The critical current of disordered superconductors near 0 K.

An increasing current through a superconductor can result in a discontinuous increase in the differential resistance at the critical current. This critical current is typically associated either with breaking of Cooper-pairs or with the onset of collective motion of vortices. Here we measure the current-voltage characteristics of superconducting films at low temperatures and high magnetic fields. Using heat-balance considerations we demonstrate that the current-voltage characteristics are well explained by electron overheating enhanced by the thermal decoupling of the electrons from the host phonons. By solving the heat-balance equation we are able to accurately predict the critical currents in a variety of experimental conditions. The heat-balance approach is universal and applies to diverse situations from critical currents to climate change. One disadvantage of the universality of this approach is its insensitivity to the details of the system, which limits our ability to draw conclusions regarding the initial departure from equilibrium.

Sensitivity of the superconducting state in thin films.

For more than two decades, there have been reports on an unexpected metallic state separating the established superconducting and insulating phases of thin-film superconductors. To date, no theoretical explanation has been able to fully capture the existence of such a state for the large variety of superconductors exhibiting it. Here, we show that for two very different thin-film superconductors, amorphous indium oxide and a single crystal of 2H-NbSe2, this metallic state can be eliminated by adequately filtering external radiation. Our results show that the appearance of temperature-independent, metallic-like transport at low temperatures is sufficiently described by the extreme sensitivity of these superconducting films to external perturbations. We relate this sensitivity to the theoretical observation that, in two dimensions, superconductivity is only marginally stable.

Absence of Cyclotron Resonance in the Anomalous Metallic Phase in InO_{x}.

It is observed that many thin superconducting films with not too high disorder level (generally R_{N}/□<2000 Ω) placed in magnetic field show an anomalous metallic phase where the resistance is low but still finite as temperature goes to zero. Here we report in weakly disordered amorphous InO_{x} thin films that this anomalous metal phase possesses no cyclotron resonance and hence non-Drude electrodynamics. The absence of a finite frequency resonant mode can be associated with a vanishing downstream component of the vortex current parallel to the supercurrent and an emergent particle-hole symmetry of this metal, which establishes its non-Fermi-liquid character.

Instability of Insulators near Quantum Phase Transitions.

Thin films of amorphous indium oxide undergo a magnetic field driven superconducting to insulator quantum phase transition. In the insulating phase, the current-voltage characteristics show large current discontinuities due to overheating of electrons. We show that the onset voltage for the discontinuities vanishes as we approach the quantum critical point. As a result, the insulating phase becomes unstable with respect to any applied voltage making it, at least experimentally, immeasurable. We emphasize that unlike previous reports of the absence of linear response near quantum phase transitions, in our system, the departure from equilibrium is discontinuous. Because the conditions for these discontinuities are satisfied in most insulators at low temperatures, and due to the decay of all characteristic energy scales near quantum phase transitions, we believe that this instability is general and should occur in various systems while approaching their quantum critical point. Accounting for this instability is crucial for determining the critical behavior of systems near the transition.

Nonequilibrium Second-Order Phase Transition in a Cooper-Pair Insulator.

In certain disordered superconductors, upon increasing the magnetic field, superconductivity terminates with a direct transition into an insulating phase. This phase is comprised of localized Cooper pairs and is termed a Cooper-pair insulator. The current-voltage characteristics measured in this insulating phase are highly nonlinear and, at low temperatures, exhibit abrupt current jumps. Increasing the temperature diminishes the jumps until the current-voltage characteristics become continuous. We show that a direct correspondence exists between our system and systems that undergo an equilibrium, second-order, phase transition. We illustrate this correspondence by comparing our results to the van der Waals equation of state for the liquid-gas mixture. We use the similarities to identify a critical point where an out of equilibrium second-order-like phase transition occurs in our system. Approaching the critical point, we find a power-law behavior with critical exponents that characterizes the transition.

Evidence for a Finite-Temperature Insulator.

In superconductors the zero-resistance current-flow is protected from dissipation at finite temperatures (T) by virtue of the short-circuit condition maintained by the electrons that remain in the condensed state. The recently suggested finite-T insulator and the "superinsulating" phase are different because any residual mechanism of conduction will eventually become dominant as the finite-T insulator sets-in. If the residual conduction is small it may be possible to observe the transition to these intriguing states. We show that the conductivity of the high magnetic-field insulator terminating superconductivity in amorphous indium-oxide exhibits an abrupt drop, and seem to approach a zero conductance at T < 0.04 K. We discuss our results in the light of theories that lead to a finite-T insulator.

Partially distinct molecular mechanisms mediate inhibitory FcgammaRIIB signaling in resting and activated B cells.

FcgammaRIIB functions as an inhibitory receptor to dampen B cell Ag receptor signals and immune responses. Accumulating evidence indicates that ex vivo B cells require the inositol 5-phosphatase, Src homology domain 2-containing inositol 5-phosphatase (SHIP), for FcgammaRIIB-mediated inhibitory signaling. However, we report here that LPS-activated primary B cells do not require SHIP and thus differ from resting B cells. SHIP-deficient B cell blasts display efficient FcgammaRIIB-dependent inhibition of calcium mobilization as well as Akt and extracellular signal-related protein kinase phosphorylation. Surprisingly, FcgammaRIIB-dependent degradation of phosphatidylinositol 3,4,5-trisphosphate and conversion into phosphatidylinositol 3,4-bisphosphate occur in SHIP-deficient B cell blasts, demonstrating the function of an additional inositol 5-phosphatase. Further analysis reveals that while resting cells express only SHIP, B cell blasts also express the recently described inositol 5-phosphatase, SHIP-2. Finally, data suggest that both SHIP-2 and SHIP can mediate downstream biologic consequences of FcgammaRIIB signaling, including inhibition of the proliferative response.

Bilevel control of B-cell activation by the inositol 5-phosphatase SHIP.

The balanced interplay between positive and negative signals pathways emanating from surface receptors has emerged as a common paradigm for regulation of cell function and the immune response. Here, we will review the recent progress in analysis of signaling pathways initiated upon antigen receptor (BCR) aggregation, and co-aggregation with the inhibitory IgG receptor FcgammaRIIB. Particular attention is paid to the function of the inositol 5-phosphatase SHIP and its effector p62i(Dok), a RasGAP adapter protein. SHIP and Dok function in FcgammaRIIB-mediated inhibition as well as in feedback regulation of signals generated through the BCR. These inhibitory molecules may play critical roles in the prevention of immune system hyperactivity and resulting autoimmunity.

Mutational analysis reveals multiple distinct sites within Fc gamma receptor IIB that function in inhibitory signaling.

The low-affinity receptor for IgG, FcgammaRIIB, functions broadly in the immune system, blocking mast cell degranulation, dampening the humoral immune response, and reducing the risk of autoimmunity. Previous studies concluded that inhibitory signal transduction by FcgammaRIIB is mediated solely by its immunoreceptor tyrosine-based inhibition motif (ITIM) that, when phosphorylated, recruits the SH2-containing inositol 5'- phosphatase SHIP and the SH2-containing tyrosine phosphatases SHP-1 and SHP-2. The mutational analysis reported here reveals that the receptor's C-terminal 16 residues are also required for detectable FcgammaRIIB association with SHIP in vivo and for FcgammaRIIB-mediated phosphatidylinositol 3-kinase hydrolysis by SHIP. Although the ITIM appears to contain all the structural information required for receptor-mediated tyrosine phosphorylation of SHIP, phosphorylation is enhanced when the C-terminal sequence is present. Additionally, FcgammaRIIB-mediated dephosphorylation of CD19 is independent of the cytoplasmic tail distal from residue 237, including the ITIM. Finally, the findings indicate that tyrosines 290, 309, and 326 are all sites of significant FcgammaRIIB1 phosphorylation following coaggregation with B cell Ag receptor. Thus, we conclude that multiple sites in FcgammaRIIB contribute uniquely to transduction of FcgammaRIIB-mediated inhibitory signals.

Differential regulation of B cell development, activation, and death by the src homology 2 domain-containing 5' inositol phosphatase (SHIP).

Although the Src homology 2 domain-containing 5' inositol phosphatase (SHIP) is a well-known mediator of inhibitory signals after B cell antigen receptor (BCR) coaggregation with the low affinity Fc receptor, it is not known whether SHIP functions to inhibit signals after stimulation through the BCR alone. Here, we show using gene-ablated mice that SHIP is a crucial regulator of BCR-mediated signaling, B cell activation, and B cell development. We demonstrate a critical role for SHIP in termination of phosphatidylinositol 3,4,5-triphosphate (PI[3,4,5]P(3)) signals that follow BCR aggregation. Consistent with enhanced PI(3,4,5)P(3) signaling, we find that splenic B cells from SHIP-deficient mice display enhanced sensitivity to BCR-mediated induction of the activation markers CD86 and CD69. We further demonstrate that SHIP regulates the rate of B cell development in the bone marrow and spleen, as B cell precursors from SHIP-deficient mice progress more rapidly through the immature and transitional developmental stages. Finally, we observe that SHIP-deficient B cells have increased resistance to BCR-mediated cell death. These results demonstrate a central role for SHIP in regulation of BCR signaling and B cell biology, from signal driven development in the bone marrow and spleen, to activation and death in the periphery.

Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction.

One of the areas of greatest recent progress in immunology has been the elucidation of inhibitory receptors and their mode of signal transduction. A common feature of members of this growing family is expression of a conserved cytoplasmic sequence motif, the immunoreceptor tyrosine-based inhibitory motif, which functions to recruit and activate phosphatases that mediate the receptors' function. Family members include the protein tyrosine phosphatases SHP-1 (Src-homology-2-domain-containing protein tyrosine phosphatase 1) and SHP-2, which function to dephosphorylate key intermediaries in antigen receptor signaling pathways. Surprisingly, whereas most data to date support a role for SHP-1 in inhibitory signaling, SHP-2 exhibits distinct functions that appear to positively regulate receptor function.

The RasGAP-binding protein p62dok is a mediator of inhibitory FcgammaRIIB signals in B cells.

The low affinity receptor for IgG, FcgammaRIIB, functions to dampen the antibody response and reduce the risk of autoimmunity. This function is reportedly mediated in part by inhibition of B cell antigen receptor (BCR)-mediated p21ras activation, though the basis of this inhibition is unknown. We show here that FcgammaRIIB-BCR coaggregation leads to increased tyrosine phosphorylation of the RasGAP-binding protein p62dok, with a concomitant increase in its binding to RasGAP. These effects require the recruitment and tyrosine phosphorylation of the phosphatidylinositol 5-phosphatase SHIP, which further recruits p62dok via the latter's phosphotyrosine-binding domain. Using chimeric FcgammaRIIB containing the RasGAP-binding domain of p62dok, we demonstrate that p62dok contains all structural information required to mediate the inhibitory effect of FcgammaRIIB on Erk activation.

Antigen receptor signaling: integration of protein tyrosine kinase functions.

Antigen receptors on T and B cells function to transduce signals leading to a variety of biologic responses minimally including antigen receptor editing, apoptotic death, developmental progression, cell activation, proliferation and survival. The response to antigen depends upon antigen affinity and valence, involvement of coreceptors in signaling and differentiative stage of the responding cell. The requirement that these receptors integrate signals that drive an array of responses may explain their evolved structural complexity. Antigen receptors are composed of multiple subunits compartmentalized to provide antigen recognition and signal transduction function. In lieu of on-board enzymatic activity these receptors rely on associated Protein Tyrosine Kinases (PTKs) for their signaling function. By aggregating the receptors, and hence their appended PTKs, antigens induce PTK transphosphorylation, activating them to phosphorylate the receptor within conserved motifs termed Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) found in transducer subunits. The tyrosyl phosphorylated ITAMs then interact with Src Homology 2 (SH2) domains within the PTKs leading to their further activation. As receptor phosphorylation is amplified, other effectors, such as Shc, dock by virtue of SH2 binding, and serve, in-turn, as substrates for these PTKs. This sequence of events not only provides a signal amplification mechanism by combining multiple consecutive steps with positive feedback, but also allows for signal diversification by differential recruitment of effectors that provide access to distinct parallel downstream signaling pathways. The subject of antigen receptor signaling has been recently reviewed in depth (DeFranco, 1997; Kurosaki, 1997). Here we discuss the biochemical basis of antigen receptor signal transduction, using the B cell receptor (BCR) as a paradigm, with specific emphasis on the involved PTKs. We review several specific mechanisms by which responses through these receptors are propagated and modified by accessory molecules, and discuss how signal amplification and diversification are achieved.

Red blood cell rouleaux formation in dextran solution: dependence on polymer conformation.

The velocity of rouleaux formation (RF), as previously shown, increases with increasing dextran concentration up to a critical concentration (Ca), beyond which the addition of dextran reduces the RF velocity (RFV). de Gennes' model for polymer solutions suggests that dextrans exist in two conformations: a coil structure at low concentrations, which changes to a network beyond a critical concentration (C*). In the present study we examined the relation between Ca and C* for dextrans of different molecular weight, and found that they coincide. This suggests that the change in dextran behavior, from increasing to decreasing RFV, occurs when their conformation changes from coil to network. In addition, it has been reported that in dilute dextran solutions the intercellular distance (D) between RBC in rouleaux increases with the molecular weight of the dextran. We found that D correlates with Rf, the end-to-end distance of the polymer molecule, and for all dextrans D < or = 1.5 Rf. In accord with de Gennes' Model for polymers between surfaces, this corresponds to intercellular interaction with two overlapping surface-associated polymer layers, which may extend "tails" to interact with the opposing cells.

Analysis of Fc(epsilon)RI-mediated mast cell stimulation by surface-carried antigens.

Clustering of the type I receptor for IgE (Fc[epsilon]RI) on mast cells initiates a cascade of biochemical processes that result in secretion of inflammatory mediators. To determine the Fc(epsilon)RI proximity, cluster size, and mobility requirements for initiating the Fc(epsilon)RI cascade, a novel experimental protocol has been developed in which mast cells are reacted with glass surfaces carrying different densities of both antigen and bound IgE, and the cell's secretory response to these stimuli is measured. The results have been analyzed in terms of a model based on the following assumptions: 1) the glass surface antigen distribution and consequently that of the bound IgE are random; 2) Fc(epsilon)RI binding to these surface-bound IgEs immobilizes the former and saturates the latter; 3) the cell surface is formally divided into small elements, which function as a secretory stimulus unit when occupied by two or more immobilized IgE-Fc(epsilon)RI complexes; 4) alternatively, similar stimulatory units can be formed by binding of surface-carried IgE dimers to two Fc(epsilon)RI. This model yielded a satisfactory and self-consistent fitting of all of the different experimental data sets. Hence the present results establish the essential role of Fc(epsilon)RI immobilization for initiating its signaling cascade. Moreover, it provides independent support for the notion that as few as two Fc(epsilon)RIs immobilized at van der Waals contact constitute an "elementary stimulatory unit" leading to mast cell (RBL-2H3 line) secretory response.

Selective modulation of protein kinase C-theta during T-cell activation.

Every cell contains many families of protein kinases, and may express several structurally related yet genetically distinct kinases of each family. The activity of the serine/threonine protein kinase C (PKC) enzymes has long been implicated in T-cell activation, but it is not known which members of the PKC family regulate the T-cell response to foreign antigens. The activation of T cells by antigen-presenting cells (APCs) is spatially restricted to their site of contact, where receptors on the T cells engage their counter-receptors on the APCs. We used this localized engagement to identify, at the single-cell level, intracellular proteins involved in the activation process. By digital immunofluorescence microscopy, we localized six isoforms of PKC in antigen-specific T-cell clones activated by APCs. Surprisingly, only PKC-theta translocated to the site of cell contact. Accordingly, in vitro kinase activity assays of PKC immunoprecipitates from the conjugates of T cells and APCs showed a selective increase in the activity of PKC-theta, indicating that the translocated enzyme is active. Several modes of partial T-cell activation that failed to cause PKC-theta translocation also failed to cause T-cell proliferation, further suggesting the involvement of PKC-theta in T-cell activation.

Immobilization of the type I receptor for IgE initiates signal transduction in mast cells.

Clustering of the type I receptor for IgE (Fc(epsilon) RI) on mast cells initiates a cascade of biochemical processes that results in the secretion of inflammatory mediators. We have studied this clustering process in order to obtain information about receptor density and mobility required for initiating that cascade. Specifically, we examined the role of new cluster formation in sustaining the secretory response and the minimal cluster density required for initiating secretion. The experimental protocol adopted for these studies employed photoactivatable antigens and antigen-carrying solid surfaces which enabled us to control the density and mobility of the Fc epsilon RI within the cluster. Our results show that recruitment of new Fc(epsilon) RI into clusters, either by antigen exchange among Fc(epsilon) RI-bound IgE molecules or by IgE-bound Fc(epsilon) RI exchange with vacant receptors, is not required for sustaining the cellular secretory response. Furthermore, we find that the cell's secretory response is very sensitive to the density of immobilized Fc(epsilon) RIs, increasing steeply above a density of ca. 1000 immobilized molecules/microns 2. Taken together, these finding suggest that immobilization of a fraction of the randomly distributed Fc(epsilon) RIs that are in sufficient proximity on the surface of mucosal-type mast cells of the RBL-2H3 line initiates a degranulation signal, and that this is maintained as long as these receptors are kept within this distance. The above conclusions and the experimental protocol presented in this study are expected to have wider applications for the study and understanding of signaling by immuno (as well as other) receptors.

Neonatal sepsis after prolonged premature rupture of membranes.

The objective of this study was to prospectively evaluate the incidence of neonatal sepsis after prolonged premature rupture of membranes (PROM), to correlate sepsis with gestational age and with the duration of PROM, and to evaluate the necessity for prophylactic antibiotic therapy in neonates born after PROM. Of 12,182 infants, 135 (1.1%) were delivered after PROM with a latency period of > 24 hours. Neonatal sepsis occurred in 11 infants (8.1%), 10 of whom were premature. The only term, septic newborn was a small-for-gestational-age infant. A latency period > 72 hours was not associated with an increased incidence of sepsis. Maternal fever, neonatal signs of infection including leukopenia, leukocytosis, thrombocytopenia, and positive gastric aspirate cultures, were not good predictors of sepsis. Of premature infants with PROM, 15% had sepsis, and thus the administration of prophylactic antibiotic therapy in these cases may be warranted. However, it may be unnecessary to administer prophylactic antibiotics to term, appropriate-for-gestational-age infants born after PROM.

Noninvasive determination of neonatal hyperbilirubinemia: standardization for variation in skin color.

The estimation of plasma bilirubin concentration in neonates, using a transcutaneous, noninvasive jaundice meter, is significantly affected by many factors, such as gestational age, birthweight, phototherapy, and skin pigmentation. In an attempt to minimize the influence of skin color and hence circumvent the need for standardization curves for different ethnic populations, we obtained noninvasive jaundice meter readings from the infant's midsternum within 4 hours of birth and subtracted this measurement from subsequent reading in infants with hyperbilirubinemia. These results were correlated with simultaneous plasma bilirubin determinations. By this method, a single standardization curve and improved sensitivity, specificity, and predictive values for the noninvasive determination of neonatal hyperbilirubinemia in a population of mixed ethnic origin was obtained.