Abstract-Phosphorylation of cardiac myofibrils by cAMP-dependent protein kinase (PKA) can increase the intrinsic rate of myofibrillar relaxation, which may contribute to the shortening of the cardiac twitch during ␤-adrenoceptor stimulation. However, it is not known whether the acceleration of myofibrillar relaxation is due to phosphorylation of troponin I (TnI) or of myosin binding protein-C (MyBP-C). To distinguish between these possibilities, we used transgenic mice that overexpress the nonphosphorylatable, slow skeletal isoform of TnI in the myocardium and do not express the normal, phosphorylatable cardiac TnI. The intrinsic rate of relaxation of myofibrils from wild-type and transgenic mice was measured using flash photolysis of diazo-2 to rapidly decrease the [Ca 2ϩ ] within skinned muscles from the mouse ventricles. Incubation with PKA nearly doubled the intrinsic rate of myofibrillar relaxation in muscles from wild-type mice (relaxation half-time fell from Ϸ150 to Ϸ90 ms at 22°C) but had no effect on the relaxation rate of muscles from the transgenic mice. In parallel studies with intact muscles, we assessed crossbridge kinetics indirectly by determining f min (the frequency for minimum dynamic stiffness) during tetanic contractions. Stimulation of ␤-adrenoceptors with isoproterenol increased f min from 1.9 to 3.1 Hz in muscles from wild-type mice but had no effect on f min in muscles from transgenic mice. We conclude that the acceleration of myofibrillar relaxation rate by PKA is due to phosphorylation of TnI, rather than MyBP-C, and that this may be due, at least in part, to faster crossbridge cycle kinetics. . This increase of relaxation rate is important for proper pump function, because it allows adequate time for diastolic filling of the ventricles despite the raised heart rate during sympathetic stimulation. The activation of ␤ 1 -adrenoceptors stimulates the cAMP/protein kinase A (PKA) pathway, and the faster relaxation of the myocardial cells is partly due to an enhanced reuptake of Ca 2ϩ into the sarcoplasmic reticulum (SR) as a result of phosphorylation of phospholamban by PKA. 1 In addition, PKA phosphorylates the cardiac myofibrils during ␤-stimulation. [2][3][4] This may lead to an acceleration of the intrinsic rate of myofibrillar relaxation, thereby contributing to the abbreviation of the twitch. Using flash photolysis of the caged chelator of Ca 2ϩ , diazo-2, to rapidly decrease Ca 2ϩ concentration inside skinned fibers, Zhang et al 5 reported that PKA accelerated relaxation in pig skinned muscles. However, a later study by Johns et al 6 found no effect in similar experiments using guinea pig skinned muscles. Recent work with intact mouse muscles has suggested that ␤-stimulation can produce an SR-independent, presumably myofibril-mediated, acceleration of relaxation that is seen in isometric but not isotonic contractions. 4 Assuming that phosphorylation does increase the relaxation rate of cardiac myofibrils, how might this be produced? It is known that phosphorylation of troponin I (...

We examined the influences of Ca2+ and crossbridge kinetics on the maximum rate of force development during Ca2+ activation of cardiac myofibrils and on the maximum rate of relaxation. Flash photolysis of diazo-2 or nitrophenyl-EGTA was used to produce a sudden decrease or increase, respectively, in [Ca2+] within Triton-skinned trabeculae from rat and guinea pig hearts (22 degrees C). Trabeculae from both species had similar Ca2+ sensitivities, suggesting that the rate of dissociation of Ca2+ from troponin C (k(off)) is similar in the 2 species. However, the rate of relaxation after diazo-2 photolysis was 5 times faster in the rat (16.1 +/- 0.9 s(-1), mean +/- SEM, n = 11) than in the guinea pig (2.99 +/- 0.26 s(-1), n = 7). This indicates that the maximum relaxation rate is limited by crossbridge kinetics rather than by k(off). The maximum rates of rapid activation by Ca2+ after nitrophenyl-EGTA photolysis (k(act)) and of force redevelopment after forcible crossbridge dissociation (k(act)) were similar and were approximately 5-fold faster in rat (k(act)= 14.4 +/- 0.9 s(-1), k(tr)= 13.0 +/- 0.6 s(-1)) than in guinea pig (k(act)= 2.57 +/- 0.14 s(-1), k(tr)= 2.69 +/- 0.30 s(-1)) trabeculae. This too may be mainly due to species differences in crossbridge kinetics. Both k(act) and k(tr) increased as [Ca2+] increased. This Ca2+ dependence of the rates of force development is consistent with current models for the Ca2+ activation of the crossbridge cycle, but these models do not explain the similarity in the maximal rates of activation and relaxation within a given species.

Topological photonic systems, with their ability to host states protected against disorder and perturbation, allow us to do with photons what topological insulators do with electrons. Topological photonics can refer to electronic systems coupled with light or purely photonic setups. By shrinking these systems to the nanoscale, we can harness the enhanced sensitivity observed in nanoscale structures and combine this with the protection of the topological photonic states, allowing us to design photonic local density of states and to push towards one of the ultimate goals of modern science: the precise control of photons at the nanoscale. This is paramount for both nano-technological applications and also for fundamental research in light matter problems. For purely photonic systems, we work with bosonic rather than fermionic states, so the implementation of topology in these systems requires new paradigms. Trying to face these challenges has helped in the creation of the exciting new field of topological nanophotonics, with far-reaching applications. In this prospective article we review milestones in topological photonics and discuss how they can be built upon at the nanoscale. I. OVERVIEWOne of the ultimate goals of modern science is the precise control of photons at the nanoscale. Topological nanophotonics offers a promising path towards this aim.A key feature of topological condensed matter systems is the presence of topologically protected surface states immune to disorder and impurities. These unusual properties can be transferred to nanophotonic systems, allowing us to combine the high sensitivity of nanoscale systems with the robustness of topological states. We expect that this new field of topological nanophotonics will lead to a plethora of new applications and increased physical insight.In this perspective, as presented schematically in FIG. 1, we begin (section II) by exploring topology in electronic systems. We aim this section towards readers who are new to the topic, so begin at an introductory level where no prior knowledge of topology is assumed.In section III we introduce light, first by discussing how topological electronic systems can interact with light (section III A), then move onto the topic of topological photonic analogues (section III B), in which purely photonic platforms are used to mimic the physics of topological condensed matter systems.In section IV we discuss various paths via which topological photonics can be steered into the nanoscale. Excellent and extensive reviews already exist on topological photonics [1][2][3][4], and many platforms showcasing unique strengths and limitations are currently being studied in the drive towards new applications in topological photonics such as cold atoms [5], liquid helium [6], polaritons [7], acoustic [8] and mechanical systems [9] but in this work * marie.rider16@imperial.ac.uk † www.GianniniLab.com FIG. 1. Schematic overview Schematic showing the topics covered in this perspective.we restrict ourselves to nanostructures. We discuss the effo...

1. We investigated the effects of acidosis, inorganic phosphate (Pi) and caffeine on the Ca2" affinity of isolated fast-twitch skeletal and cardiac troponin C (TnC), labelled with fluorescent probes to report Ca2" binding to the regulatory sites. We also measured the effects of these interventions on the maximum force development and the Ca2" sensitivity of skinned fibres from fast-twitch skeletal muscle and cardiac muscle, as has been done previously. The two types of experiment were carried out under similar solution conditions, so that we could assess the contribution of any direct actions on TnC to the modulation of Ca2" sensitivity in the skinned muscle fibres.2. In skinned fibres, acidosis (decreasing pH from 7 0 to 6 2) and Pi (20 mM) suppressed maximum force to the same extent within a given muscle type, but had greater effects on cardiac fibres compared with skeletal fibres. Caffeine (20 mM) depressed maximum force equally in cardiac and skeletal muscle. Thus, the fall of force induced by acidosis or P1 may involve a different mechanism from that induced by caffeine. 3. Skinned skeletal fibres were more Ca2" sensitive than cardiac fibres by 0-29 pCa units (pCa = -log1O[Ca2"]). Isolated skeletal TnC also had a greater Ca2" affinity than cardiac TnC, by 0-20 pCa units. These results suggest that the Ca2+ sensitivity of skinned fibres is at least partly determined by the type of TnC present.4. Acidosis reduced the Ca2+ sensitivity of force in skinned fibres profoundly and had a 2-fold greater effect in cardiac muscle than skeletal muscle (falls in pCa for 50% activation, pCa50, were 1-09 and 0 55, respectively). Acidosis also reduced the Ca2+ affinity of TnC, again having double the effect on the pCa50 for cardiac TnC (0 58) as on that for skeletal TnC (0 28). The greater effect of acidosis on cardiac skinned fibres, compared with skeletal, may be partly explained, therefore, by the type of TnC present, and one-half of the effect on fibres may be attributed to the direct effect of H+ on TnC.5. Pi reduced the Ca2`sensitivity of force in skeletal and cardiac skinned fibres by 0 30 and 0X19 pCa units, respectively. However, the Ca2+ affinity of isolated cardiac and skeletal TnC was unaffected by Pi, indicating that the decrease in muscle Ca2+ sensitivity is not mediated by a direct action of Pi on TnC.6. Caffeine increased the Ca2+ sensitivity of cardiac skinned fibres by 0f31 pCa units, which was 3 times greater than for the skeletal fibres (0 09 pCa units). Caffeine had no effect on Ca2+ binding to isolated TnC, so its Ca2+ sensitizing action on skinned fibres is unlikely to be due to a direct effect on TnC. 7. We conclude that the different Ca2+ and pH sensitivities of cardiac and skeletal fibres are partly accounted for by the properties of the TnC present. However, the actions of caffeine and Pi on skinned fibres are not explained by any direct actions on TnC. Some of the Pi-induced decrease in Ca2`sensitivity probably results from a reduced Ca2+ affinity of TnC in the thin filament as a result of a decr...

The design of achromatic optical components requires materials with high transparency and low dispersion. We show that although metals are highly opaque, densely packed arrays of metallic nanoparticles can be more transparent to infrared radiation than dielectrics such as germanium, even when the arrays are over 75% metal by volume. Such arrays form effective dielectrics that are virtually dispersion-free over ultra-broadband ranges of wavelengths from microns up to millimeters or more. Furthermore, the local refractive indices may be tuned by altering the size, shape, and spacing of the nanoparticles, allowing the design of gradient-index lenses that guide and focus light on the microscale. The electric field is also strongly concentrated in the gaps between the metallic nanoparticles, and the simultaneous focusing and squeezing of the electric field produces strong ‘doubly-enhanced’ hotspots which could boost measurements made using infrared spectroscopy and other non-linear processes over a broad range of frequencies.

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During heart failure, force production by the heart decreases. This may be overcome by Ca 2+ -sensitizing drugs, which increase myofibril Ca 2+ sensitivity without necessarily altering intracellular Ca 2+ concentration. However, Ca 2+ sensitizers slow the relaxation of intact cardiac muscle. We used diazo-2, a caged chelator of Ca 2+ , to study the effects of the Ca 2+ sensitizers caffeine and CGP 48506 on the intrinsic relaxation rate of cardiac myofibrils. Trabeculae from rat right ventricles were skinned by 1% Triton X-100 and were activated in a 10-μL bath. In steady state experiments, CGP 48506 (10 μmol/L) shifted the force-pCa curve leftward by 0.41±0.03 pCa units (mean±SEM, n=6). An identical shift was induced by caffeine (20 mmol/L). Photolysis of diazo-2 by a flash of light (160 mJ, 310 to 400 nm) caused an immediate decrease in Ca 2+ -activated force produced by the trabeculae. Relaxation was fitted by a double-exponential decay, and the rate constants were found to be independent of force and preflash Ca 2+ concentration. The initial fast rate, corresponding to myofibrillar relaxation, was increased from 17.3±2.0 to 30.9±3.7 s −1 (n=4) by caffeine but was unaffected by CGP 48506 (16.6±1.7 and 14.4±2.3 s −1 in the absence and presence of drug, respectively; n=5). Thus, myofibril relaxation need not be slowed by Ca 2+ -sensitizing agents but can even be accelerated. Despite similarities in their effects on myofibril Ca 2+ sensitivity, caffeine and CGP 48506 affect the myofibrils at least partly via different mechanisms.

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