A shortening muscle is a machine that converts metabolic energy into mechanical work, but, when a muscle is stretched, it acts as a brake, generating a high resistive force at low metabolic cost. The braking action of muscle can be activated with remarkable speed, as when the leg extensor muscles rapidly decelerate the body at the end of a jump. Here we used time-resolved x-ray and mechanical measurements on isolated muscle cells to elucidate the molecular basis of muscle braking and its rapid control. We show that a stretch of only 5 nm between each overlapping set of myosin and actin filaments in a muscle sarcomere is sufficient to double the number of myosin motors attached to actin within a few milliseconds. Each myosin molecule has two motor domains, only one of which is attached to actin during shortening or activation at constant length. A stretch strains the attached motor domain, and we propose that combined steric and mechanical coupling between the two domains promotes attachment of the second motor domain. This mechanism allows skeletal muscle to resist external stretch without increasing the force per motor and provides an answer to the longstanding question of the functional role of the dimeric structure of muscle myosin.motor proteins ͉ myosin II S keletal muscle primarily acts as a machine that uses metabolic energy to drive macroscopic movements of the body. When an active muscle shortens, the force decreases, mechanical work is done, and ATP is hydrolyzed at a faster rate. However, skeletal muscle can also act as a brake to resist a sudden increase in load. When an active muscle is lengthened, the force increases (1), work is done on the muscle, and the rate of ATP hydrolysis decreases (2-4). The braking action of muscle is a matter of everyday experience, for example, when the extensor muscles of the legs have to oppose the momentum of the body when walking downstairs or landing at the end of a jump.The molecular basis of the braking action of muscle is unknown. Muscle fibers become stiffer during a stretch (5), provided that the length change is distributed uniformly along the fiber (6-9), suggesting that force enhancement by stretch is related to the presence of an additional elastic structure. Because fiber stiffness during isometric contraction depends on myosin motors cross-linking the arrays of myosin and actin filaments in each muscle sarcomere, the stretch response might be due to recruitment of additional myosin motors. Alternatively, resistance to stretch could be due to other protein components; cytoskeletal proteins, for example, might become taut during the stretch. Whatever its molecular basis, the response must be activated during the stretch itself, i.e., on the millisecond timescale in the case of an extensor muscle during landing of the body after a jump. We therefore focused on the mechanical and structural changes in the muscle within the first few milliseconds after a rapid (120 s) stretch imposed on an isolated intact muscle fiber during isometric contraction. Using a com...

The discovery of antibiotics in the last century is considered one of the most important achievements in the history of medicine. Antibiotic usage has significantly reduced morbidity and mortality associated with bacterial infections. However, inappropriate use of antibiotics has led to emergence of antibiotic resistance at an alarming rate. Antibiotic resistance is regarded as a major health care challenge of this century. Despite extensive research, well-documented biochemical mechanisms and genetic changes fail to fully explain mechanisms underlying antibiotic resistance. Several recent reports suggest a key role for epigenetics in the development of antibiotic resistance in bacteria. The intrinsic heterogeneity as well as transient nature of epigenetic inheritance provides a plausible backdrop for high-paced emergence of drug resistance in bacteria. The methylation of adenines and cytosines can influence mutation rates in bacterial genomes, thus modulating antibiotic susceptibility. In this review, we discuss a plethora of recently discovered epigenetic mechanisms and their emerging roles in antibiotic resistance. We also highlight specific epigenetic mechanisms that merit further investigation for their role in antibiotic resistance.

Core/intermediate/shell (C/I/S) structures with Type-I emission are well-known and are gaining immense importance due to their superior luminescence properties. Here, we report a unique C/I/S structure composed of CdSe/CdS/ZnSe that exhibits both Type-I and Type-II phenomena. The structures have been well characterized using a combination of optical and structural techniques. The photoluminescence (PL) and photoluminescence excitation (PLE) data indicate the formation of a combined Type-I and Type-II structure in one material, results supported by simple theoretical calculations. Single particle fluorescence reveals colocalization of both the emissions. The X-ray diffraction (XRD) and transmission electron microscopy (TEM) results confirm the structure of these particles. The time-resolved fluorescence studies show the possibility of tuning the lifetime of these materials by changing the Type-I/Type-II thickness ratios. It is possible to form these two separate excitons in the same system separated by a CdS intermediate layer that acts both as a barrier and an active member of the Type-II system allowing the generation and recombination of two excitons, in violation of Kasha's rule.

Rapid attachment to actin of the detached motor domain of myosin dimers with one motor domain already attached has been hypothesized to explain the stretch-induced changes in X-ray interference and stiffness of active muscle. Here, using half-sarcomere mechanics in single frog muscle fibres (2.15 μm sarcomere length and 4• C), we show that: (1) an increase in stiffness of the half-sarcomere under stretch is specific to isometric contraction and does not occur in rigor, indicating that the mechanism of stiffness increase is an increase in the number of attached motors; (2) 2 ms after 100 μs stretches (amplitude 2-8 nm per half-sarcomere) imposed during an isometric tetanus, the stiffness of the array of myosin motors in each half-sarcomere (e m ) increases above the isometric value (e m0 ); (3) e m has a sigmoidal dependence on the distortion of the motor domains ( z) attached in isometric contraction, with a maximum ∼2 e m0 for a distortion of ∼6 nm; e m is influenced by detachment of motors at z > 6 nm; (4) at the end of the 100 μs stretch the relation between e m /e m0 and z lies slightly but not significantly above that at 2 ms. These results support the idea that stretch-induced sliding of the actin filament distorts the actin-attached motor domain of the myosin dimers away from the centre of the sarcomere, providing the steric conditions for rapid attachment of the second motor domain. The rate of new motor attachment must be as high as 7.5 × 10 4 s −1 and explains the rapid and efficient increase of the resistance of active muscle to stretch. Abbreviations hs, half-sarcomere; T 0 , isometric tetanic force; e, half-sarcomere stiffness; e 0 , half-sarcomere stiffness at T 0 ; C f , myofilament compliance; e m , motor array stiffness; e m0 , motor array stiffness at T 0 ; z, distortion of the myosin motor; M3, third order of the myosin-based meridional reflections; I M3 , intensity of M3; R M3 , ratio of the intensities of the higher and lower angle peaks of M3.