The overall mechanics of fold‐and‐thrust belts and accretionary wedges along compressive plate boundaries is considered to be analogous to that of a wedge of soil or snow in front of a moving bulldozer. The material within the wedge deforms until a critical taper is attained, after which it slides stably, continuing to grow at constant taper as additional material is encountered at the toe. The critical taper is the shape for which the wedge is on the verge of failure under horizontal compression everywhere, including the basal decollement. A wedge of less than critical taper will not slide when pushed but will deform internally, steepening its surface slope until the critical taper is attained. Common silicate sediments and rocks in the upper 10–15 km of the crust have pressure‐dependent brittle compressive strengths which can be approximately represented by the empirical Coulomb failure criterion, modified to account for the weakening effects of pore fluid pressure. A simple analytical theory that predicts the critical tapers of subaerial and submarine Coulomb wedges is developed and tested quantitatively in three ways: First, laboratory model experiments with dry sand match the theory. Second, the known surface slope, basal dip, and pore fluid pressures in the active fold‐and‐thrust belt of western Taiwan are used to determine the effective coefficient of internal friction within the wedge, μ = 1.03, consistent with Byerlee's empirical law of sliding friction, μb = 0.85, on the base. This excess of internal strength over basal friction suggests that although the Taiwan wedge is highly deformed by imbricate thrusting, it is not so pervasively fractured that frictional sliding is always possible on surfaces of optimum orientation. Instead, the overall internal strength apparently is controlled by frictional sliding along suboptimally oriented planes and by the need to fracture some parts of the observed geometrically complex structure for continued deformation. Third, using the above values of μb and μ we predict Hubbert‐Rubey fluid pressure ratios λ = λb for a number of other active subaerial and submarine accretionary wedges based on their observed tapers, finding values everywhere in excess of hydrostatic. These predicted overpressures are reasonable in light of petroleum drilling experience in general and agree with nearby fragmentary well data in specific wedges where they are available. The pressure‐dependent Coulomb wedge theory developed here is expected to break down if the decollement exhibits pressure‐independent plastic behavior because of either temperature or rock type. The effects of this breakdown are observed in the abrupt decrease in taper where wedge thicknesses exceed about 15 km, which is the predicted depth of the brittle‐plastic transition in quartz‐rich rocks for typical geothermal gradients. We conclude that fold‐and‐thrust belts and accretionary wedges have the mechanics of bulldozer wedges in compression and that normal laboratory fracture and frictional strengths are appropriate to mo...

Natural killer (NK) cells destroy virus-infected and tumour cells, apparently without the need for previous antigen stimulation. In part, target cells are recognized by their diminished expression of major histocompatibility complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface. NK cells also express triggering receptors that are specific for non-MHC ligands; but the nature of the ligands recognized on target cells is undefined. NKp46 is thought to be the main activating receptor for human NK cells. Here we show that a soluble NKp46-immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin-neuraminidase of parainfluenza virus. In a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent with the known sialic binding capacity of the viral glycoproteins. These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein.

Transmission of HIV-1 via intercellular connections has been estimated as 100-1000 times more efficient than a cell-free process, perhaps in part explaining persistent viral spread in the presence of neutralizing antibodies. Such effective intercellular transfer of HIV-1 could occur through virological synapses or target-cell filopodia connected to infected cells. Here we report that membrane nanotubes, formed when T cells make contact and subsequently part, provide a new route for HIV-1 transmission. Membrane nanotubes are known to connect various cell types, including neuronal and immune cells, and allow calcium-mediated signals to spread between connected myeloid cells. However, T-cell nanotubes are distinct from open-ended membranous tethers between other cell types, as a dynamic junction persists within T-cell nanotubes or at their contact with cell bodies. We also report that an extracellular matrix scaffold allows T-cell nanotubes to adopt variably shaped contours. HIV-1 transfers to uninfected T cells through nanotubes in a receptor-dependent manner. These data lead us to propose that HIV-1 can spread using nanotubular connections formed by short-term intercellular unions in which T cells specialize.

To avoid detection by CTL, HIV encodes mechanisms for removal of class I MHC proteins from the surface of infected cells. However, class I downregulation potentially exposes the virus-infected cell to attack by NK cells. Human lymphoid cells are protected from NK cell cytotoxicity primarily by HLA-C and HLA-E. We present evidence that HIV-1 selectively downregulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E. We then identify the residues in HLA-C and HLA-E that protect them from HIV down-regulation. This selective downregulation allows HIV-infected cells to avoid NK cell-mediated lysis and may represent for HIV a balance between escape from CTL and maintenance of protection from NK cells. These results suggest that subpopulations of CTL and NK cells may be uniquely suited for combating HIV.

We report that two classes of membrane nanotubes between human monocyte-derived macrophages can be distinguished by their cytoskeletal structure and their functional properties. Thin membrane nanotubes contained only F-actin, whereas thicker nanotubes, i.e., those > approximately 0.7 microm in diameter, contained both F-actin and microtubules. Bacteria could be trapped and surf along thin, but not thick, membrane nanotubes toward connected macrophage cell bodies. Once at the cell body, bacteria could then be phagocytosed. The movement of bacteria is aided by a constitutive flow of the nanotube surface because streptavidin-coated beads were similarly able to traffic along nanotubes between surface-biotinylated macrophages. Mitochondria and intracellular vesicles, including late endosomes and lysosomes, could be detected within thick, but not thin, membrane nanotubes. Analysis from kymographs demonstrated that vesicles moved in a stepwise, bidirectional manner at approximately 1 microm/s, consistent with their traffic being mediated by the microtubules found only in thick nanotubes. Vesicular traffic in thick nanotubes and surfing of beads along thin nanotubes were both stopped upon the addition of azide, demonstrating that both processes require ATP. However, microtubule destabilizing agents colchicine or nocodazole abrogated vesicular transport but not the flow of the nanotube surface, confirming that distinct cytoskeletal structures of nanotubes give rise to different functional properties. Thus, membrane nanotubes between macrophages are more complex than unvarying ubiquitous membrane tethers and facilitate several means for distal interactions between immune cells.

A critically tapered fold‐and‐thrust belt or submarine accretionary wedge is one that is on the verge of Coulomb failure everywhere, including its base where frictional sliding along a decollement is assumed to be occurring. Cohesion within a wedge can add significantly to the overall strength near the toe; the effect of this is to decrease the near‐toe taper, leading to a critical topographic profile that is concave upward if the decollement is planar. We obtain an approximate self‐consistent solution for the state of stress within a thin‐skinned cohesive critical Coulomb wedge, and determine the relationship between the wedge taper and its strength and basal friction. The theory is then applied to the presently deforming fold‐and‐thrust belt of western Taiwan. Fitting of theoretical critical wedge shapes to topographic profiles and measurements of the step‐up angles of thrust faults from the basal decollement are used to constrain the Taiwan wedge strength parameters. An attractive assertion fully consistent with all the observations is that the mechanics of fold‐and‐thrust belts and accretionary wedges is governed by normal frictional and fracture strengths of rocks measured in the laboratory. In particular, if Byerlee's law µb = 0.85 is adopted as the coefficient of sliding friction on the base, we find a coefficient of internal friction µ = 0.9–1.0 in the wedge and a wedge cohesion So = 5–20 MPa. Other solutions having strengths and ambient stresses up to 4 times lower than this can also, however, satisfy the data.

N atural killer (NK) cells express a variety of inhibitory killer Ig-like receptors (KIR) that inhibit cytotoxicity upon recognition of class I MHC proteins (1). In this manner NK cells detect diseased cells through their loss of expression of self-MHC protein rather than by directly detecting foreign antigen, a conjecture known as the missing self-hypothesis (2). Inhibitory NK receptors containing two Ig domains, denoted KIR1 (or KIR2DL1) and KIR2 (or KIR2DL2), recognize the class I MHC proteins, HLA-Cw4 or -Cw6 and HLA-Cw3 or -Cw7, respectively (3, 4). Crystal structures of both class I MHC and KIR extracellular domains have been determined (5-9), and the appropriate binding sites have been mapped by site-directed mutagenesis (10-15). Although the binding kinetics between soluble KIR͞MHC proteins, determined by surface plasmon resonance, are extremely fast (16-18), video microscopy of NK cell immunosurveillance shows that intercellular contacts last for minutes (not shown). Thus, we set out to delineate the molecular mechanisms of NK cell recognition that occur over this time frame.An enhanced variant of green fluorescent protein (EGFP) (19), originally discovered and cloned from Aequorea victoria jellyfish (20, 21), was used to mark the location of HLA-C. Plasmids encoding EGFP attached to the intracellular C terminus of class I MHC protein were transfected into 721.221, a B cell line derived by mutagenesis that does not express class I MHC protein (22,23). These transfectants then were incubated with various NK cell lines for 20 min at 37°C, after which time many NK cell͞target cell conjugates were formed. Conjugates of living NK and target cells were imaged by laser-scanning confocal fluorescence microscopy. This methodology advances previous imaging of mouse T cell͞target cell intercellular contacts that used paraformaldehyde-fixed cells (24) or live T cells interacting with MHC protein-rich lipid bilayers (25). Here, immune synapses are shown to exist at the contact between two living human cells. Materials and MethodsCell Lines and Transfectants. Plasmids encoding EGFP attached to the C terminus of HLA-Cw3 or -Cw4 were prepared by PCR of the appropriate HLA-C allele to remove the stop codon and add an EcoRI restriction site at the 5Ј end and a NotI site at the 3Ј end. EGFP was prepared by PCR from the plasmid pEGFP (CLONTECH) to contain a NotI site at the 5Ј end and a BamHI site at the 3Ј end. These PCR products then were joined and amplified together by PCR by using primers at the 5Ј end of HLA-C and the 3Ј end of EGFP. The product was cloned first into pBABE and then into pcDNA3 (Invitrogen). Plasmids encoding other GFP-linked proteins were prepared by PCR of the appropriate HLA-C allele to remove the stop codon and cloned as KpnI͞NotI fragments into the vector initially encoding HLA-Cw3-GFP. All primers were purchased from Life Technologies (Gaithersburg, MD) and all plasmid inserts were sequenced by the Core Facilities, Dana-Farber Cancer Institute (Boston, MA). 721.221 cells were transfected with 10...

The Makran subduction zone of Iran and Pakistan exhibits strong variation in seismicity between its eastern and western segments and has one of the world's largest forearcs. We determine the source parameters for 14 earthquakes at Makran including the great (Mw 8.1) earthquake of 1945 (the only instrumentally recorded great earthquake at Makran); we determine the loci of seismic and aseismic slip along the plate boundary, and we assess the effects of the large forearc and accretionary wedge on the style of plate boundary slip. We apply body waveform inversions and, for small‐magnitude events, use first motions of P waves to estimate earthquake source parameters. For the 1945 event we also employ dislocation modeling of uplift data. We find that the earthquake of 1945 in eastern Makran is an interplate thrust event that ruptured approximately one‐fifth the length of the subduction zone. Nine smaller events in eastern Makran that are also located at or close to the plate interface have thrust mechanisms similar to that of the 1945 shock. Seaward of these thrust earthquakes lies the shallowest 70–80 km of the plate boundary; we find that this segment and the overlying accretionary wedge remain aseismic both during and between great earthquakes. This aseismic zone, as in other subduction zones, lies within that part of the accretionary wedge that consists of largely uconsolidated sediments (seismic velocities less than 4.0 km/s). The existence of thrust earthquakes indicates that either the sediments along the plate boundary in eastern Makran become sufficiently well consolidated and de watered about 70 km from the deformation front or older, lithified rocks are present within the forearc so that stick‐slip sliding behavior becomes possible. This study shows that a large quantity of unconsolidated sediment does not necessarily indicate a low potential for great thrust earthquakes. In contrast to the east, the plate boundary in western Makran has no clear record of historic great events, nor has modem instrumentation detected any shallow thrust events for at least the past 25 years. Most earthquakes in western Makran occur within the downgoing plate at intermediate depths. The large change in seismicity between eastern and western Makran along with two shallow events that exhibit right‐lateral strike‐slip motion in central Makran suggest segmentation of the subduction zone. Two Paleozoic continental blocks dominate the overriding plate. The boundary between them is approximately coincident with the transition in seismicity. Although relative motion between these blocks may account for some of the differing seismic behavior, the continuity of the deformation front and of other tectonic features along the subduction zone suggests that the rate of subduction does not change appreciably from east to west. The absence of plate boundary events in western Makran indicates either that entirely aseismic subduction occurs or that the plate boundary is currently locked and experiences great earthquakes with long repeat times. Ev...