M line–deficient titin causes cardiac lethality through impaired maturation of the sarcomere

Titin, the largest protein known to date, has been linked to sarcomere assembly and function through its elastic adaptor and signaling domains. Titin's M-line region contains a unique kinase domain that has been proposed to regulate sarcomere assembly via its substrate titin cap (T-cap). In this study, we use a titin M line–deficient mouse to show that the initial assembly of the sarcomere does not depend on titin's M-line region or the phosphorylation of T-cap by the titin kinase. Rather, titin's M-line region is required to form a continuous titin filament and to provide mechanical stability of the embryonic sarcomere. Even without titin integrating into the M band, sarcomeres show proper spacing and alignment of Z discs and M bands but fail to grow laterally and ultimately disassemble

Midregional pro-Adrenomedullin in addition to b-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study

The identification of patients at highest risk for adverse outcome who are presenting with acute dyspnea to the emergency department remains a challenge. This study investigates the prognostic value of the newly described midregional fragment of the pro-Adrenomedullin molecule (MR-proADM) alone and combined to B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) in patients with acute dyspnea.; We conducted a prospective, observational cohort study in the emergency department of a University Hospital and enrolled 287 unselected, consecutive patients (48% women, median age 77 (range 68 to 83) years) with acute dyspnea.; MR-proADM levels were elevated in non-survivors (n = 77) compared to survivors (median 1.9 (1.2 to 3.2) nmol/L vs. 1.1 (0.8 to 1.6) nmol/L; P > 0.001). The areas under the receiver operating characteristic curve (AUC) to predict 30-day mortality were 0.81 (95% CI 0.73 to 0.90), 0.76 (95% CI 0.67 to 0.84) and 0.63 (95% CI 0.53 to 0.74) for MR-proADM, NT-proBNP and BNP, respectively (MRproADM vs. NTproBNP P = 0.38; MRproADM vs. BNP P = 0.009). For one-year mortality the AUC were 0.75 (95% CI 0.69 to 0.81), 0.75 (95% CI 0.68 to 0.81), 0.69 (95% CI 0.62 to 0.76) for MR-proADM, NT-proBNP and BNP, respectively without any significant difference. Using multivariate linear regression analysis, MR-proADM strongly predicted one-year all-cause mortality independently of NT-proBNP and BNP levels (OR = 10.46 (1.36 to 80.50), P = 0.02 and OR = 24.86 (3.87 to 159.80) P = 0.001, respectively). Using quartile approaches, Kaplan-Meier curve analyses demonstrated a stepwise increase in one-year all-cause mortality with increasing plasma levels (P > 0.0001). Combined levels of MR-proADM and NT-proBNP did risk stratify acute dyspneic patients into a low (90% one-year survival rate), intermediate (72 to 82% one-year survival rate) or high risk group (52% one-year survival rate).; MR-proADM alone or combined to NT-proBNP has a potential to assist clinicians in risk stratifying patients presenting with acute dyspnea regardless of the underlying disease

The proteolytic activation of (H3N2) influenza A virus hemagglutinin is facilitated by different type II transmembrane serine proteases

Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is necessary for viral activation and infectivity. In humans and mice, members of the type II transmembrane protease family (TTSP), e.g., TMPRSS2, TMPRSS4, and TMPRSS11d (HAT), have been shown to cleave influenza virus HA for viral activation and infectivity in vitro. Recently, we reported that inactivation of a single HA-activating protease gene, Tmprss2, in knockout mice inhibits the spread of H1N1 influenza viruses. However, after infection of Tmprss2 knockout mice with an H3N2 influenza virus, only a slight increase in survival was observed, and mice still lost body weight. In this study, we investigated an additional trypsin-like protease, TMPRSS4. Both TMPRSS2 and TMPRSS4 are expressed in the same cell types of the mouse lung. Deletion of Tmprss4 alone in knockout mice does not protect them from body weight loss and death upon infection with H3N2 influenza virus. In contrast, Tmprss2-/- Tmprss4-/- double-knockout mice showed a remarkably reduced virus spread and lung pathology, in addition to reduced body weight loss and mortality. Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus in vivo

Local anesthesia in piglets undergoing castration-A comparative study to investigate the analgesic effects of four local anesthetics on the basis of acute physiological responses and limb movements

Surgical castration of male piglets without analgesia is a painful procedure. This prospective, randomized and double-blinded study aimed to evaluate the analgesic effects of four different local anesthetics for piglet castration during the first week of life. In total, 54 piglets aged 3 to 7 days were distributed into 6 treatment groups: handling (H);castration without pain relief (sodium chloride, NaCl);and castration with a local anesthetic: 4% procaine (P), 2% lidocaine (L), 0.5% bupivacaine (B) or 20 mg/ml mepivacaine (M). By excluding stress and fear as disruptive factors via a minimum anesthesia model, all piglets received individual minimum alveolar concentration (MAC) isoflurane anesthesia. Twenty minutes before castration, all treatment groups except group H received one injection per testis. Then, 0.5 ml of a local anesthetic or NaCl was injected intratesticularly (i.t.), and 0.5 ml was administered subscrotally. Acute physiological responses to noxious stimuli at injection and castration were evaluated by measuring blood pressure (BP), heart rate (HR), cortisol, epinephrine, norepinephrine and chromogranin A (CgA);limb movements were quantified. The results confirm that castration without analgesia is highly painful. Surgical castration without pain relief revealed significant changes in mean arterial blood pressure (MAP) and HR. Local anesthetic administration significantly reduced changes in BP and HR associated with castration. Piglets receiving a preoperative local anesthetic exhibited the fewest limb movements during castration, while the NaCl group exhibited the most. Injection itself was not associated with significant changes in MAP or HR. However, many piglets exhibited limb movements during injection, indicating that the injection itself causes nociceptive pain. No significant differences were found between groups regarding parameters of plasma cortisol, catecholamines and CgA. In conclusion, all four local anesthetics administered are highly effective at reducing signs of nociception during castration under light isoflurane anesthesia. However, injection of a local anesthetic seems to be painful

On the enzymatic activity of catalase: an iron L-edge X-ray absorption study of the active centre

Catalase and methaemoglobin have very similar haem groups, which are both ferric, yet catalase decomposes hydrogen peroxide to water and oxygen very efficiently, while methaemoglobin does not. Structural studies have attributed this behaviour to their different distal environments. Here we present Fe L-2,L-3-edge X-ray absorption spectra of these proteins in physiological solutions, which reveal clear differences in their electronic structures, in that pi back-donation of the Fe atom occurs in catalase, which confers on it a partial ferryl (Fe4+) character, while this is not the case in methaemoglobin. The origin of the Fe4+ character stems from the proximal tyrosine residue. We also find that both systems are in a high spin state. Temperature effects influence the spectra of catalase only weakly, in agreement with previous studies of its chemical activity. We conclude that the high activity of catalase is not only determined by its distal environment but also by its partial ferryl character

Gas inflows in the polar ring of NGC 4111 : the birth of an AGN

We have used Hubble Space Telescope (HST) images, SAURON Integral Field Spectroscopy (IFS), and adaptative optics assisted Gemini NIFS near-infrared K-band IFS to map the stellar and gas distribution, excitation and kinematics of the inner few kpc of the nearby edge-on S0 galaxy NGC 4111. The HST images map its ≈450 pc diameter dusty polar ring, with an estimated gas mass ≥107 M . The NIFS data cube maps the inner 110 pc radius at ≈7 pc spatial resolution, revealing a ≈220 pc diameter polar ring in hot (2267 ± 166 K) molecular H2 1–0 S(1) gas embedded in the polar ring. The stellar velocity field shows disc-dominated kinematics along the galaxy plane both in the SAURON large scale and in the NIFS nuclear-scale data. The large-scale [O III] λ5007 Å velocity field shows a superposition of two disc kinematics: one similar to that of the stars and another along the polar ring, showing non-circular motions that seem to connect with the velocity field of the nuclear H2 ring, whose kinematics indicate accelerated inflow to the nucleus. The estimated mass inflow rate is enough not only to feed an active galactic nucleus (AGN) but also to trigger circumnuclear star formation in the near future. We propose a scenario in which gas from the polar ring, which probably originated from the capture of a dwarf galaxy, is moving inwards and triggering an AGN, as supported by the local X-ray emission, which seems to be the source of the H2 1–0 S(1) excitation. The fact that we see neither near-UV nor Br γ emission suggests that the nascent AGN is still deeply buried under the optically thick dust of the polar ring

Gas inflows in the polar ring of NGC 4111: the birth of an AGN

We have used Hubble Space Telescope (HST) images, SAURON Integral Field Spectroscopy (IFS) and adaptative optics assisted Gemini NIFS near-infrared K-band IFS to map the stellar and gas distribution, excitation and kinematics of the inner few kpc of the nearby edge-on S0 galaxy NGC 4111. The HST images map its $\approx$ 450 pc diameter dusty polar ring, with an estimated gas mass $\ge10^7$ M$_\odot$. The NIFS datacube maps the inner 110 pc radius at $\approx$ 7 pc spatial resolution revealing a $\approx$ 220 pc diameter polar ring in hot ($2267\pm166$ K) molecular H$_2$ 1-0 S(1) gas embedded in the polar ring. The stellar velocity field shows disk-dominated kinematics along the galaxy plane both in the SAURON large-scale and in the NIFS nuclear-scale data. The large-scale [O III] $\lambda5007$ \AA velocity field shows a superposition of two disk kinematics: one similar to that of the stars and another along the polar ring, showing non-circular motions that seem to connect with the velocity field of the nuclear H$_2$ ring, whose kinematics indicate accelerated inflow to the nucleus. The estimated mass inflow rate is enough not only to feed an Active Galactic Nucleus (AGN) but also to trigger circumnuclear star formation in the near future. We propose a scenario in which gas from the polar ring, which probably originated from the capture of a dwarf galaxy, is moving inwards and triggering an AGN, as supported by the local X-ray emission, which seems to be the source of the H$_2$ 1-0 S(1) excitation. The fact that we see neither near-UV nor Br$\gamma$ emission suggests that the nascent AGN is still deeply buried under the optically thick dust of the polar ring.Comment: 18 pages, 21 figure

Creation of Coherent Superposition States in Inhomogeneously Broadened Media with Relaxation

We propose and analyze a scheme for "on demand" creation of coherent superposition of meta-stable states in a tripod-structured atom using frequency-chirped laser pulses. Negligible excitation of the atoms during the creation of the superposition states is a priority in our consideration. The underlying physics of the scheme is explained using the formalism of adiabatic states. By numerically solving master equation for the density matrix operator, we analyze the influence of the spontaneous decay and transverse relaxation on the efficiency of the creation of superposition states. We show that the proposed scheme is robust against small-to-medium variations of the parameters of the laser pulses. We provide a detailed analysis of the effect of the inhomogeneous (Doppler-) broadening on the efficiency of the coherence creation and show that the proposed scheme may be equally efficient in both homogeneously and Doppler-broadened media