Pc2-3 geomagnetic pulsations on the ground, in the ionosphere, and in the magnetosphere: MM100, CHAMP, and THEMIS observations

We analyze Pc2-3 pulsations recorded by the CHAMP (CHAllenging Minisatellite Payload) satellite in the F layer of the Earth’s ionosphere, on the ground, and in the magnetosphere during quiet geomagnetic conditions. The spectra of Pc2-3 pulsations recorded in the F layer are enriched with frequencies above 50 mHz in comparison to the ground Pc2-3 spectra. These frequencies are higher than the fundamental harmonics of the field line resonances in the magnetosphere. High quality signals with dominant frequencies 70–200 mHz are a regular phenomenon in the F layer and in the magnetosphere. The mean latitude of the maximum Pc2-3 occurrence rate lies at L � 3:5 in the F layer, i.e., inside the plasmasphere. Day-to-day variations of the L value of the CHAMP Pc2-3 occurrence rate maximum follow the plasmapause day-to-day variations. Polarization and amplitude of Pc2-3s in the magnetosphere, in the ionosphere, and on the ground allow us to suggest that they are generated as fast magnetosonic (FMS) waves in the outer magnetosphere and are partly converted into shear Alfven waves near the plasmapause. The observed ground-to-ionosphere amplitude ratio during the night is interpreted as a result of the Alfven wave transmission through the ionosphere. The problem of wave transmission through the ionosphere is solved theoretically by means of a numerical solution of the full-wave equation for the Alfven wave reflection from and transmission through a horizontally stratified ionosphere. The best agreement between the calculated and measured values of the ground-to-ionosphere amplitude ratio is found for k D 5�1

A Characterisation of the Weylian Structure of Space-Time by Means of Low Velocity Tests

The compatibility axiom in Ehlers, Pirani and Schild's (EPS) constructive axiomatics of the space-time geometry that uses light rays and freely falling particles with high velocity, is replaced by several constructions with low velocity particles only. For that purpose we describe in a space-time with a conformal structure and an arbitrary path structure the radial acceleration, a Coriolis acceleration and the zig-zag construction. Each of these quantities give effects whose requirement to vanish can be taken as alternative version of the compatibility axiom of EPS. The procedural advantage lies in the fact, that one can make null-experiments and that one only needs low velocity particles to test the compatibility axiom. We show in addition that Perlick's standard clock can exist in a Weyl space only.Comment: to appear in Gen.Rel.Gra

3D high throughput screening and profiling of embryoid bodies in thermoformed microwell plates

3D organoids using stem cells to study development and disease are now widespread. These models are powerful to mimic in vivo situations but are currently associated with high variability and low throughput. For biomedical research, platforms are thus necessary to increase reproducibility and allow high-throughput screens (HTS). Here, we introduce a microwell platform, integrated in standard culture plates, for functional HTS. Using micro-thermoforming, we form round-bottom microwell arrays from optically clear cyclic olefin polymer films, and assemble them with bottom-less 96-well plates. We show that embryonic stem cells aggregate faster and more reproducibly (centricity, circularity) as compared to a state-of-the-art microwell array. We then run a screen of a chemical library to direct differentiation into primitive endoderm (PrE) and, using on-chip high content imaging (HCI), we identify molecules, including regulators of the cAMP pathway, regulating tissue size, morphology and PrE gene activity. We propose that this platform will benefit to the systematic study of organogenesis in vitro

Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1

Primary microcephaly, Seckel syndrome, and microcephalic osteodysplastic primordial dwarfism type II (MOPD II) are disorders exhibiting marked microcephaly, with small brain sizes reflecting reduced neuron production during fetal life. Although primary microcephaly can be caused by mutations in microcephalin (MCPH1), cells from patients with Seckel syndrome and MOPD II harbor mutations in ataxia telangiectasia and Rad3 related (ATR) or pericentrin (PCNT), leading to disturbed ATR signaling. In this study, we show that a lack of MCPH1 or PCNT results in a loss of Chk1 from centrosomes with subsequently deregulated activation of centrosomal cyclin B–Cdk1

Existence of families of spacetimes with a Newtonian limit

J\"urgen Ehlers developed \emph{frame theory} to better understand the relationship between general relativity and Newtonian gravity. Frame theory contains a parameter $\lambda$, which can be thought of as $1/c^2$, where $c$ is the speed of light. By construction, frame theory is equivalent to general relativity for $\lambda >0$, and reduces to Newtonian gravity for $\lambda =0$. Moreover, by setting \ep=\sqrt{\lambda}, frame theory provides a framework to study the Newtonian limit \ep \searrow 0 (i.e. $c\to \infty$). A number of ideas relating to frame theory that were introduced by J\"urgen have subsequently found important applications to the rigorous study of both the Newtonian limit and post-Newtonian expansions. In this article, we review frame theory and discuss, in a non-technical fashion, some of the rigorous results on the Newtonian limit and post-Newtonian expansions that have followed from J\"urgen's work

Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism

The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists

The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity.

Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1 <sup>C284A</sup> , we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1 <sup>C284A</sup> , we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis

The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence

The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case–control analysis (N=908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N=3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA;N=81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N=22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P=0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P=0.033). The 168Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD