mechanics of surface area regulation in cells examined with confined lipid membranes

Cells are wrapped in inelastic membranes, yet they can sustain large mechanical strains by regulating their area. The area regulation in cells is achieved either by membrane folding or by membrane exo- and endocytosis. These processes involve complex morphological transformations of the cell membrane, i.e., invagination, vesicle fusion, and fission, whose precise mechanisms are still under debate. Here we provide mechanistic insights into the area regulation of cell membranes, based on the previously neglected role of membrane confinement, as well as on the strain-induced membrane tension. Commonly, the membranes of mammalian and plant cells are not isolated, but rather they are adhered to an extracellular matrix, the cytoskeleton, and to other cell membranes. Using a lipid bilayer, coupled to an elastic sheet, we are able to demonstrate that, upon straining, the confined membrane is able to regulate passively its area. In particular, by stretching the elastic support, the bilayer laterally expands without rupture by fusing adhered lipid vesicles; upon compression, lipid tubes grow out of the membrane plane, thus reducing its area. These transformations are reversible, as we show using cycles of expansion and compression, and closely reproduce membrane processes found in cells during area regulation. Moreover, we demonstrate a new mechanism for the formation of lipid tubes in cells, which is driven by the membrane lateral compression and may therefore explain the various membrane tubules observed in shrinking cells.     

Mobility of cholera toxin receptors on rat lymphocyte membranes.

Fluorescein-labeled cholera toxin binds detectably to 40-60% of rat mesenteric lymph node cells and induces a temperature-dependent redistribution (patch and cap formation) of cell surface toxin receptors. The redistribution is inhibited by several "metabolic," "microtubule," and "microfilament" inhibitors, by concanavalin A, and by anticholera toxin IgG. Various studies indicate that cholera toxin is at least bivalent, and that this property may be related to both the induction of receptor redistribution and to the activation of adenylate cyclase. Membrane components which are probably identical to the sialo-glycolipid, GM1 ganglioside, appear to be mobile in the plane of the membrane. The possible role of toxin multivalency and receptor mobility in the mechanism of toxin action is considered.     

Inhomogeneous dynamics in confined water nanodroplets

The effect of confinement on the dynamical properties of liquid water was studied by mid-infrared ultrafast pump-probe spectroscopy on HDO:D2O in reverse micelles. By preparing water-containing reverse micelles of different well defined sizes, we varied the degree of geometric confinement in water nanodroplets with radii ranging from 0.2 to 4.5 nm. We find that water molecules located near the interface confining the droplet exhibit slower vibrational energy relaxation and have a different spectral absorption than those located in the droplet core. As a result, we can measure the orientational dynamics of these different types of water with high selectivity. We observe that the water molecules in the core show similar orientational dynamics as bulk water and that the water layer solvating the interface is highly immobile.     

In situ assembly of linked geometrically coupled microdevices

Complex systems require their distinct components to function in a dynamic, integrated, and cooperative fashion. To accomplish this in current microfluidic networks, individual valves are often switched and pumps separately powered by using macroscopic methods such as applied external pressure. Direct manipulation and control at the single-device level, however, limits scalability, restricts portability, and hinders the development of massively parallel architectures that would take best advantage of microscale systems. In this article, we demonstrate that local geometry combined with a simple global field can not only reversibly drive component assembly but also power distinct devices in a parallel, locally uncoupled, and integrated fashion. By employing this single approach, we assemble and demonstrate the operation of check valves, mixers, and pistons within specially designed microfluidic environments. In addition, we show that by linking these individual components together, more complex devices such as pumps can be both fabricated and powered in situ.     

Homocysteine and Mobility in Older Adults

OBJECTIVES: To determine the influence of homocysteine on mobility decline in older adults. DESIGN: Prospective cohort. SETTING: Einstein Aging Study, community‐based aging study. PARTICIPANTS: Five hundred seventy‐four older adults without dementia (mean age 80.2 ± 5.4, 61% women). MEASUREMENTS: Mobility decline defined using gait velocity measurements at baseline and annual follow‐up visits. Linear mixed effects models were used to adjust for age, sex, education, and other potential confounders. RESULTS: Higher homocysteine levels were associated with slower gait velocity at baseline. Adjusted for age, sex, and education, a one‐unit increase in baseline log homocysteine levels was associated with a 2.95‐cm/s faster mobility decline per year (P=.01) over a median follow‐up of 1.4 years. The 140 subjects in the highest quartile of homocysteine had a faster rate of mobility decline (1.75 cm/s per year faster, P=.01) than the 434 subjects in the lowest three quartiles of homocysteine (≤15 μmol/L). The association between homocysteine and mobility decline remained robust even after adjusting for multiple confounders and accounting for the presence of clinical gait abnormalities. CONCLUSION: Higher homocysteine levels are associated with greater risk of mobility decline in community‐residing older adults.     

Mobility impairments in crash-involved older drivers

OBJECTIVE. To evaluate potential associations of impairments in physical function with motor vehicle crash involvement in older drivers. METHODS. Case participants were randomly selected residents of Mobile County, Alabama, greater or less than 65 years old who had sustained an at-fault motor vehicle crash in 1996. Similarly selected crash-free controls were frequency matched to cases on gender and age. Self-report data on demographic variables, medical conditions, medications, driving exposure, and function were collected by telephone interviewers. RESULTS. Relative to crash-free subjects, crash-involved drivers were significantly more likely to report difficulty walking one fourth mile and moving outdoors. Marginally significant associations were observed for trouble carrying a heavy object 100 yards and for the occurrence of falls in the prior year. Increasing numbers of functional limitations were directly related to the odds of crash involvement. DISCUSSION. In comparison to crash-free controls, crash-involved older drivers are more likely to report other mobility-related impairments, possibly including falls.     

Formation of geometrically complex lipid nanotube-vesicle networks of higher-order topologies

We present a microelectrofusion method for construction of fluid-state lipid bilayer networks of high geometrical complexity up to fully connected networks with genus = 3 topology. Within networks, self-organizing branching nanotube architectures could be produced where intersections spontaneously arrange themselves into three-way junctions with an angle of 120 degrees between each nanotube. Formation of branching nanotube networks appears to follow a minimum-bending energy algorithm that solves for pathway minimization. It is also demonstrated that materials can be injected into specific containers within a network by nanotube-mediated transport of satellite vesicles having defined contents. Using a combination of microelectrofusion, spontaneous nanotube pattern formation, and satellite-vesicle injection, complex networks of containers and nanotubes can be produced for a range of applications in, for example, nanofluidics and artificial cell design. In addition, this electrofusion method allows integration of biological cells into lipid nanotube-vesicle networks.     

Dynamics of confined water molecules

We present femtosecond midinfrared pump-probe measurements of the molecular motion and energy-transfer dynamics of a water molecule that is enclosed by acetone molecules. These confined water molecules show hydrogen-bond and orientational dynamics that are much slower than in bulk liquid water. This behavior is surprising because the hydrogen bonds to the C=O groups of the acetone molecules are weaker than the hydrogen bonds in bulk water. The energy transfer between the O-H groups of the confined water molecules has a time constant of 1.3 +/- 0.2 ps, which is >20 times slower than in bulk water. We find that this energy transfer is governed completely by the rate at which hydrogen bonds are broken and reformed, and we identify the short-lived molecular complex that forms the transition state of this process.     

Morphogenesis and cell ordering in confined bacterial biofilms

Biofilms are aggregates of bacterial cells surrounded by an extracellular matrix. Much progress has been made in studying biofilm growth on solid substrates; however, little is known about the biophysical mechanisms underlying biofilm development in three-dimensional confined environments in which the biofilm-dwelling cells must push against and even damage the surrounding environment to proliferate. Here, combining single-cell imaging, mutagenesis, and rheological measurement, we reveal the key morphogenesis steps of Vibrio cholerae biofilms embedded in hydrogels as they grow by four orders of magnitude from their initial size. We show that the morphodynamics and cell ordering in embedded biofilms are fundamentally different from those of biofilms on flat surfaces. Treating embedded biofilms as inclusions growing in an elastic medium, we quantitatively show that the stiffness contrast between the biofilm and its environment determines biofilm morphology and internal architecture, selecting between spherical biofilms with no cell ordering and oblate ellipsoidal biofilms with high cell ordering. When embedded in stiff gels, cells self-organize into a bipolar structure that resembles the molecular ordering in nematic liquid crystal droplets. In vitro biomechanical analysis shows that cell ordering arises from stress transmission across the biofilm–environment interface, mediated by specific matrix components. Our imaging technique and theoretical approach are generalizable to other biofilm-forming species and potentially to biofilms embedded in mucus or host tissues as during infection. Our results open an avenue to understand how confined cell communities grow by means of a compromise between their inherent developmental program and the mechanical constraints imposed by the environment.

The growth of living organisms is critically influenced by the external environment. One form of such environmental influence is the transmission of mechanical stress, which can instruct morphogenesis in systems ranging from stem cells to tissues to the entire organisms (1, 2). In the prokaryotic domain, bacteria commonly live in complex communities encased by an extracellular matrix (3) known as biofilms (4). Biofilm formation is a morphogenetic process whereby a single founder cell develops into a three-dimensional (3D) aggregate in which bacterial cells interact with each other and with the environment (4–8). Recent work has revealed biophysical mechanisms underlying biofilm morphogenesis on solid substrates, which is controlled by cell–substrate adhesion and the resulting shear stress (9–15). In addition to those living on surfaces, bacterial communities are also commonly found inside soft, structured environments, such as hydrogels. Examples include biofilms growing in mucus layers and host tissues during an infection or food contamination (16). Indeed, many common biofilm formers including Pseudomonas aeruginosa and Vibrio cholerae encounter biological hydrogels as their niche during infection (17, 18). Under these conditions, embedded biofilms must grow against 3D confinement and potentially damage the surrounding environment—a process that is fundamentally different from how surface-attached biofilms expand against friction with the surface (10, 13, 15, 19). However, little is known about how biofilms develop under such 3D mechanical constraints, including how cells collectively organize in response to the confinement and how the confining environment, in turn, is modified by cell proliferation. This is in stark contrast to the accumulating knowledge on the growth dynamics of mammalian cell aggregates and tumors under confinement (20, 21).In this study, we integrate single-cell live imaging, mutagenesis, in vitro mechanical testing, and numerical modeling to investigate how the 3D confinement determines the morphodynamics and cell ordering of an embedded biofilm. A model system is established by embedding V. cholerae, the causal agent of the cholera pandemic and a model biofilm former (22, 23), inside agarose gels (24). By using 3D visualization techniques with high spatiotemporal resolution, we reveal that embedded biofilms undergo a shape transition and a series of self-organization events that are distinct from those in surface-attached biofilms. We first show that the stiffness contrast between the biofilm and the confining hydrogels controls a transition between spherical and ellipsoidal biofilms. Furthermore, we discover that embedded biofilms display a core-shell structure with intricate ordering similar to nematic liquid crystal (LC) droplets (25). Finally, we demonstrate that Vibrio polysaccharide (VPS) and cell-to-surface adhesion proteins effectively transmit stress between the environment and the biofilm, giving rise to distinct cell ordering patterns in embedded biofilms.     

Receptor Mobility and Receptor-Cytoplasmic Interactions in Lymphocytes

An analysis of the inhibition by concanavalin A of the mobility of lymphocyte surface receptors is used to construct an hypothesis on membrane receptor-cytoplasmic interactions. It is proposed that binding of multivalent lectins alters the interaction of an assembly of colchicine-binding proteins with lectin receptors and other receptors, and reciprocally that the state of the colchicine-binding assembly alters the mobility and distribution of surface receptors on the cell membrane. Observations of the effect of colchicine and related drugs on the inhibition of receptor mobility by concanavalin A lend support to this hypothesis. The proposed model has several implications for studies of the initial events of mitogenesis in lymphocytes as well as for cell-cell interactions in general.     

Defective Neutrophil Mobility in the May-Hegglin Anomaly

S ummary . A case of May-Hegglin anomaly is reported in which functional studies of PMN cells showed abnormalities consisting of impairment of chemotactic and chemokinetic responses, random mobility being otherwise normal. These abnormalities seem unrelated to microtubule system dysfunction or to abnormal cell deformability, since no defect was observed in the concanavalin A (Con A) surface receptors and no improvement of directional movement resulted when filters of larger pore size were used in the assays. Other possible mechanisms of the functional defect, such as abnormal membrane receptors to kinetic signals or metabolic abnormalities cannot be excluded. PMN function should be studied in additional cases in order to ascertain if these findings are a constant feature in the May-Hegglin anomaly, a syndrome in which undue susceptibility to infection has not been reported.     

Crohn's disease confined to the appendix

Crohn's disease confined to the appendix is a rare entity, less than 50 cases having been reported. The present study reports on another 12 cases representing 6 per cent of all 194 patients operated upon for Crohn's disease in a total, unselected series. The indications for surgery were appendicitis in eight patients, appendiceal abscess in two, suspected pyosalpinx in one, and an ovarian cyst in one. The appendices were in all cases strikingly enlarged. Giant-cell granulomas, without microabscesses, were detected in all but one patient. Two patients had early septic postoperative complications. Fistulization from the cecum did not occur. The median observation time after operation was 13.8 years. Since none of the patients had further manifestations of the disease, it is concluded that patients with Crohn's disease confined to the appendix have a favorable prognosis.     

Discontinuous shear thickening in confined dilute carbon nanotube suspensions

A monotonic decrease in viscosity with increasing shear stress is a known rheological response to shear flow in complex fluids in general and for flocculated suspensions in particular. Here we demonstrate a discontinuous shear-thickening transition on varying shear stress where the viscosity jumps sharply by four to six orders of magnitude in flocculated suspensions of multiwalled carbon nanotubes (MWNT) at very low weight fractions (approximately 0.5%). Rheooptical observations reveal the shear-thickened state as a percolated structure of MWNT flocs spanning the system size. We present a dynamic phase diagram of the non-Brownian MWNT dispersions revealing a starting jammed state followed by shear-thinning and shear-thickened states. The present study further suggests that the shear-thickened state obtained as a function of shear stress is likely to be a generic feature of fractal clusters under flow, albeit under confinement. An understanding of the shear-thickening phenomena in confined geometries is pertinent for flow-controlled fabrication techniques in enhancing the mechanical strength and transport properties of thin films and wires of nanostructured composites as well as in lubrication issues.     

Pressure-driven transport of confined DNA polymers in fluidic channels

The pressure-driven transport of individual DNA molecules in 175-nm to 3.8-microm high silica channels was studied by fluorescence microscopy. Two distinct transport regimes were observed. The pressure-driven mobility of DNA increased with molecular length in channels higher than a few times the molecular radius of gyration, whereas DNA mobility was practically independent of molecular length in thin channels. In addition, both the Taylor dispersion and the self-diffusion of DNA molecules decreased significantly in confined channels in accordance with scaling relationships. These transport properties, which reflect the statistical nature of DNA polymer coils, may be of interest in the development of "lab-on-a-chip" technologies.     

A Tool to Assess Mobility Status in Critically Ill Patients: The Perme Intensive Care Unit Mobility Score

The benefits of early mobilization for adult patients in the intensive care unit (ICU) are reduced length of ICU and hospital stays, fewer readmissions to the ICU, decreased duration of mechanical ventilation, fewer days of detrimental bedrest, minimal adverse or unsafe events, and improved walking distance. Because there are no available tools to specifically measure mobility status of patients in the ICU setting, there is an urgent need to create a reliable tool that measures and standardizes the assessment of mobility status for these patients. The purpose of this study was to describe the development of this novel ICU-specific tool to assess a patient’s mobility status, examine the initial reliability of the tool, and address its clinical application. The Perme ICU Score was quickly and easily administered by physical therapists. Overall, the inter-rater agreement was 94%. A total of six items had kappa values of < .6, and these low scores may have been the result of the procedure to collect inter-rater scores, wherein one rater assisted with the activity while a second rater observed. In order to improve reliability, the authors developed directions to standardize the assessment. The Perme ICU Mobility Score is a tool developed to measure the patient’s mobility status starting with the ability to follow commands and culminating in the distance walked in two minutes. Preliminary data suggest that the validity of this tool is supported by expert concurrence, its overall reliability is high, and its clinical use is acceptable.