Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes

The joints of mammals are lined with cartilage, comprised of individual chondrocytes embedded in a specialized extracellular matrix. Chondrocytes experience a complex mechanical environment and respond to changing mechanical loads in order to maintain cartilage homeostasis. It has been proposed that mechanically gated ion channels are of functional importance in chondrocyte mechanotransduction; however, direct evidence of mechanical current activation in these cells has been lacking. We have used high-speed pressure clamp and elastomeric pillar arrays to apply distinct mechanical stimuli to primary murine chondrocytes, stretch of the membrane and deflection of cell-substrate contacts points, respectively. Both TRPV4 and PIEZO1 channels contribute to currents activated by stimuli applied at cell-substrate contacts but only PIEZO1 mediates stretch-activated currents. These data demonstrate that there are separate, but overlapping, mechanoelectrical transduction pathways in chondrocytes

Collagen organization within the cartilage of TRPV4(-/-) mice studied with two-photon microscopy and polarized second harmonic generation

The polymodal channel TRPV4 has been shown to regulate development and maintenance of cartilage. Here we investigate whether TRPV4 activity regulates the early deposition and structure of collagen matrix in the femoral head cartilage by comparing the 3D morphology and the sub-micrometer organization of the collagen matrix between wild type and TRPV4(-/-) mice pups four to five days old. Two-photon microscopy can be used to conduct label-free imaging of cartilage, as collagen generates a second harmonic signal (second harmonic generation [SHG]) under pulsed infrared excitation. In one set of measurements, we use circularly polarized laser light to reconstruct the 3D morphology of the femoral head cartilage and to measure the tissue thickness. Second, by rotating the direction of the linearly polarized light and using polarized SHG detection, we investigate the sub-micrometer orientation of collagen fibers in the cartilage. At this developmental stage, we cannot detect statistically significant differences between the two mice strains, although a tendency toward a more random orientation of collagen fibers and a higher thickness of the whole cartilage seems to characterize the TRPV4(-/-) mice. We discuss possible reasons for these observations

Voltage gating of mechanosensitive PIEZO channels

Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Older invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive, but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts

Permeable conformal walls and holography

We study conformal field theories in two dimensions separated by domain walls, which preserve at least one Virasoro algebra. We develop tools to study such domain walls, extending and clarifying the concept of `folding' discussed in the condensed-matter literature. We analyze the conditions for unbroken supersymmetry, and discuss the holographic duals in AdS3 when they exist. One of the interesting observables is the Casimir energy between a wall and an anti-wall. When these separate free scalar field theories with different target-space radii, the Casimir energy is given by the dilogarithm function of the reflection probability. The walls with holographic duals in AdS3 separate two sigma models, whose target spaces are moduli spaces of Yang-Mills instantons on T4 or K3. In the supergravity limit, the Casimir energy is computable as classical energy of a brane that connects the walls through AdS3. We compare this result with expectations from the sigma-model point of view.Comment: Latex file, 34 pages, 8 figures, uses JHEP3.cls. Typos corrected and references adde

Spacetime Properties of ZZ D-Branes

We study the tachyon and the RR field sourced by the $(m,n)$ ZZ D-branes in type 0 theories using three methods. We first use the mini-superspace approximation of the closed string wave functions of the tachyon and the RR scalar to probe these fields. These wave functions are then extended beyond the mini-superspace approximation using mild assumptions which are motivated by the properties of the corresponding wave functions in the mini-superspace limit. These are then used to probe the tachyon and the RR field sourced. Finally we study the space time fields sourced by the $(m,n)$ ZZ D-branes using the FZZT brane as a probe. In all the three methods we find that the tension of the $(m,n)$ ZZ brane is $mn$ times the tension of the $(1,1)$ ZZ brane. The RR charge of these branes is non-zero only for the case of both $m$ and $n$ odd, in which case it is identical to the charge of the $(1,1)$ brane. As a consistency check we also verify that the space time fields sourced by the branes satisfy the corresponding equations of motion.Comment: 32 pages, 4 figures. Clarifications on the principal characterization of ZZ branes added. Reference adde

ONE LOOP QED VERTEX IN ANY COVARIANT GAUGE: ITS COMPLETE ANALYTIC FORM

The one loop vertex in QED is calculated in arbitrary covariant gauges as an analytic function of its momenta. The vertex is decomposed into a longitudinal part, that is fully responsible for ensuring the Ward and Ward-Takahashi identities are satisfied, and a transverse part. The transverse part is decomposed into 8 independent components each being separately free of kinematic singularities in $\bf any$ covariant gauge in a basis that modifies that proposed by Ball and Chiu. Analytic expressions for all 11 components of the ${O(\alpha)}$ vertex are given explicitly in terms of elementary functions and one Spence function. These results greatly simplify in particular kinematic regimes.Comment: 35 pages, latex, 2 figures, Complete postscript file available from: ftp://cpt1.dur.ac.uk/pub/preprints/dtp95/dtp9506/dtp9406.p

Search for Neutral Q-balls in Super-Kamiokande II

A search for Q-balls induced groups of successive contained events has been carried out in Super-Kamiokande II with 541.7 days of live time. Neutral Q-balls would emit pions when colliding with nuclei, generating a signal of successive contained pion events along a track. No candidate for successive contained event groups has been found in Super-Kamiokande II, so upper limits on the possible flux of such Q-balls have been obtained.Comment: 5 pages, 5 figures, Submitted to Phys. Lett.

Microflares and the Statistics of X-ray Flares

This review surveys the statistics of solar X-ray flares, emphasising the new views that RHESSI has given us of the weaker events (the microflares). The new data reveal that these microflares strongly resemble more energetic events in most respects; they occur solely within active regions and exhibit high-temperature/nonthermal emissions in approximately the same proportion as major events. We discuss the distributions of flare parameters (e.g., peak flux) and how these parameters correlate, for instance via the Neupert effect. We also highlight the systematic biases involved in intercomparing data representing many decades of event magnitude. The intermittency of the flare/microflare occurrence, both in space and in time, argues that these discrete events do not explain general coronal heating, either in active regions or in the quiet Sun.Comment: To be published in Space Science Reviews (2011

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd