Downgoing plate topography stopped rupture in the A.D. 2005 Sumatra earthquake

Earthquakes in subduction zones rupture the plate boundary fault in discrete segments. One factor that may control this segmentation is topography on the downgoing plate, although it is controversial whether this is by weakening or strengthening of the fault. We use multichannel seismic and gravity data to map the top of the downgoing oceanic crust offshore central Sumatra, Indonesia. Our survey spans a complex segment boundary zone between the southern termination of the Mw = 8.7, A.D. 2005 Simeulue-Nias earthquake, and the northern termination of a major 1797 earthquake that was partly filled by an Mw = 7.7 event in 1935. We identify an isolated 3 km basement high at the northern edge of this zone, close to the 2005 slip termination. The high probably originated at the Wharton fossil ridge, and is almost aseismic in both local and global data sets, suggesting that while the region around it may be weakened by fracturing and fluids, the basement high locally strengthens the plate boundary, stopping rupture propagation

Phosphorylation and calcium antagonistically tune myosin-binding protein C\u27s structure and function

During each heartbeat, cardiac contractility results from calcium-activated sliding of actin thin filaments toward the centers of myosin thick filaments to shorten cellular length. Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filament that appears to tune these mechanochemical interactions by its N-terminal domains transiently interacting with actin and/or the myosin S2 domain, sensitizing thin filaments to calcium and governing maximal sliding velocity. Both functional mechanisms are potentially further tunable by phosphorylation of an intrinsically disordered, extensible region of cMyBP-C\u27s N terminus, the M-domain. Using atomic force spectroscopy, electron microscopy, and mutant protein expression, we demonstrate that phosphorylation reduced the M-domain\u27s extensibility and shifted the conformation of the N-terminal domain from an extended structure to a compact configuration. In combination with motility assay data, these structural effects of M-domain phosphorylation suggest a mechanism for diminishing the functional potency of individual cMyBP-C molecules. Interestingly, we found that calcium levels necessary to maximally activate the thin filament mitigated the structural effects of phosphorylation by increasing M-domain extensibility and shifting the phosphorylated N-terminal fragments back to the extended state, as if unphosphorylated. Functionally, the addition of calcium to the motility assays ablated the impact of phosphorylation on maximal sliding velocities, fully restoring cMyBP-C\u27s inhibitory capacity. We conclude that M-domain phosphorylation may have its greatest effect on tuning cMyBP-C\u27s calcium-sensitization of thin filaments at the low calcium levels between contractions. Importantly, calcium levels at the peak of contraction would allow cMyBP-C to remain a potent contractile modulator, regardless of cMyBP-C\u27s phosphorylation state

Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism

Myosin-binding protein C (MyBP-C) is an accessory protein of striated muscle thick filaments and a modulator of cardiac muscle contraction. Defects in the cardiac isoform, cMyBP-C, cause heart disease. cMyBP-C includes 11 Ig- and fibronectin-like domains and a cMyBP-C-specific motif. In vitro studies show that in addition to binding to the thick filament via its C-terminal region, cMyBP-C can also interact with actin via its N-terminal domains, modulating thin filament motility. Structural observations of F-actin decorated with N-terminal fragments of cMyBP-C suggest that cMyBP-C binds to actin close to the low Ca(2+) binding site of tropomyosin. This suggests that cMyBP-C might modulate thin filament activity by interfering with tropomyosin regulatory movements on actin. To determine directly whether cMyBP-C binding affects tropomyosin position, we have used electron microscopy and in vitro motility assays to study the structural and functional effects of N-terminal fragments binding to thin filaments. 3D reconstructions suggest that under low Ca(2+) conditions, cMyBP-C displaces tropomyosin toward its high Ca(2+) position, and that this movement corresponds to thin filament activation in the motility assay. At high Ca(2+), cMyBP-C had little effect on tropomyosin position and caused slowing of thin filament sliding. Unexpectedly, a shorter N-terminal fragment did not displace tropomyosin or activate the thin filament at low Ca(2+) but slowed thin filament sliding as much as the larger fragments. These results suggest that cMyBP-C may both modulate thin filament activity, by physically displacing tropomyosin from its low Ca(2+) position on actin, and govern contractile speed by an independent molecular mechanism

Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling

The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within the sarcomere, the elementary contractile unit. On a beat-to-beat basis, calcium is released from the ends of the sarcomere and must diffuse toward the sarcomere center to fully activate the myosin- and actin-based contractile proteins. The resultant spatial and temporal gradient in free calcium across the sarcomere should lead to nonuniform and inefficient activation of contraction. We show that myosin-binding protein C (MyBP-C), through its positioning on the myosin thick filaments, corrects this nonuniformity in calcium activation by exquisitely sensitizing the contractile apparatus to calcium in a manner that precisely counterbalances the calcium gradient. Thus, the presence and correct localization of MyBP-C within the sarcomere is critically important for normal cardiac function, and any disturbance of MyBP-C localization or function will contribute to the consequent cardiac pathologies

Introspective physicalism as an approach to the science of consciousness

Most ‘theories of consciousness’ are based on vague speculations about the properties of conscious experience. We aim to provide a more solid basis for a science of consciousness. We argue that a theory of consciousness should provide an account of the very processes that allow us to acquire and use information about our own mental states – the processes underlying introspection. This can be achieved through the construction of information processing models that can account for ‘Type-C’ processes. Type-C processes can be specified experimentally by identifying paradigms in which awareness of the stimulus is necessary for an intentional action. The Shallice (1988b) framework is put forward as providing an initial account of Type-C processes, which can relate perceptual consciousness to consciously performed actions. Further, we suggest that this framework may be refined through the investigation of the functions of prefrontal cortex. The formulation of our approach requires us to consider fundamental conceptual and methodological issues associated with consciousness. The most significant of these issues concerns the scientific use of introspective evidence. We outline and justify a conservative methodological approach to the use of introspective evidence, with attention to the difficulties historically associated with its use in psychology

Quantitative Deep Sequencing Reveals Dynamic HIV-1 Escape and Large Population Shifts during CCR5 Antagonist Therapy In Vivo

High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000–140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8–2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists

Formal Alliances, 1816-1965: an Extension of the Basic Data

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69121/2/10.1177_002234336900600305.pd

The Constraint Interpretation of Physical Emergence

I develop a variant of the constraint interpretation of the emergence of purely physical (non-biological) entities, focusing on the principle of the non-derivability of actual physical states from possible physical states (physical laws) alone. While this is a necessary condition for any account of emergence, it is not sufficient, for it becomes trivial if not extended to types of constraint that specifically constitute physical entities, namely, those that individuate and differentiate them. Because physical organizations with these features are in fact interdependent sets of such constraints, and because such constraints on physical laws cannot themselves be derived from physical laws, physical organization is emergent. These two complementary types of constraint are components of a complete non-reductive physicalism, comprising a non-reductive materialism and a non-reductive formalism

Mary's Powers of Imagination

One common response to the knowledge argument is the ability hypothesis. Proponents of the ability hypothesis accept that Mary learns what seeing red is like when she exits her black-and-white room, but they deny that the kind of knowledge she gains is propositional in nature. Rather, she acquires a cluster of abilities that she previously lacked, in particular, the abilities to recognize, remember, and imagine the color red. For proponents of the ability hypothesis, knowing what an experience is like simply consists in the possession of these abilities. Criticisms of the ability hypothesis tend to focus on this last claim. Such critics tend to accept that Mary gains these abilities when she leaves the room, but they deny that such abilities constitute knowledge of what an experience is like. To my mind, however, this critical strategy grants too much. Focusing specifically on imaginative ability, I argue that Mary does not gain this ability when she leaves the room for she already had the ability to imagine red while she was inside it. Moreover, despite what some have thought, the ability hypothesis cannot be easily rescued by recasting it in terms of a more restrictive imaginative ability. My purpose here is not to take sides in the debate about physicalism, i.e., my criticism of the ability hypothesis is not offered in an attempt to defend the anti-physicalist conclusion of the knowledge argument. Rather, my purpose is to redeem the imagination from the misleading picture of it that discussion of the knowledge argument has fostered