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Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE-infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with a potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.

We analyze the cosmic-ray variations during a significant Forbush decrease observed with world-wide networks of ground-based neutron monitors and muon detectors during November 3-5, 2021. Utilizing the difference between primary cosmic-ray rigidities monitored by neutron monitors and muon detectors, we deduce the rigidity spectra of the cosmic-ray density (or omnidirectional intensity) and the first- and second-order anisotropies separately, for each hour of data. A clear two-step decrease is seen in the cosmic-ray density with the first $\sim2\%$ decrease after the interplanetary shock arrival followed by the second $\sim5\%$ decrease inside the magnetic flux rope (MFR) at 15 GV. Most strikingly, a large bidirectional streaming along the magnetic field is observed in the MFR with a peak amplitude of $\sim5\%$ at 15 GV which is comparable to the total density decrease inside the MFR. The bidirectional streaming could be explained by adiabatic deceleration and/or focusing in the expanding MFR, which have stronger effects for pitch angles near 90$^\circ$, or by selective entry of GCRs along a leg of the MFR. The peak anisotropy and density depression in the flux rope both decrease with increasing rigidity. The spectra vary dynamically indicating that the temporal variations of density and anisotropy appear different in neutron monitor and muon detector data., Accepted for publication in the Astrophysical Journal

We have previously reported that in salt-resistant rat phenotypes brain, Gαi 2 (guanine nucleotide–binding protein alpha inhibiting activity polypeptide 2) proteins are required to maintain blood pressure and sodium balance. However, the impact of hypothalamic paraventricular nucleus (PVN) Gαi 2 proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi 2 oligodeoxynucleotide, we show that PVN-specific Gαi 2 proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi 2 oligodeoxynucleotide 18±4; P 2 proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi 2 oligodeoxynucleotide 147±3; P 2 signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi 2 oligodeoxynucleotide 850±27; P 2 protein downregulation prevented PVN parvocellular neuron activation, assessed by FosB immunohistochemistry, in response to increased dietary salt intake. In our analysis of the UK BioBank data set, it was observed that 2 GNAI2 single nucleotide polymorphism (SNP) (rs2298952, P =0.041; rs4547694, P =0.017) significantly correlate with essential hypertension. Collectively, our data suggest that selective targeting and activation of PVN Gαi 2 proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension.

The mechanisms that sense alterations in total body sodium content to facilitate sodium homeostasis in response to an acute sodium challenge that does not increase blood pressure have not been fully elucidated. We hypothesized that the renal sympathetic nerves are critical to mediate natriuresis via α1- or β-adrenoceptors signal transduction pathways to maintain sodium balance in the face of acute increases in total body sodium content that do not activate the pressure-natriuresis mechanism. To address this hypothesis, we used acute bilateral renal denervation (RDNX), an anteroventral third ventricle (AV3V) lesion and α1- or β-antagonism during an acute 1M NaCl sodium challenge in conscious male Sprague Dawley rats. An acute 1M NaCl infusion did not alter blood pressure and evoked profound natriuresis and sympathoinhibition. Acute bilateral RDNX attenuated the natriuretic and sympathoinhibitory responses evoked by a 1M NaCl infusion [peak natriuresis (μeq/min) sham 14.5 ± 1.3 vs. acute RDNX: 9.2 ± 1.4, p < 0.05; plasma NE (nmol/L) sham control: 44 ± 4 vs. sham 1M NaCl infusion 11 ± 2, p < 0.05; acute RDNX control: 42 ± 6 vs. acute RDNX 1M NaCl infusion 25 ± 3, p < 0.05]. In contrast, an AV3V lesion did not impact the cardiovascular, renal excretory or sympathoinhibitory responses to an acute 1M NaCl infusion. Acute i.v. α1-adrenoceptor antagonism with terazosin evoked a significant drop in baseline blood pressure and significantly attenuated the natriuretic response to a 1M NaCl load [peak natriuresis (μeq/min) saline 17.2 ± 1.4 vs. i.v. terazosin 7.8 ± 2.5, p < 0.05]. In contrast, acute β-adrenoceptor antagonism with i.v. propranolol infusion did not impact the cardiovascular or renal excretory responses to an acute 1M NaCl infusion. Critically, the natriuretic response to an acute 1M NaCl infusion was significantly blunted in rats receiving a s.c. infusion of the α1-adrenoceptor antagonist terazosin at a dose that did not lower baseline blood pressure [peak natriuresis (μeq/min) sc saline: 18 ± 1 vs. sc terazosin 7 ± 2, p < 0.05]. Additionally, a s.c. infusion of the α1-adrenoceptor antagonist terazosin further attenuated the natriuretic response to a 1M NaCl infusion in acutely RDNX animals. Collectively these data indicate a specific role of a blood pressure-independent renal sympathetic nerve-dependent α1-adrenoceptor-mediated pathway in the natriuretic and sympathoinhibitory responses evoked by acute increases in total body sodium.

We have previously reported that brain Gαi2 subunit proteins are required to maintain sodium homeostasis and are endogenously upregulated in the hypothalamic paraventricular nucleus (PVN) in response to increased dietary salt intake to maintain a salt resistant phenotype in rats. However, the origin of the signal that drives the endogenous activation and up-regulation of PVN Gαi2 subunit protein signal transduction pathways is unknown. By central oligodeoxynucleotide (ODN) administration we show that the pressor responses to central acute administration and central infusion of sodium chloride occur independently of brain Gαi2 protein pathways. In response to an acute volume expansion, we demonstrate, via the use of selective afferent renal denervation (ADNX) and anteroventral third ventricle (AV3V) lesions, that the sensory afferent renal nerves, but not the sodium sensitive AV3V region, are mechanistically involved in Gαi2 protein mediated natriuresis to an acute volume expansion [peak natriuresis (μeq/min) sham AV3V: 43 ± 4 vs. AV3V 45 ± 4 vs. AV3V + Gαi2 ODN 25 ± 4, p < 0.05; sham ADNX: 43 ± 4 vs. ADNX 23 ± 6, AV3V + Gαi2 ODN 25 ± 3, p < 0.05]. Furthermore, in response to chronically elevated dietary sodium intake, endogenous up-regulation of PVN specific Gαi2 proteins does not involve the AV3V region and is mediated by the sensory afferent renal nerves to counter the development of the salt sensitivity of blood pressure (MAP [mmHg] 4% NaCl; Sham ADNX 124 ± 4 vs. ADNX 145 ± 4, p < 0.05; Sham AV3V 125 ± 4 vs. AV3V 121 ± 5). Additionally, the development of the salt sensitivity of blood pressure following central ODN-mediated Gαi2 protein down-regulation occurs independently of the actions of the brain angiotensin II type 1 receptor. Collectively, our data suggest that in response to alterations in whole body sodium the peripheral sensory afferent renal nerves, but not the central AV3V sodium sensitive region, evoke the up-regulation and activation of PVN Gαi2 protein gated pathways to maintain a salt resistant phenotype. As such, both the sensory afferent renal nerves and PVN Gαi2 protein gated pathways, represent potential targets for the treatment of the salt sensitivity of blood pressure.

The mechanisms that sense alterations in total body sodium content to facilitate sodium homeostasis in response to an acute sodium challenge that does not increase blood pressure have not been fully elucidated. We hypothesized that the renal sympathetic nerves are critical to mediate natriuresis via α1- or β-adrenoceptors signal transduction pathways to maintain sodium balance in the face of acute increases in total body sodium content that do not activate the pressure-natriuresis mechanism. To address this hypothesis, we used acute bilateral renal denervation (RDNX), an anteroventral third ventricle (AV3V) lesion and α1- or β-antagonism during an acute 1M NaCl sodium challenge in conscious male Sprague Dawley rats. An acute 1M NaCl infusion did not alter blood pressure and evoked profound natriuresis and sympathoinhibition. Acute bilateral RDNX attenuated the natriuretic and sympathoinhibitory responses evoked by a 1M NaCl infusion [peak natriuresis (μeq/min) sham 14.5 ± 1.3 vs. acute RDNX: 9.2 ± 1.4, p < 0.05; plasma NE (nmol/L) sham control: 44 ± 4 vs. sham 1M NaCl infusion 11 ± 2, p < 0.05; acute RDNX control: 42 ± 6 vs. acute RDNX 1M NaCl infusion 25 ± 3, p < 0.05]. In contrast, an AV3V lesion did not impact the cardiovascular, renal excretory or sympathoinhibitory responses to an acute 1M NaCl infusion. Acute i.v. α1-adrenoceptor antagonism with terazosin evoked a significant drop in baseline blood pressure and significantly attenuated the natriuretic response to a 1M NaCl load [peak natriuresis (μeq/min) saline 17.2 ± 1.4 vs. i.v. terazosin 7.8 ± 2.5, p < 0.05]. In contrast, acute β-adrenoceptor antagonism with i.v. propranolol infusion did not impact the cardiovascular or renal excretory responses to an acute 1M NaCl infusion. Critically, the natriuretic response to an acute 1M NaCl infusion was significantly blunted in rats receiving a s.c. infusion of the α1-adrenoceptor antagonist terazosin at a dose that did not lower baseline blood pressure [peak natriuresis (μeq/min) sc saline: 18 ± 1 vs. sc terazosin 7 ± 2, p < 0.05]. Additionally, a s.c. infusion of the α1-adrenoceptor antagonist terazosin further attenuated the natriuretic response to a 1M NaCl infusion in acutely RDNX animals. Collectively these data indicate a specific role of a blood pressure-independent renal sympathetic nerve-dependent α1-adrenoceptor-mediated pathway in the natriuretic and sympathoinhibitory responses evoked by acute increases in total body sodium.

We demonstrate that global observations of high-energy cosmic rays contribute to understanding unique characteristics of a large-scale magnetic flux rope (MFR) causing a magnetic storm in August 2018. Following a weak interplanetary shock on 25 August 2018, a MFR caused an unexpectedly large geomagnetic storm. It is likely that this event became geoeffective because the MFR was accompanied by a corotating interaction region (CIR) and compressed by high-speed solar wind following the MFR. In fact, a Forbush decrease was observed in cosmic-ray data inside the MFR as expected, and a significant cosmic-ray density increase exceeding the unmodulated level before the shock was also observed near the trailing edge of the MFR. The cosmic-ray density increase can be interpreted in terms of the adiabatic heating of cosmic rays near the trailing edge of the MFR, as the corotating interaction region prevents free expansion of the MFR and results in the compression near the trailing edge. A northeast-directed spatial gradient in the cosmic-ray density was also derived during the cosmic-ray density increase, suggesting that the center of the heating near the trailing edge is located northeast of Earth. The second order anisotropy is observed during the density increase clearly representing an intensity enhancement of cosmic rays with approximately 90 degree pitch angle, possibly indicating the betatron acceleration of CRs during the cosmic-ray density increase and/or accelerated CRs leaking along the magnetic field from the density increase region toward the south where lower CR population is expected. This is one of the best examples demonstrating that the observation of high-energy cosmic rays provides us with information of the three-dimensional macroscopic picture of the interaction between coronal mass ejections and the ambient solar wind, which is essential for prediction of large magnetic storms.

NEW FINDINGS What is the central question of this study? What are the differential roles of the mechanosensitive and chemosensitive afferent renal nerves in the reno-renal reflex that promotes natriuresis, sympathoinhibition and normotension during acute and chronic challenges to sodium homeostasis? What is the main finding and its importance? The mechanosensitive afferent renal nerves contribute to an acute natriuretic sympathoinhibitory reno-renal reflex that may be integrated within the paraventricular nucleus of the hypothalamus. Critically, the afferent renal nerves are required for the maintenance of salt resistance in Sprague-Dawley and Dahl salt-resistant rats and attenuate the development of Dahl salt-sensitive hypertension. ABSTRACT These studies tested the hypothesis that in normotensive salt-resistant rat phenotypes the mechanosensitive afferent renal nerve (ARN) reno-renal reflex promotes natriuresis, sympathoinhibition and normotension during acute and chronic challenges to fluid and electrolyte homeostasis. Selective ARN ablation was conducted prior to (1) an acute isotonic volume expansion (VE) or 1 m NaCl infusion in Sprague-Dawley (SD) rats and (2) chronic high salt intake in SD, Dahl salt-resistant (DSR), and Dahl salt-sensitive (DSS) rats. ARN responsiveness following high salt intake was assessed ex vivo in response to noradrenaline and sodium concentration (SD, DSR and DSS) and via in vivo manipulation of renal pelvic pressure and sodium concentration (SD and DSS). ARN ablation attenuated the natriuretic and sympathoinhibitory responses to an acute VE [peak natriuresis (µeq min-1 ) sham 52 ± 5 vs. ARN ablation 28 ± 3, P

Owing to their small interaction cross-section, neutrinos are unparalleled astronomical tracers. Ultra-high energy (UHE; E > 10 PeV) neutrinos probe the most distant, most explosive sources in the Universe, often obscured to optical telescopes. Radio-frequency (RF) detection of Askaryan radiation in cold polar ice is currently regarded as the best experimental measurement technique for UHE neutrinos, provided the RF properties of the ice target can be well-understood. To that end, the Askaryan Radio Array (ARA) experiment at the South Pole has used long-baseline RF propagation to extract information on the index-of-refraction ( n = ϵ r ) in South Polar ice. Owing to the increasing ice density over the upper 150–200 m, rays are measured along two, nearly parallel paths, one of which refracts through an inflection point, with differences in both arrival time and arrival angle that can be used to constrain the neutrino properties. We also observe (first) indications for RF ice birefringence for signals propagating along predominantly horizontal trajectories, corresponding to an asymmetry of order 0.1% between the ordinary and extra-ordinary birefringent axes, numerically compatible with previous measurements of birefringent asymmetries for vertically-propagating radio-frequency signals at South Pole. Qualitatively, these effects offer the possibility of redundantly measuring the range from receiver to a neutrino interaction in Antarctic ice, if receiver antennas are deployed at shallow (z ∼ −25 m) depths. Such range information is essential in determining both the neutrino energy, as well as the incident neutrino direction.

Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE-infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with a potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.

We demonstrate that global observations of high-energy cosmic rays contribute to understanding unique characteristics of a large-scale magnetic flux rope causing a magnetic storm in August 2018. Following a weak interplanetary shock on 25 August 2018, a magnetic flux rope caused an unexpectedly large geomagnetic storm. It is likely that this event became geoeffective because the flux rope was accompanied by a corotating interaction region and compressed by high-speed solar wind following the flux rope. In fact, a Forbush decrease was observed in cosmic-ray data inside the flux rope as expected, and a significant cosmic-ray density increase exceeding the unmodulated level before the shock was also observed near the trailing edge of the flux rope. The cosmic-ray density increase can be interpreted in terms of the adiabatic heating of cosmic rays near the trailing edge of the flux rope, as the corotating interaction region prevents free expansion of the flux rope and results in the compression near the trailing edge. A northeast-directed spatial gradient in the cosmic-ray density was also derived during the cosmic-ray density increase, suggesting that the center of the heating near the trailing edge is located northeast of Earth. This is one of the best examples demonstrating that the observation of high-energy cosmic rays provides us with information that can only be derived from the cosmic ray measurements to observationally constrain the three-dimensional macroscopic picture of the interaction between coronal mass ejections and the ambient solar wind, which is essential for prediction of large magnetic storms., Comment: 19 pages, 3 figures, accepted for publication in the Space Weather

BACKGROUND: Cardiac fibroblasts are the main non-myocyte population responsible for extracellular matrix (ECM) production. During perinatal development, fibroblast expansion coincides with the transition from hyperplastic to hypertrophic myocardial growth. Therefore, we investigated the consequences of fibroblast loss at the time of cardiomyocyte maturation by depleting fibroblasts in the perinatal mouse. METHODS AND RESULTS: We evaluated the microenvironment of the perinatal heart in the absence of fibroblasts and the potential functional impact of fibroblast loss in regulation of cardiomyocyte cell cycle arrest and binucleation. Cre-mediated expression of diphtheria toxin A in PDGFRα expressing cells immediately after birth eliminated 70–80% of the cardiac fibroblasts. At postnatal day 5, hearts lacking fibroblasts appeared similar to controls with normal morphology and comparable numbers of endothelial and smooth muscle cells, despite a pronounced reduction in fibrillar collagen. Immunoblotting and proteomic analysis of control and fibroblast-deficient hearts identified differential abundance of several ECM proteins. In addition, fibroblast loss decreased tissue stiffness and resulted in increased cardiomyocyte mitotic index, DNA synthesis, and cytokinesis. Moreover, decellularized matrix from fibroblast-deficient hearts promoted cardiomyocyte DNA replication. While cardiac architecture was not overtly affected by fibroblast reduction, few pups survived past postnatal day 11, suggesting an overall requirement for PDGFRα expressing fibroblasts. CONCLUSIONS: These studies demonstrate the key role of fibroblasts in matrix production and cardiomyocyte cross-talk during mouse perinatal heart maturation and revealed that fibroblast-derived ECM may modulate cardiomyocyte maturation in vivo. Neonatal depletion of fibroblasts demonstrated that although hearts can tolerate reduced ECM composition, fibroblast loss eventually leads to perinatal death as the approach simultaneously reduced fibroblast populations in other organs.

We have previously reported that in salt resistant rat phenotypes brain guanine nucleotide-binding protein alpha inhibiting activity polypeptide 2 (Gαi(2)) proteins are required to maintain blood pressure and sodium balance. However, the impact of hypothalamic paraventricular nucleus (PVN) Gαi(2) proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi(2) oligodeoxynucleotide (ODN), we show PVN specific Gαi(2) proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] SCR ODN 41±3 vs. Gαi(2) ODN 18±4, P

The effect of cosmic rays on the Parker-Jeans instability in magnetized self-gravitating gaseous disks is studied by three-dimensional magnetohydrodynamic (MHD) simulations with cosmic rays taken as a massless fluid with notable pressure. Cosmic ray diffusion along the magnetic field is taken into account in the simulation. The initial configuration of the disk is a magnetized cold gas slab sandwiched between hot corona (on top and bottom). We show that cosmic rays play an important role in the formation of filaments or clumps in some parameter regimes. In a certain range of the thickness of the gas slab, the cosmic ray diffusion coefficient plays a decisive role in determining whether the filaments lie along or perpendicular to the magnetic field. We also consider the effect of rotation on the system.

Cells present in the adventitia, or outermost layer of the blood vessel, contribute to the progression of vascular diseases, such as atherosclerosis, hypertension, and aortic dissection. The adventitial fibroblast of the aorta is the prototypic perivascular fibroblast, but the adventitia is composed of multiple distinct cell populations. Therefore, methods for uniquely identifying the fibroblast are critical for a better understanding of how these cells contribute to disease processes. A popular method for distinguishing adventitial cell types relies on the use of genetic tools in the mouse to trace and manipulate these cells. Because lineage tracing relying on Cre-recombinase expressing mice is used more frequently in studies of vascular disease, it is important to outline the advantages and limitations of these genetic tools. The purpose of this article is to provide an overview of the various genetic tools available in the mouse for the study of resident adventitial fibroblasts.

The Global Muon Detector Network (GMDN) is composed by four ground cosmic ray detectors distributed around the Earth: Nagoya (Japan), Hobart (Australia), Sao Martinho da Serra (Brazil) and Kuwait city (Kuwait). The network has operated since March 2006. It has been upgraded a few times, increasing its detection area. Each detector is sensitive to muons produced by the interactions of ~50 GeV Galactic Cosmic Rays (GCR) with the Earth′s atmosphere. At these energies, GCR are known to be affected by interplanetary disturbances in the vicinity of the earth. Of special interest are the interplanetary counterparts of coronal mass ejections (ICMEs) and their driven shocks because they are known to be the main origins of geomagnetic storms. It has been observed that these ICMEs produce changes in the cosmic ray gradient, which can be measured by GMDN observations. In terms of applications for space weather, some attempts have been made to use GMDN for forecasting ICME arrival at the earth with lead times of the order of few hours. Scientific space weather studies benefit the most from the GMDN network. As an example, studies have been able to determine ICME orientation at the earth using cosmic ray gradient. Such determinations are of crucial importance for southward interplanetary magnetic field estimates, as well as ICME rotation.

Following the detection of high-energy astrophysical neutrinos in 2013, their origin is still unknown. Aiming for the identification of an electromagnetic counterpart of a rapidly fading source, we have implemented a realtime analysis framework for the IceCube neutrino observatory. Several analyses selecting neutrinos of astrophysical origin are now operating in realtime at the detector site in Antarctica and are producing alerts to the community to enable rapid follow-up observations. The goal of these observations is to locate the astrophysical objects responsible for these neutrino signals. This paper highlights the infrastructure in place both at the South Pole detector site and at IceCube facilities in the north that have enabled this fast follow-up program to be developed. Additionally, this paper presents the first realtime analyses to be activated within this framework, highlights their sensitivities to astrophysical neutrinos and background event rates, and presents an outlook for future discoveries., Comment: 33 pages, 9 figures, Published in Astroparticle Physics

The objective of this study is to investigate the effects of neutron (n) irradiation on hydrogen isotope transport in tungsten (W). W samples were irradiated with neutrons in a fission reactor and then exposed to high flux deuterium (D) plasma at 563 K in a linear plasma device. The fraction of D release increased with increasing exposure time. In addition, the D retention in n-irradiated W increased in proportion to the square root of the plasma exposure time. These observations were explained by increase in the penetration depth of D with filling up displacement damages acting as strong trapping sites.

Platelet-derived growth factor receptor α (PDGFRα), a receptor tyrosine kinase required for cardiac fibroblast development, is uniquely expressed by fibroblasts in the adult heart. Despite the consensus that PDGFRα is expressed in adult cardiac fibroblasts, we know little about its function when these cells are at rest. Here, we demonstrate that loss of PDGFRα in cardiac fibroblasts resulted in a rapid reduction of resident fibroblasts. Furthermore, we observe that phosphatidylinositol 3-kinase signaling was required for PDGFRα-dependent fibroblast maintenance. Interestingly, this reduced number of fibroblasts was maintained long-term, suggesting that there is no homeostatic mechanism to monitor fibroblast numbers and restore hearts to wild-type levels. Although we did not observe any systolic functional changes in hearts with depleted fibroblasts, the basement membrane and microvasculature of these hearts were perturbed. Through in vitro analyses, we showed that PDGFRα signaling inhibition resulted in an increase in fibroblast cell death, and PDGFRα stimulation led to increased levels of the cell survival factor activating transcription factor 3. Our data reveal a unique role for PDGFRα signaling in fibroblast maintenance and illustrate that a 50% loss in cardiac fibroblasts does not result in lethality.NEW & NOTEWORTHY Platelet-derived growth factor receptor α (PDGFRα) is required in developing cardiac fibroblasts, but a functional role in adult, quiescent fibroblasts has not been identified. Here, we demonstrate that PDGFRα signaling is essential for cardiac fibroblast maintenance and that there are no homeostatic mechanisms to regulate fibroblast numbers in the heart. PDGFR signaling is generally considered mitogenic in fibroblasts, but these data suggest that this receptor may direct different cellular processes depending on the cell’s maturation and activation status.

Physical review / D 88(4), 042004 (2013). doi:10.1103/PhysRevD.88.042004, We report on the measurement of the all-particle cosmic ray energy spectrum with the IceTop air shower array in the energy range from 1.58 PeV to 1.26 EeV. The IceTop air shower array is the surface component of the IceCube Neutrino Observatory at the geographical South Pole. The analysis was performed using only information from IceTop. The data used in this work were taken from June 1, 2010 to May 13, 2011. During that period the IceTop array consisted of 73 stations, compared to 81 in its final configuration. The measured spectrum exhibits a clear deviation from a single power law above the knee around 4 PeV and below 1 EeV. We observe spectral hardening around 18 PeV and steepening around 130 PeV., Published by Soc., [S.l.]

Melatonin is a pineal hormone that has acquired several unique modes of regulating the physiological effects in mammals due to its characteristic phylogenetic history. While melatonin exhibits immediate nocturnal effects, it also has next-day prospective effects that take place in the absence of this hormone. Besides that, the daily repetition and the annual variation in the duration of its synthesis determine its circadian and seasonal effects that characterize melatonin as a chronobiotic, a molecule that encodes time to the internal environment. Additionally, it presents transgenerational effects that are important for fetal programming, leading to a balanced energy metabolism in the adult life.Physiology, pathophysiology and therapeutic value of melatonin in metabolism and metabolic disorders.The typical mechanisms of action of melatonin (immediate, prospective, chronobiotic and transgenerational) should be considered to adequately understand its physiological effects on the regulation of metabolism in humans and, as a result, to understand the metabolic pathophysiological consequences caused by its synthesis and/or signaling disturbances. That points to the importance of a broader understanding of melatonin actions, besides the classical endocrinological point of view, that would allow the clinician/research to proper interpret its role in health maintenance.

We have investigated the particle flux flowing into the axisymmetric end-target in the transient state from attached to detached divertor conditions in the linear plasma device NAGDIS-II. In the transient state, a dramatic decrease of the mean particle flux and a large-amplitude fluctuation with negative and positive spikes were observed. We have analyzed the fluctuation with a newly suggested analysis technique: pre-multiplied cubic spectrum with the wavelet transform. Analysis result indicates that these spikes consist of a few kilohertz components. (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

We have adapted the EMC3-EIRENE code for modeling of a linear divertor plasma simulator in order to demonstrate plasma-wall interactions with three-dimensional (3D) effects. 3D distributions of hydrogen plasma and neutrals can be successfully calculated for four different types of target plates: a V-shaped target, inclined targets with open and closed structures, and a planer target. Hydrogen atoms and molecules are accumulated more effectively in the V-shaped target plate, leading to a higher electron density with lower electron temperature than the planar target plate. (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Rationale: Accurate knowledge of the cellular composition of the heart is essential to fully understand the changes that occur during pathogenesis and to devise strategies for tissue engineering and regeneration. Objective: To examine the relative frequency of cardiac endothelial cells, hematopoietic-derived cells, and fibroblasts in the mouse and human heart. Methods and Results: Using a combination of genetic tools and cellular markers, we examined the occurrence of the most prominent cell types in the adult mouse heart. Immunohistochemistry revealed that endothelial cells constitute >60%, hematopoietic-derived cells 5% to 10%, and fibroblasts Conclusions: This new perspective on the abundance of different cell types in the heart demonstrates that fibroblasts comprise a relatively minor population. By contrast, endothelial cells constitute the majority of noncardiomyocytes and are likely to play a greater role in physiological function and response to injury than previously appreciated.

Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension.

We report on analysis of englacial radio-frequency (RF) pulser data received over horizontal baselines of 1--5 km, based on broadcasts from two sets of transmitters deployed to depths of up to 1500 meters at the South Pole. First, we analyze data collected usingtwo RF bicone transmitters 1400 meters below the ice surface, and frozen into boreholes drilled for the IceCube experiment in 2011. Additionally, in Dec., 2018, a fat-dipole antenna, fed by one of three high-voltage (~1 kV), fast (~(1-5 ns)) signal generators was lowered into the 1700-m deep icehole drilled for the South Pole Ice Core Experiment (SPICE), approximately 3 km from the geographic South Pole. Signals from transmitters were recorded on the five englacial multi-receiver ARA stations, with receiver depths between 60--200 m. We confirm the long, >1 km RF electric field attenuation length, test our observed signal arrival timing distributions against models, and measure birefringent asymmetries at the 0.15% level.

This overview presents recent results regarding hydrogen isotope absorption and emission dynamics in neutron-irradiated tungsten (W) using our recently developed Compact Diverter Plasma Simulator (CDPS), a linear plasma device in a radiation-controlled area. Neutron irradiation to 0.016 - 0.06 displacement per atom resulted in a significant increase in deuterium (D) retention due to trapping effects of radiation-induced defects. We analyzed the dependency of D retention on the D plasma fluence by exposing neutron-irradiated pure W to D plasma at 563 K over a range of D fluence values. The total retention was revealed to be proportional to the square root of D fluence, indicating that the implanted D atoms first occupy the defects caused by neutron-irradiation near the surface and then the defects located in deeper regions. We further investigated the effects of post-plasma annealing on D emission; neutron-irradiated pure W was exposed to D plasma at 573 K and was then annealed at the same temperature for 30 hours. Approximately 10% of the absorbed D was released by annealing, suggesting that a heat treatment of the plasma-facing component of a fusion reactor at moderately elevated temperatures could contribute to the removal of accumulated hydrogen isotopes. The experimental results obtained in this study were only available by investigating neutron-irradiated specimens with the CDPS system, which will be essential for future studies of material behavior and plasma-wall interactions in the fusion reactor environment.

We examine the effect of neutron irradiation on the release of deuterium from tungsten at 573 K to understand the efficiency of tritium removal by baking out at moderate temperatures. Tungsten samples, undamaged and neutron-irradiated to a damage level of approximately 0.016 displacements per atom, are exposed to low-energy (108 eV), high-flux (3.0 × 1021 to 9.4 × 1021 m−2 s−1) deuterium plasma at temperatures ranging from 573 to 773 K to an ion fluence of 1.1 × 1025 m−2. At each exposure temperature, two undamaged and two neutron-irradiated tungsten samples are exposed to plasma. The deuterium content in the tungsten samples is measured by thermal desorption spectrometry soon after the plasma exposure and after post-plasma annealing at 573 K for 30 h. It is found that: (i) the deuterium retention in the neutron-irradiated tungsten samples is significantly higher than that in the undamaged tungsten samples; (ii) annealing at 573 K of undamaged tungsten samples pre-exposed to deuterium plasma at 573–773 K leads to an almost complete (60%–99%) release of deuterium from the samples; (iii) annealing at 573 K of neutron-irradiated tungsten samples pre-exposed to deuterium plasma at 573–773 K leads to a significant (8%–20%) release of deuterium from the samples.