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Background The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy. Objectives This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy. Methods Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients. Results AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p Conclusions The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.

Silicon bolometers for space and astronomy applications, fabricated in standard CMOS-SOI technology are now successfully used as cryogenic detectors working at very low temperature, typically in the range of 0.05–0.1 K. They feature a remarkably high electromagnetic absorption, high temperature sensitivity and low noise. However, the mechanical behavior of suspended silicon bolometers results from the fabrication process parameters and a good understanding of these mechanisms is necessary to better control their deformation. In this work, silicon bolometer pixels with a pitch of 1200 μm and 500 μm for millimeter-wave (mm-wave) polarization detection have been fabricated and their mechanical behavior is investigated at room temperature and cryogenic temperature. First, a mechanical model was developed based on simulated and experimental deformations at room temperature of multi-layer cantilever test structures with different Young’s modulus and thickness (Ei, hi). The actual multi-layer suspended structures are modeled as an equivalent composite layer with an effective Young’s modulus (Eeff), an effective thickness (heff) and residual stresses (σ0, σ1). The residual stress values are positive, corresponding to a tensile stress in the fabricated multilayer stack. The impact of the a-Si passivation thickness on the total stress is discussed. The equivalent model is used in the simulation of the full pixel structure and results in excellent agreement with optical measurements of the deflection at room temperature. At cryogenic temperatures, mechanical deformations can hardly be measured, so the mechanical behavior of a 500-μm pixel was simulated at 0.1 K assuming that tensile residual stresses coming from defects are independent on temperature, and a good mechanical stability of the pixel was obtained. The optical performance simulation of this 500-μm pixel is discussed and showed that the mechanical deformations result in a degradation of the Noise Equivalent Power (NEP) from 1.59 × 10−18 to 1.05 × 10-17 W/Hz1/2 for an optical load of 6 × 10−15 W at 0.1 K.

Recently, we showed that disgusting sound cues direct spatial attention away from the location of their origin to the opposite location indicating spatial disgust avoidance (Zimmer et al., 2015, Psychophysiology; 2016, Neuroimage). However, in these studies, we had solely used an inter-stimulus interval (ISI) of 200–300 ms, leaving unclear how disgust avoidance develops over time. Studies have shown that spatial attraction due to anger persists longer when induced by auditory rather than visual stimuli. In the present ERP-study, one of two laterally presented sounds (neutral/disgust) cued a laterally presented visual target. ISIs varied from short (50–150 ms) over middle (350–450 ms) to long (650–750 ms). For disgust stimuli, response times were longer for invalidly cued targets compared to validly cued targets, reflecting disgust avoidance. There was an increased P3 amplitude for validly versus invalidly cued targets consistent with disgust avoidance. In contrast, in the neutral condition, we found evidence of inhibition of return (IOR), as we observed a reversal of the usual validity effect from short to long ISI in the behavioral data and on the P1-component. These results indicate that spatial avoidance motivated by auditory disgust persists over time, presumably enforced by emotional rather than general attentional processes.

Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSC), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSC are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP-deficiency (Nep-/-) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep-/- in addition to AT1R blocker (ARB) or ACE-inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto®, a combination of ARB and NEP-inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension.

Dr. Haugli and colleagues raised the issue that 2 recent papers published in the Journal on angiotensin (Ang) peptide levels in heart failure patients might have presented contradicting Ang data for heart failure patients treated with angiotensin-converting enzyme (ACE) inhibitors. The statement by

Little is known about the proteolytic turnover of mitochondrial proteins under static growth conditions. Combining dynamic isotope labeling and mass spectrometry in yeast cells, we found an exceptionally high turnover for the NADH dehydrogenase Nde1. This homolog of the mammalian apoptosis inducing factor AIF forms two distinct topomers in mitochondria, one residing in the intermembrane space and one cytosol-exposed form that spans the outer membrane. The latter serves as trigger of cell death with the potential to kill yeast cells in response to pro-apoptotic stimuli. The surface-exposed topomer is degraded by the cytosolic proteasome/Cdc48 system and the mitochondrial protease Yme1 in wild type cells, however, it is strongly enriched in respiratory deficient cells. Our data suggest that in addition to their role in electron transfer, mitochondrial NADH dehydrogenases such as Nde1 or AIF integrate signals from energy metabolism and cytosolic proteostasis to eliminate compromised individuals from growing cell populations.

Blockade of the renin-angiotensin system (RAS) represents a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF) [(1)][1]. Beside established pharmacological therapy with angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II type 1 receptor (AT1R) blocker

L’hyperaldosteronisme primaire est la forme la plus frequente d’hypertension arterielle secondaire. Bien que des mutations somatiques recurrentes dans differents genes codant pour des canaux ioniques et des ATPases, impliquees dans la regulation de la biosynthese d’aldosterone, aient ete identifiees dans les adenomes produisant de l’aldosterone (APA), leur role dans les phenomenes de tumorigenese reste a demontrer. L’analyse transcriptomique de 48 echantillons d’APA et 11 surrenales controles ont permis d’identifier la voie de signalisation de l’acide retinoique comme un element central dans le developpement de l’APA. L’objectif de ce projet etait d’etudier le role du recepteur α a l’acide retinoique (RARα) dans le developpement du cortex surrenalien. Resultats L’etude du phenotype surrenalien de souris rarα−/− revele une desorganisation complete de la zone fasciculee qui s’accompagne d’une dysplasie de la zone glomerulee a 12 semaines et d’une hyperplasie de cette zone a 52 semaines. Ce phenotype est egalement associe a une desorganisation de l’architecture vasculaire. A 12 semaines, on observe une diminution de l’expression de genes effecteurs et cibles impliques dans la voie de signalisation WNT, associee a une diminution de l’expression des genes de la steroidogenese. Conclusion Ces resultats suggerent que RARα contribue a la morphologie normale et la zonation fonctionnelle du cortex surrenalien en modulant la voie de signalisation WNT/β-catenine et que des alterations de cette voie pourrait contribuer a une proliferation cellulaire anormale du cortex surrenalien, creant un environnement propice a l’emergence de mutations somatiques responsables du profil secretoire des APA.

Renin-angiotensin system inhibitors (RASi) aim to reduce the negative effects of Angiotensin (Ang) II, either by decreasing its production or by inhibiting its binding to the Ang II receptor Type 1 (AT1R) using angiotensin-converting enzyme inhibitors (ACEi) or Ang receptor blockers (ARB)

Summary The innate inflammatory immune response must be tightly controlled to avoid damage to the host. Here, we showed that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Inhibition of mTOR by rapamycin promoted production of proinflammatory cytokines via the transcription factor NF-κB but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-κB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift. Rapamycin-hyperactivated monocytes displayed a strong T helper 1 (Th1) cell- and Th17 cell-polarizing potency. Inhibition of mTOR in vivo regulated the inflammatory response and protected genetically susceptible mice against lethal Listeria monocytogenes infection. These data identify the TSC2-mTOR pathway as a key regulator of innate immune homeostasis with broad clinical implications for infectious and autoimmune diseases, vaccination, cancer, and transplantation.

Two far-infrared studies on the Orion Nebula M42 are presented. The observation of the 13C+F = 1 → 0 hyperfine component in M42 shows that the optical depth of the [ 12 C II ] at 158 μm is about one, consistent with values for temperature and density of the emitting material derived in earlier studies of photodissociation regions. The observations of the 63.2 and 145.5 μm [OI] and 158 μm [CII] fine structure lines around the Orion HII region and the quiescent northern ridge might allow to derive a relative atomic oxygen abundance [O] [H] in the range of 7 × 10−5 to 3 × 10−4 using the knowledge on the [CII] emission of PDRs.

FIR [CII] images of galaxies have been made using the MPE/UCB Far-Infrared Fabry-Perot Imaging Spectrometer (FIFI) on the KAO with 55” resolution. The 158 μm cooling line of ionized carbon shows emission extended over very large scales: peaking in the nucleus and present at least out to the extent of the spiral arms as seen in the CO(1-0) line in the galaxies NGC6946, M83, NGC891 and Centaurus A and often beyond the molecular disks. Evidence for photodissociation of molecular gas over kpc scales in the spiral arms is seen in the nearly face-on galaxies M83 and NGC6946. The [CII] emission present in the disk beyond the extent of molecular gas can be produced in the diffuse HI gas, thereby allowing us to derive properties of the atomic medium, such as temperatures and pressures.

We report velocity resolved maps of the 158 μm [CII] fine structure line, of the 63 μm [OI] fine structure line, and of the 88 μm and 52μm [OIII] fine structure lines toward the center region of the Galaxy. Observations were carried out on board the Kuiper Airborne Observatory (KAO) using the MPE/UCB Far-infrared Imaging Fabry-Perot interferometer (FIFI). The angular resolution was 55″ for the [CII] line and 22″ for the oxygen lines. The [CII] emission, tracing the distribution of dense gas dissociated and partially ionized by far-UV photons, is strongest toward the rotating circumnuclear disk surrounding Sgr A West. A continuous bridge of [CII] line emission connects the Sgr A complex to the thermal radio filaments in the Radio Arc 10' north of the center, thus strongly suggesting a direct physical connection between the two. Outside the nuclear region, there is an anticorrelation between the [CII] intensity and the distribution of dense molecular material. The brightest emission occurs near the edges of the massive Galactic Center molecular clouds. We conclude that these clouds are predominantly ionized by external UV photons, partly from the Sgr A West region and partly from OB stars near the center. Our data indicate a physical connection between the center and the massive interstellar clouds in the surrounding 50 pc. Our 88 μm [OIII] maps of the “sickle” region within the Radio Arc and of the thermal arches approximately follow the thermal radio continuum. The line width varies substantially over the mapped area; we find a narrow (Δv ≈ 60km/s) and a broad (Δv ≈ 150km/s) component, with the broad component being more prominent in the sickle. From the 52 μm 88 μm line ratio we derive a density ≈ 300 cm−3 and a hydrogen column density ≈3 × 1021cm−1 in the [OIII] emitting medium. This rules out shocks or fast winds from stars as excitation mechaniμs. UV excitation, however, could produce the observed amount of O2+. About 10 to 100 O-stars would be required to ionize the gas in the “pistol/sickle” region. The broad linewidth could be due to interaction between the ionized gas and magnetic fields. Our maps of both [OIII] lines toward the circum-nuclear disk show the brightest emission from inside the central, “ionized cavity” in the molecular ring. The high 52 μm/88μm ratio requires a density ⩾ 104cm−3. The derived hydrogen column density, however, is low, which could be understood by a small ionization ratio N o2+ N o0 or a small beam filling factor of the ionized gas. We infer about 10 m⊙ of ionized gas inside the cavity, with no indication of an additional low-density component. The [OI] data, on the other hand, reveal the presence of a large amount of neutral atomic gas inside the central cavity, and associated with the “northern” and “eastern” arms of ionized gas. We estimate about 300 M⊙ of dense neutral hydrogen gas within the 1.5 pc radius of the circumnuclear ring, about a factor 10 more than the amount of ionized gas. The northern arm appears to be a bright, ionized rim at the surface of this neutral gas streamer, which is probably in the plane of the circumnuelear disk and falling from a gap in the 1.5pc ring into the central 0.5pc. We infer a mass inflow rate into the central parsec of 0.03M⊙/year.