Detailed molecular structural information of the living state is of enormous significance to the medical and biological communities. Since hydrated biologically active structures are small delicate complex three-dimensional (3D) entities, it is essential to have molecular scale spatial resolution, high contrast, distortionless, direct 3D modalities of visualization of naturally functioning specimens in order to faithfully reveal their full molecular architectures. An x-ray holographic microscope equipped with an x-ray laser as the illuminator would be uniquely capable of providing these images. A quantitative interlocking concordance of physical evidence, that includes (a) the observation of strong enhancement of selected spectral components of several Xeq+ hollow-atom transition arrays (q = 31, 32, 34, 35, 36, 37) radiated axially from confined plasma channels, (b) the measurement of line narrowing that is spectrally correlated with the amplified transitions, (c) evidence for spectral hole-burning in the spontaneous emission, a manifestation of saturated amplification, that corresponds spectrally with the amplified lines, and (d) the detection of an intense narrow (δθx ∼ 0.2 mrad) directed beam of radiation, (1) experimentally demonstrates in the λ ∼ = 2.71–2.93 Å range (ℏωx ∼ = 4230–4570 eV) the operation of a new concept capable of producing the ideal conditions for amplification of multikilovolt x-rays and (2) proves the feasibility of a compact x-ray illuminator that can cost-effectively achieve the mission of biological x-ray microholography. The measurements also (α) establish the property of tunability in the quantum energy over a substantial fraction of the spectral region exhibiting amplification (Δℏωx ∼ 345 eV) and (β) demonstrate the coherence of the x-ray output through the observation of a canonical spatial mode pattern. An analysis of the physical scaling revealed by these results indicates that the capability of the x-ray source potentially includes single-molecule microimaging, the key for the in situ structural analysis of membrane proteins, a cardinal class of drug targets. An estimate of the peak brightness achieved in these initial experiments gives a value of ∼1031–1032 photons s−1 mm−2 mrad−2/(0.1% bandwidth), a magnitude that is ∼107–108-fold higher than presently available synchrotron technology.

A ventricular myocyte experiences changes in length and load during every beat of the heart and has the ability to remodel cell shape to maintain cardiac performance. Specifically, myocytes elongate in response to increased diastolic strain by adding sarcomeres in series, and they thicken in response to continued systolic stress by adding filaments in parallel. Myocytes do this while still keeping the resting sarcomere length close to its optimal value at the peak of the length-tension curve. This review focuses on the little understood mechanisms by which direction of growth is matched in a physiologically appropriate direction. We propose that the direction of strain is detected by differential phosphorylation of proteins in the costamere, which then transmit signaling to the Z-disc for parallel or series addition of thin filaments regulated via the actin-capping processes. In this review, we link mechanotransduction to the molecular mechanisms for regulation of myocyte length and width.

Single-pulse measurements of spectral hole burning of Xe(L) 3d → 2p hollow atom transition arrays observed from a self-trapped plasma channel provide new information on the dynamics of saturated amplification in the λ ∼ 2.8-2.9 Å region. The spectral hole burning on transitions in the Xe 34+ and Xe 35+ arrays reaches full suppression of the spontaneous emission and presents a corresponding width hω x ∼ = 60 eV, a value adequate for efficient amplification of multikilovolt x-ray pulses down to a limiting length τ x ∼ 30 as. The depth of the suppression at 2.86 Å indicates that the gain-to-loss ratio is 10. An independent determination of the x-ray pulse energy from damage produced on the surface of a Ti foil in the far field of the source gives a pulse energy of 20-30 µJ, a range that correlates well with the observation of the spectral hole burning and indicates an overall extraction efficiency of ∼10%.

Background: Talin is an integrin-actin linker essential for integrin activation.Results: Talin1 has distinct developmental and postnatal expression in heart versus Talin2. Cardiac-myocyte specific Talin1 deletion alters physiological and molecular responses of the myocardium to stress.Conclusion: Talin1 has a unique mechanotransductive role in the cardiomyocyte.Significance: Reduction of talin1 in cardiomyocytes may have beneficial effects in the stressed myocardium.

Background Heart failure (HF) is associated with excessive extracellular matrix (ECM) deposition and abnormal ECM degradation leading to cardiac fibrosis. Connective Tissue Growth Factor (CTGF) modulates ECM production during inflammatory tissue injury, but available data on CTGF gene expression in failing human heart and its response to mechanical unloading are limited. Methods and Results LV tissue from patients undergoing cardiac transplantation for ischemic (ICM; n=20) and dilated (DCM; n=20) cardiomyopathies, and from nonfailing (NF; n=20) donor hearts were examined. Paired samples (n=15) from patients undergoing LV assist device (LVAD) implantation as “bridge to transplant” (34-1145 days) were also analyzed. There was more interstitial fibrosis in both ICM and DCM compared to NF hearts. Hydroxyproline concentration was also significantly increased in DCM relative to NF samples. The expression of CTGF,TGFB1, COL1-A1, COL3-A1, MMP2 and MMP9 mRNAs in ICM and DCM were also significantly elevated as compared to NF controls. Although TGFB1, CTGF, COL1-A1, and COL3-A1 mRNA levels were reduced by unloading, there was only a modest reduction in tissue fibrosis and no difference in protein-bound hydroxyproline concentration between pre- and post-LVAD tissue samples. The persistent fibrosis may be related to a concomitant reduction in MMP9 mRNA and protein levels following unloading. Conclusions CTGF may be a key regulator of fibrosis during maladaptive remodeling and progression to HF. Although mechanical unloading normalizes most genotypic and functional abnormalities, its effect on ECM remodeling during HF is incomplete.