Novel control of cardiac myofilament response to calcium by S-glutathionylation at specific sites of myosin binding protein C

Our previous studies demonstrated a relation between glutathionylation of cardiac myosin binding protein C (cMyBP-C) and diastolic dysfunction in a hypertensive mouse model stressed by treatment with salt, deoxycorticosterone acetate, and unilateral nephrectomy. Although these results strongly indicated an important role for S-glutathionylation of myosin binding protein C as a modifier of myofilament function, indirect effects of other post-translational modifications may have occurred. Moreover, we did not determine the sites of thiol modification by glutathionylation. To address these issues, we developed an in vitro method to mimic the in situ S-glutathionylation of myofilament proteins and determined direct functional effects and sites of oxidative modification employing Western blotting and mass spectrometry. We induced glutathionylation in vitro by treatment of isolated myofibrils and detergent extracted fiber bundles (skinned fibers) with oxidized glutathione (GSSG). Immuno-blotting results revealed increased glutathionylation with GSSG treatment of a protein band around 140 kDa. Using tandem mass spectrometry, we identified the 140 kDa band as cMyBP-C and determined the sites of glutathionylation to be at cysteines 655, 479, and 627. Determination of the relation between Ca(2+)-activation of myofibrillar acto-myosin ATPase rate demonstrated an increased Ca(2+)-sensitivity induced by the S-glutathionylation. Force generating skinned fiber bundles also showed an increase in Ca-sensitivity when treated with oxidized glutathione, which was reversed with the reducing agent, dithiothreitol (DTT). Our data demonstrate that a specific and direct effect of S-glutathionylation of myosin binding protein C is a significant increase in myofilament Ca(2+)-sensitivity. Our data also provide new insights into the functional significance of oxidative modification of myosin binding protein C and the potential role of domains not previously considered to be functionally significant as controllers of myofilament Ca(2+)-responsiveness and dynamics

Speech with pauses sounds deceptive to listeners with and without hearing impairment

Purpose: Communication is as much persuasion as it is the transfer of information. This creates a tension between the interests of the speaker and those of the listener as dishonest speakers naturally attempt to hide deceptive speech, and listeners are faced with the challenge of sorting truths from lies. Hearing impaired listeners in particular may have differing levels of access to the acoustical cues that give away deceptive speech. A greater tendency towards speech pauses has been hypothesised to result from the cognitive demands of lying convincingly. Higher vocal pitch has also been hypothesised to mark the increased anxiety of a dishonest speaker.// Method: listeners with or without hearing impairments heard short utterances from natural conversations some of which had been digitally manipulated to contain either increased pausing or raised vocal pitch. Listeners were asked to guess whether each statement was a lie in a two alternative forced choice task. Participants were also asked explicitly which cues they believed had influenced their decisions.// Results: Statements were more likely to be perceived as a lie when they contained pauses, but not when vocal pitch was raised. This pattern held regardless of hearing ability. In contrast, both groups of listeners self-reported using vocal pitch cues to identify deceptive statements, though at lower rates than pauses.// Conclusions: Listeners may have only partial awareness of the cues that influence their impression of dishonesty. Hearing impaired listeners may place greater weight on acoustical cues according to the differing degrees of access provided by hearing aids./

Simulation Study of Photon-to-Digital Converter (PDC) Timing Specifications for LoLX Experiment

The Light only Liquid Xenon (LoLX) experiment is a prototype detector aimed to study liquid xenon (LXe) light properties and various photodetection technologies. LoLX is also aimed to quantify LXe's time resolution as a potential scintillator for 10~ps time-of-flight (TOF) PET. Another key goal of LoLX is to perform a time-based separation of Cerenkov and scintillation photons for new background rejection methods in LXe experiments. To achieve this separation, LoLX is set to be equipped with photon-to-digital converters (PDCs), a photosensor type that provides a timestamp for each observed photon. To guide the PDC design, we explore requirements for time-based Cerenkov separation. We use a PDC simulator, whose input is the light information from the Geant4-based LoLX simulation model, and evaluate the separation quality against time-to-digital converter (TDC) parameters. Simulation results with TDC parameters offer possible configurations supporting a good separation. Compared with the current filter-based approach, simulations show Cerenkov separation level increases from 54% to 71% when using PDC and time-based separation. With the current photon time profile of LoLX simulation, the results also show 71% separation is achievable with just 4 TDCs per PDC. These simulation results will lead to a specification guide for the PDC as well as expected results to compare against future PDC-based experimental measurements. In the longer term, the overall LoLX results will assist large LXe-based experiments and motivate the assembly of a LXe-based TOF-PET demonstrator system.Comment: 5 pages, 7 figure

Speech with pauses sounds deceptive to listeners with and without hearing impairment

Purpose: Communication is as much persuasion as it is the transfer of information. This creates a tension between the interests of the speaker and those of the listener as dishonest speakers naturally attempt to hide deceptive speech, and listeners are faced with the challenge of sorting truths from lies. Hearing impaired listeners in particular may have differing levels of access to the acoustical cues that reliably give away deceptive speech. A greater tendency towards speech pauses has been hypothesised to result from the cognitive demands of lying convincingly. Higher vocal pitch has also been hypothesised to mark the increased anxiety of a dishonest speaker. Method: listeners with or without hearing impairments heard short utterances from natural conversations some of which had been digitally manipulated to contain either increased pausing or raised vocal pitch. Listeners were asked to guess whether each statement was a lie in a two alternative forced choice task. Participants were also asked explicitly which cues they believed had influenced their decisions. Results: Statements were more likely to be perceived as a lie when they contained pauses, but not when vocal pitch was raised. This pattern held regardless of hearing ability. In contrast, both groups of listeners self-reported using vocal pitch cues, though at lower rates than pauses. Conclusions: Listeners may have only partial awareness of the cues that influence their impression of dishonesty. Hearing impaired listeners may place greater weight on acoustical cues according to the differing degrees of access provided by hearing aids

Study Of Widely Divergent Development Of Niosomes And Its Appliances

Niosomes are vesicles composed of non-ionic surfactants, which are biodegradable, relatively nontoxic, more stable andinexpensive, an alternative to liposomes. They present a structure similar to liposome and hence they can representalternative vesicular systems with respect to liposomes. The niosome ability to encapsulate different type of drugs withintheir multi environmental structure. Niosomes have been developed as an alternative to phospholipids based liposomes. Thetechnology utilized in niosomes is still greatly in its infancy, and already it is showing promise in the fields of cancer andinfectious disease treatments. Niosomes can also be utilized for targeting drugs to organs other than the RES. They arebased on several families of synthetic non ionic amphiphilic molecule. This review article focuses on the structure ofniosome, advantages of niosomes, methods of preparation, characterization of nisosomes, application of niosomes

Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure.

Although cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macrophages and dendritic cells (DCs), are key contributors to cardiac remodeling after myocardial infarction, their role in pressure-overload remodeling is unclear. We tested the hypothesis that these immune cells are required for the progression of remodeling in pressure-overload heart failure (HF), and that MP depletion would ameliorate remodeling.C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation, and assessed for alterations in MPs. As compared with sham, TAC mice exhibited expansion of circulating LyC6hi monocytes and pro-inflammatory CD206- cardiac macrophages early (1 w) after pressure-overload, prior to significant hypertrophy and systolic dysfunction, with subsequent resolution during chronic HF. In contrast, classical DCs were expanded in the heart in a biphasic manner, with peaks both early, analogous to macrophages, and late (8 w), during established HF. There was no significant expansion of circulating DCs, or Ly6C+ monocytes and DCs in the spleen. Periodic systemic MP depletion from 2 to 16 w after TAC in macrophage Fas-induced apoptosis (MaFIA) transgenic mice did not alter cardiac remodeling progression, nor did splenectomy in mice with established HF after TAC. Lastly, adoptive transfer of splenocytes from TAC HF mice into naïve recipients did not induce immediate or long-term cardiac dysfunction in recipient mice.Mononuclear phagocytes populations expand in a phasic manner in the heart during pressure-overload. However, they are dispensable for the progression of remodeling and failure once significant hypertrophy is evident and blood monocytosis has normalized