Achieving ultra-low and -uniform residual magnetic fields in a very large magnetically shielded room for fundamental physics experiments.

High-precision searches for an electric dipole moment of the neutron (nEDM) require stable and uniform magnetic field environments. We present the recent achievements of degaussing and equilibrating the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute. We present the final degaussing configuration that will be used for n2EDM after numerous studies. The optimized procedure results in a residual magnetic field that has been reduced by a factor of two. The ultra-low field is achieved with the full magnetic-field-coil system, and a large vacuum vessel installed, both in the MSR. In the inner volume of ∼1.4m3, the field is now more uniform and below 300 pT. In addition, the procedure is faster and dissipates less heat into the magnetic environment, which in turn, reduces its thermal relaxation time from 12h down to 1.5h.

A large 'Active Magnetic Shield' for a high-precision experiment: nEDM collaboration.

We present a novel Active Magnetic Shield (AMS), designed and implemented for the n2EDM experiment at the Paul Scherrer Institute. The experiment will perform a high-sensitivity search for the electric dipole moment of the neutron. Magnetic-field stability and control is of key importance for n2EDM. A large, cubic, 5 m side length, magnetically shielded room (MSR) provides a passive, quasi-static shielding-factor of about 105 for its inner sensitive volume. The AMS consists of a system of eight complex, feedback-controlled compensation coils constructed on an irregular grid spanned on a volume of less than 1000 m3 around the MSR. The AMS is designed to provide a stable and uniform magnetic-field environment around the MSR, while being reasonably compact. The system can compensate static and variable magnetic fields up to ±50µT (homogeneous components) and ±5µT/m (first-order gradients), suppressing them to a few µT in the sub-Hertz frequency range. The presented design concept and implementation of the AMS fulfills the requirements of the n2EDM experiment and can be useful for other applications, where magnetically silent environments are important and spatial constraints inhibit simpler geometrical solutions.

Search for Neutron-to-Hidden-Neutron Oscillations in an Ultracold Neutron Beam.

Models that postulate the existence of hidden sectors address contemporary questions, such as the source of baryogenesis and the nature of dark matter. Neutron-to-hidden-neutron oscillations are among the possible mixing processes and have been tested with ultracold neutron storage and passing-through-wall experiments to set constraints on the oscillation period τ_{nn^{'}}. These searches probe the oscillations as a function of the mass splitting due to the neutron-hidden-neutron energy degeneracy. In this work, we present a new limit derived from neutron disappearance in ultracold neutron beam experiments. The overall limit, given by τ_{nn^{'}}>1 s for |δm|∈[2,69] peV(95.45% C.L.), covers the yet unexplored intermediate mass-splitting range and contributes to the ongoing research on hidden sectors.

Final Results of GERDA on the Two-Neutrino Double-ß Decay Half-Life of

We present the measurement of the two-neutrino double-ß decay rate of ^{76}Ge performed with the GERDA Phase II experiment. With a subset of the entire GERDA exposure, 11.8 kg yr, the half-life of the process has been determined: T_{1/2}^{2ν}=(2.022±0.018_{stat}±0.038_{syst})×10^{21} yr. This is the most precise determination of the ^{76}Ge two-neutrino double-ß decay half-life and one of the most precise measurements of a double-ß decay process. The relevant nuclear matrix element can be extracted: M_{eff}^{2ν}=(0.101±0.001).

Search for tri-nucleon decays of 76Ge in GERDA.

We search for tri-nucleon decays of 76Ge in the dataset from the GERmanium Detector Array (GERDA) experiment. Decays that populate excited levels of the daughter nucleus above the threshold for particle emission lead to disintegration and are not considered. The ppp-, ppn-, and pnn-decays lead to 73Cu, 73Zn, and 73Ga nuclei, respectively. These nuclei are unstable and eventually proceed by the beta decay of 73Ga to 73Ge (stable). We search for the 73Ga decay exploiting the fact that it dominantly populates the 66.7 keV 73mGa state with half-life of 0.5 s. The nnn-decays of 76Ge that proceed via 73mGe are also included in our analysis. We find no signal candidate and place a limit on the sum of the decay widths of the inclusive tri-nucleon decays that corresponds to a lower lifetime limit of 1.2×1026 yr  (90% credible interval). This result improves previous limits for tri-nucleon decays by one to three orders of magnitude.

Liquid argon light collection and veto modeling in GERDA Phase II.

The ability to detect liquid argon scintillation light from within a densely packed high-purity germanium detector array allowed the Gerda experiment to reach an exceptionally low background rate in the search for neutrinoless double beta decay of 76 Ge. Proper modeling of the light propagation throughout the experimental setup, from any origin in the liquid argon volume to its eventual detection by the novel light read-out system, provides insight into the rejection capability and is a necessary ingredient to obtain robust background predictions. In this paper, we present a model of the Gerda liquid argon veto, as obtained by Monte Carlo simulations and constrained by calibration data, and highlight its application for background decomposition.

The very large n2EDM magnetically shielded room with an exceptional performance for fundamental physics measurements.

We present the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute, which features an interior cubic volume with each side of length 2.92 m, thus providing an accessible space of 25 m3. The MSR has 87 openings of diameter up to 220 mm for operating the experimental apparatus inside and an intermediate space between the layers for housing sensitive signal processing electronics. The characterization measurements show a remanent magnetic field in the central 1 m3 below 100 pT and a field below 600 pT in the entire inner volume, up to 4 cm to the walls. The quasi-static shielding factor at 0.01 Hz measured with a sinusoidal 2 µT peak-to-peak signal is about 100 000 in all three spatial directions and increases rapidly with frequency to reach 108 above 1 Hz.

The design of the n2EDM experiment: nEDM Collaboration.

We present the design of a next-generation experiment, n2EDM, currently under construction at the ultracold neutron source at the Paul Scherrer Institute (PSI) with the aim of carrying out a high-precision search for an electric dipole moment of the neutron. The project builds on experience gained with the previous apparatus operated at PSI until 2017, and is expected to deliver an order of magnitude better sensitivity with provision for further substantial improvements. An overview is of the experimental method and setup is given, the sensitivity requirements for the apparatus are derived, and its technical design is described.

Data blinding for the nEDM experiment at PSI.

Psychological bias towards, or away from, prior measurements or theory predictions is an intrinsic threat to any data analysis. While various methods can be used to try to avoid such a bias, e.g. actively avoiding looking at the result, only data blinding is a traceable and trustworthy method that can circumvent the bias and convince a public audience that there is not even an accidental psychological bias. Data blinding is nowadays a standard practice in particle physics, but it is particularly difficult for experiments searching for the neutron electric dipole moment (nEDM), as several cross measurements, in particular of the magnetic field, create a self-consistent network into which it is hard to inject a false signal. We present an algorithm that modifies the data without influencing the experiment. Results of an automated analysis of the data are used to change the recorded spin state of a few neutrons within each measurement cycle. The flexible algorithm may be applied twice (or more) to the data, thus providing the option of sequentially applying various blinding offsets for separate analysis steps with independent teams. The subtle manner in which the data are modified allows one subsequently to adjust the algorithm and to produce a re-blinded data set without revealing the initial blinding offset. The method was designed for the 2015/2016 measurement campaign of the nEDM experiment at the Paul Scherrer Institute. However, it can be re-used with minor modification for the follow-up experiment n2EDM, and may be suitable for comparable projects elsewhere.

Measurement of the Permanent Electric Dipole Moment of the Neutron.

We present the result of an experiment to measure the electric dipole moment (EDM) of the neutron at the Paul Scherrer Institute using Ramsey's method of separated oscillating magnetic fields with ultracold neutrons. Our measurement stands in the long history of EDM experiments probing physics violating time-reversal invariance. The salient features of this experiment were the use of a ^{199}Hg comagnetometer and an array of optically pumped cesium vapor magnetometers to cancel and correct for magnetic-field changes. The statistical analysis was performed on blinded datasets by two separate groups, while the estimation of systematic effects profited from an unprecedented knowledge of the magnetic field. The measured value of the neutron EDM is d_{n}=(0.0±1.1_{stat}±0.2_{sys})×10^{-26} e.cm.

Disparate effects of thrombin receptor activating peptide on platelets and peripheral vasculature in rats.

The hemodynamic and platelet effects of the thrombin receptor activating peptide SFLLRN (TRAP) were evaluated in rats. TRAP failed to aggregate rat platelets in vitro (platelet rich plasma) or in vivo in the pulmonary microcirculation. In contrast, TRAP aggregated washed human platelets. Intravenous injection of TRAP (1 mg/kg) in inactin-anesthetized rats produced a biphasic response in blood pressure characterized by an initial depressor response (-25 +/- 3 mmHg for 15-30 s) followed by a pronounced pressor response (50 +/- 7 mmHg for 2-3 min). This increase in blood pressure can be attributed to increases in total peripheral resistance since cardiac output remained unchanged. Further, only the pressor responses were observed in pithed rats suggesting a direct effect of TRAP in causing smooth muscle contraction. Consequently, rat platelets differ from human platelets in that they are resistant to TRAP whereas rat vasculature is highly sensitive to TRAP. These observations suggest that while the thrombin receptors on rat vasculature may be similar to those on human platelets, the receptors and/or the coupling mechanisms in rat platelets appear different from human platelets.

Inhibition of platelet adhesion and aggregation by E4021, a type V phosphodiesterase inhibitor, in guinea pigs.

E4021 (sodium 1-[6-chloro-4-(3, 4-methylenedioxybenzyl)-aminoquinazolin-2-yl]piperidine-4-ca rboxylate sesquihydrate) is a highly selective and potent inhibitor of type V phosphodiesterase(PDE5). The in vitro and in vivo effect of E4021 on platelet function was evaluated, using echistatin, a potent disintegrin, as a positive reference agent. E4021 inhibits aggregatory response to collagen in washed human platelets (IC50 = 5 microM, vs. 0.14 microM with echistatin). In the ex vivo-platelet aggregation assay using whole blood from treated guinea pigs, E4021 (9 mg/kg i.v.) showed a moderate inhibition (43%) against collagen (0.125 microg/ml), whereas echistatin (250 microg/kg i.v.) exerted a 88% inhibition. The absence of endothelium-derived factors (NO) may account for the moderate in vitro and ex vivo antiplatelet activity of E4021. In an in vivo model of reversible platelet aggregation elicited by collagen (100 microg/kg i.v.), both E4021 and echistatin attenuated the intrapulmonary platelet accumulation in guinea pigs (-36% and -44%, respectively). In addition, E4021 (9 mg/kg i.v.) and echistatin (250 microg/kg i.v.) caused a similar inhibition of platelet adhesion at sites of microfilament-induced vascular injury in guinea pigs (52% and 65%, respectively). The two agents in combination did not show additive effect, suggesting that E4021 inhibits platelet activation and impairs interactions of adhesion receptors with matrix proteins. E4021 caused a selective increase in cGMP concentrations in the platelets isolated from treated guinea pigs: cAMP was not affected. It is concluded that the antiplatelet activity of E4021 is mediated through cGMP mechanism by virtue of selective inhibition of PDE5 in the platelets.

Characterization of in vitro and in vivo platelet responses to thrombin and thrombin receptor-activating peptides in guinea pigs.

Guinea pig platelets are similar to human platelets in their responsiveness to thrombin receptor-activating peptides and other agonists. Therefore, guinea pigs anesthetized with Inactin (90 mg/kg i.p.) were used to assess in vivo activities of thrombin and thrombin receptor-activating peptides (TRAPs) using 111 In-labeled platelets and a microcomputer-based system. The aggregatory responses are expressed as percent change for a 20 min period over basal radioactivity (AUC). Reversible accumulation of platelets occurred in the pulmonary microcirculation in response to stimuli. Human thrombin (50 and 100 U/kg i.v.) caused a dose-related platelet accumulation. Responses of similar magnitude were induced by SFLLRN (TRAP-(1-6)) and Ala-Phe(p-F)-Arg-Cha-HArg-Tyr-NH2 (high-affinity thrombin receptor-activating peptide, 0.03, 0.1 and 0.3 mg/kg i.v.). High-affinity thrombin receptor-activating peptide, a new synthetic oligopeptide agonist, is about 3-fold more potent than TRAP-(1-6), a wild-type sequence. Similarly, high-affinity thrombin receptor-activating peptide is about 4 times more potent than TRAP-(1-6) in the radioligand binding study using platelet membrane. By comparison, high-affinity thrombin receptor-activating peptide manifested an aggregatory activity (EC60 = 1.2 microM) about 15 times more potent than that of TRAP-(1-6)(EC60 = 18.6 microM) in washed guinea pig platelets. The intrapulmonary platelet aggregation in response to thrombin, TRAP-(1-6) and high-affinity thrombin receptor-activating peptide was characterized by long duration (approximately 30 min); a reduction in response (18-54%) tended to occur with repeated challenges, presumably due to desensitization and consumption. The response to thrombin (100 U/kg) was greatly inhibited by (D)-Phe-Pro-Arg-chloromethyl ketone (PPACK), a potent thrombin inhibitor (250 micrograms/kg + 6 micrograms/kg per min i.v. x 30): AUC, 150 +/- 552 vs. 7171 +/- 1052 in the control period (n = 8, P < 0.05). The response to high-affinity thrombin receptor-activating peptide (0.03 mg/kg), which acts on thrombin receptor directly, was not affected by PPACK. It is concluded that guinea pigs are an appropriate preparation for evaluation of in vivo activity of thrombin inhibitors as well as thrombin receptor agonists and antagonists.

In vivo inhibition of platelet adhesion by a cGMP-mediated mechanism in balloon catheter injured rat carotid artery.

The role of cyclic guanosine monophosphate (cGMP) versus cyclic adenosine monophosphate (cAMP) mediated mechanism in modulating platelet adhesion was investigated in balloon catheter injured rat carotid arteries. Vascular injury with balloon angioplasty significantly increased the adherence of platelets to the injured carotid arteries. Intravenous infusion of zaprinast (1 mg/kg/min), a cGMP phosphodiesterase inhibitor, or sodium nitroprusside (8 micrograms/kg/min), a stimulator of soluble guanylate cyclase, significantly attenuated the adherence of platelets to the injured carotid arteries. In comparison, infusion of milrinone, a cAMP phosphodiesterase inhibitor, or 8-bromo-cAMP failed to affect the platelet deposition in the injured carotid arteries. Nifedipine or aspirin also failed to attenuate the adherence of platelets to the injured carotid arteries. In conclusion, agents known to elevate intracellular platelet cGMP but not cAMP appear to afford the most effective protection in vivo against the adhesion of platelets to the vessel wall without intact endothelium.

Interleukin-10 pharmacokinetics in intact and nephrectomized mice.

The influence of kidney function on interleukin-10 (IL-10) pharmacokinetics was assessed by comparing the disappearance of IL-10 from the circulation in the intact and acutely nephrectomized mice over 1 h following a single bolus injection of E. coli-derived recombinant h IL-10 at 250 micrograms/kg i.v. The intact mice demonstrated a C(max) of 1,172 ng/ml and an AUC(tf) of 385 n g.h/ml. By comparison, there was a 4-fold elevation in C(max) and a 7-fold increase in AUC(tf) in the anephric mice. The serum IL-10 concentration at 1 h post-injection was 87 ng/ml in the intact vs 1,684 ng/ml in the anephric mice. The results imply that IL-10, in common with other cytokines, is eliminated through the kidney.

EDRF(NO)-Mediated Modulation of Collagen-Induced Platelet Accumulation in Rat Pulmonary Microcirculation.

Endothelium-derived relaxing factor (EDRF) or nitric oxide (NO) biosynthesis from L-arginine occurs in the endothelium and platelets and may modulate platelet function and contribute to thromboresistance in the vessel wall. A rat model was used to evaluate selective accumulation of (III)In-labeled platelets in the pulmonary microcirculation following the administration of collagen, adenosine 5'-diphosphate (ADP) or thrombin. Platelet aggregation was monitored continuously over the thorax using a microcomputer-based system. Sodium nitroprusside, a stimulator of soluble guanylate cyclase and zaprinast, a phosphodiesterase V inhibitor, both known to cause accumulation of cyclic guanosine monophosphate, exhibited moderate inhibitory activity, which was shared by L-arginine. N(G)-monomethyl-L-arginine (L-NMMA; 1 mg/kg/min), an inhibitor of EDRF(NO), potentiated the aggregatory response to collagen at an intravenous dose of 100 &mgr;g/kg but not at one of 30 &mgr;g/kg. D-NMMA had no such effect. The augmenting effect of L-NMMA was abolished by L-arginine. N(G)-nitro-L-arginine methyl ester (L-NAME; 0.1 mg/kg/min) also markedly augmented the collagen-induced platelet response, and, at higher doses, all treated animals died upon collagen challenge. Both L-NMMA and L-NAME did not affect the responses to ADP and thrombin. The results suggest that in the intact vascular system, basal releae of EDRF(NO) is not critically involved in modulation of platelet function but becomes a significant factor when platelets are exposed to great amounts of collagen fibrils. Copyright 1994 S. Karger AG, Basel

Cyclic GMP but not cyclic AMP prevents renal platelet accumulation after ischemia-reperfusion in anesthetized rats.

Platelets have been implicated in the pathophysiology of ischemia-reperfusion injury. In this study, antiplatelet effects of cyclic GMP (cGMP)- and cyclic AMP (cAMP)-mediated agents were evaluated in renal ischemia in pentobarbital-anesthetized rats. Renal ischemia was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion (30 min) with the contralateral kidney serving as control. 111Indium-labeled platelets, drugs or vehicle were administered 30 min before induction of renal ischemia. Occlusion of the left renal artery for 20, 40 or 60 min resulted in a 100, 300 and 600% increase (over contralateral right kidney) in the platelet-associated 111indium activity in the ischemic kidney. In all subsequent studies the kidney was occluded for 40 min to test the antiplatelet activity of individual agents. 8-Br-cGMP (0.1 and 0.3 mg/kg/min i.v.), zaprinast (0.1 mg/kg/min i.v.) and sodium nitroprusside (0.003 and 0.01 mg/kg/min i.v.) significantly attenuated platelet accumulation in renal ischemia, whereas 8-Br-cAMP (0.3 mg/kg/min i.v.) or milrinone (0.1 mg/kg i.v. bolus, plus 0.01 mg/kg/min) did not. Minoxidil (0.01 and 0.03 mg/kg/min i.v.), a vasodilator which produced equihypotensive effects as the cGMP-mediated agents, and milrinone failed to prevent platelet accumulation. These results demonstrate that modulation of the platelet function by cGMP agents can be dissociated from their blood pressure lowering effects. cGMP is known to inhibit both platelet adhesion and aggregation, whereas cAMP is only active against aggregation. The present findings provide further evidence that cGMP-mediated drugs may afford effective antiplatelet action in an in vivo model of ischemia-reperfusion injury.

In vivo and ex vivo effects of adenosine A1 and A2 receptor agonists on platelet aggregation in the rabbit.

We have investigated both in vivo and ex vivo antiaggregatory activity of three adenosine receptor agonists in the anesthetized rabbit: the non-selective, 5'-N-ethyl-carboxamidoadenosine (NECA), the selective adenosine A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA) and the new selective A2 receptor agonist, 2-hexynyl-NECA. The drugs were administered by 30-min intravenous infusion at a dose reducing mean blood pressure by 40-50%. NECA and CCPA also markedly decreased heart rate. In ex vivo experiments, NECA (10 micrograms/kg) and 2-hexynyl-NECA (10 micrograms/kg) maximally inhibited adenosine 5'-diphosphate (ADP)-induced platelet aggregation at the end of drug infusion by 26.7 +/- 2.9% and 25.2 +/- 3.5%, respectively. In in vivo studies, the inhibition of platelet aggregation was evaluated using the technique based on selective accumulation of 111In-labeled platelets in pulmonary microcirculation upon challenge with ADP 100 micrograms/kg. NECA (10 micrograms/kg) and 2-hexynyl-NECA (10 micrograms/kg) decreased peak values for platelet accumulation by 35.3 +/- 6.9% and 52.5 +/- 5.9% and the area under curve values by 37.7 +/- 8.7% and 41.2 +/- 12.0%, respectively. In comparison, CCPA (100 micrograms/kg) did not affect platelet responses to ADP in either of the experimental models. Thus, the present study clearly demonstrates for the first time the in vivo antiplatelet activity of adenosine A2 receptor agonists, whereas the adenosine A1 receptor agonist was inactive, in consonance with the in vitro data.

Phosphoramidon does not inhibit endogenous endothelin-1 release stimulated by hemorrhage, cytokines and hypoxia in rats.

The role of phosphoramidon-sensitive endothelin converting enzyme in the release of endogenous endothelin-1 was investigated in anesthetized rats. Intravenous infusion of phosphoramidon 0.3 mg/kg/min did not suppress the release of endothelin-1 stimulated by hemorrhage or cytokines. Elevation of endothelin-1 in rats subjected to hypoxia was not modified by phosphoramidon (0.1 or 0.3 mg/kg/min for 2 h). A high dose of phosphoramidon (10 mg/kg i.v. +0.1 mg/kg/min) significantly potentiated the hypoxia-induced increases in plasma endothelin-1 levels. Increases in endothelin-1 release caused by bilateral nephrectomy were further enhanced by hypoxia. It is concluded that the release of endogenous endothelin-1 release stimulated by hemorrhage, cytokines and hypoxia is resistant to inhibition by phosphoramidon, and at high doses, phosphoramidon potentiates hemorrhage- and hypoxia-induced increases in endothelin-1 levels, most likely by preventing its degradation.