Quenching and morphological evolution due to circumgalactic gas expulsion in a simulated galaxy with a controlled assembly history

We examine the influence of dark matter halo assembly on the evolution of a simulated ∼L⋆ galaxy. Starting from a zoom-in simulation of a star-forming galaxy evolved with the EAGLE galaxy formation model, we use the genetic modification technique to create a pair of complementary assembly histories: one in which the halo assembles later than in the unmodified case, and one in which it assembles earlier. Delayed assembly leads to the galaxy exhibiting a greater present-day star formation rate than its unmodified counterpart, while in the accelerated case the galaxy quenches at z ≃ 1, and becomes spheroidal. We simulate each assembly history nine times, adopting different seeds for the random number generator used by EAGLE’s stochastic subgrid implementations of star formation and feedback. The systematic changes driven by differences in assembly history are significantly stronger than the random scatter induced by this stochasticity. The sensitivity of ∼L⋆ galaxy evolution to dark matter halo assembly follows from the close coupling of the growth histories of the central black hole (BH) and the halo, such that earlier assembly fosters the formation of a more massive BH, and more efficient expulsion of circumgalactic gas. In response to this expulsion, the circumgalactic medium reconfigures at a lower density, extending its cooling time and thus inhibiting the replenishment of the interstellar medium. Our results indicate that halo assembly history significantly influences the evolution of ∼L⋆ central galaxies, and that the expulsion of circumgalactic gas is a crucial step in quenching them

Neuroactive Steroids Reverse Tonic Inhibitory Deficits in Fragile X Syndrome Mouse Model

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. A reduction in neuronal inhibition mediated by γ-aminobutyric acid type A receptors (GABAARs) has been implicated in the pathophysiology of FXS. Neuroactive steroids (NASs) are known allosteric modulators of GABAAR channel function, but recent studies from our laboratory have revealed that NASs also exert persistent metabotropic effects on the efficacy of tonic inhibition by increasing the protein kinase C (PKC)-mediated phosphorylation of the α4 and β3 subunits which increase the membrane expression and boosts tonic inhibition. We have assessed the GABAergic signaling in the hippocampus of fragile X mental retardation protein (FMRP) knock-out (Fmr1 KO) mouse. The GABAergic tonic current in dentate gyrus granule cells (DGGCs) from 3- to 5-week-old (p21–35) Fmr1 KO mice was significantly reduced compared to WT mice. Additionally, spontaneous inhibitory post synaptic inhibitory current (sIPSC) amplitudes were increased in DGGCs from Fmr1 KO mice. While sIPSCs decay in both genotypes was prolonged by the prototypic benzodiazepine diazepam, those in Frm1-KO mice were selectively potentiated by RO15-4513. Consistent with this altered pharmacology, modifications in the expression levels and phosphorylation of receptor GABAAR subtypes that mediate tonic inhibition were seen in Fmr1 KO mice. Significantly, exposure to NASs induced a sustained elevation in tonic current in Fmr1 KO mice which was prevented with PKC inhibition. Likewise, exposure reduced elevated membrane excitability seen in the mutant mice. Collectively, our results suggest that NAS act to reverse the deficits of tonic inhibition seen in FXS, and thereby reduce aberrant neuronal hyperexcitability seen in this disorder

Quenching and morphological evolution due to circumgalactic gas expulsion in a simulated galaxy with a controlled assembly history

We examine the influence of dark matter halo assembly on the evolution of a simulated $\sim L^\star$ galaxy. Starting from a zoom-in simulation of a star-forming galaxy evolved with the EAGLE galaxy formation model, we use the genetic modification technique to create a pair of complementary assembly histories: one in which the halo assembles later than in the unmodified case, and one in which it assembles earlier. Delayed assembly leads to the galaxy exhibiting a greater present-day star formation rate than its unmodified counterpart, whilst in the accelerated case the galaxy quenches at $z\simeq 1$, and becomes spheroidal. We simulate each assembly history nine times, adopting different seeds for the random number generator used by EAGLE's stochastic subgrid implementations of star formation and feedback. The systematic changes driven by differences in assembly history are significantly stronger than the random scatter induced by this stochasticity. The sensitivity of $\sim L^\star$ galaxy evolution to dark matter halo assembly follows from the close coupling of the growth histories of the central black hole (BH) and the halo, such that earlier assembly fosters the formation of a more massive BH, and more efficient expulsion of circumgalactic gas. In response to this expulsion, the circumgalactic medium reconfigures at a lower density, extending its cooling time and thus inhibiting the replenishment of the interstellar medium. Our results indicate that halo assembly history significantly influences the evolution of $\sim L^\star$ central galaxies, and that the expulsion of circumgalactic gas is a crucial step in quenching them

Sequence learning in Associative Neuronal-Astrocytic Network

The neuronal paradigm of studying the brain has left us with limitations in both our understanding of how neurons process information to achieve biological intelligence and how such knowledge may be translated into artificial intelligence and its most brain-derived branch, neuromorphic computing. Overturning our fundamental assumptions of how the brain works, the recent exploration of astrocytes is revealing that these long-neglected brain cells dynamically regulate learning by interacting with neuronal activity at the synaptic level. Following recent experimental evidence, we designed an associative, Hopfield-type, neuronal-astrocytic network and analyzed the dynamics of the interaction between neurons and astrocytes. We show that astrocytes were sufficient to trigger transitions between learned memories in the neuronal component of the network. Further, we mathematically derived the timing of the transitions that was governed by the dynamics of the calcium-dependent slow-currents in the astrocytic processes. Overall, we provide a brain-morphic mechanism for sequence learning that is inspired by, and aligns with, recent experimental findings. To evaluate our model, we emulated astrocytic atrophy and showed that memory recall becomes significantly impaired after a critical point of affected astrocytes was reached. This brain-inspired and brain-validated approach supports our ongoing efforts to incorporate non-neuronal computing elements in neuromorphic information processing.Comment: 8 pages, 5 figure

Imaging with therapeutic acoustic wavelets–short pulses enable acoustic localization when time of arrival is combined with delay and sum

—Passive acoustic mapping (PAM) is an algorithm that reconstructs the location of acoustic sources using an array of receivers. This technique can monitor therapeutic ultrasound procedures to confirm the spatial distribution and amount of microbubble activity induced. Current PAM algorithms have an excellentlateral resolution but have a poor axial resolution, making it difficult to distinguish acoustic sources within the ultrasound beams. With recent studies demonstrating that short-length and low-pressure pulses—acoustic wavelets—have the therapeutic function, we hypothesizedthat the axial resolution could be improved with a quasi-pulse-echo approach and that the resolution improvement would depend on the wavelet’s pulse length. This article describes an algorithm that resolves acoustic sources axially using time of flight and laterally using delayand-sum beamforming, which we named axial temporal position PAM (ATP-PAM). The algorithm accommodates a rapid short pulse (RaSP) sequence that can safely deliver drugs across the blood–brain barrier. We developed our algorithm with simulations (k-wave) and in vitro experiments for one-, two-, and five-cycle pulses, comparing our resolution against that of two current PAM algorithms. We then tested ATP-PAM in vivo and evaluated whether the reconstructed acoustic sources mapped to drug deliver

Using the theory of planned behaviour as a process evaluation tool in randomised trials of knowledge translation strategies : A case study from UK primary care

Peer reviewedPublisher PD

Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi

Limited data address the impact of HIV co-infection on the pharmacokinetics of anti-tuberculosis drugs in Sub-Saharan Africa. 47 Malawian adults underwent rich pharmacokinetic sampling at 0-0.5-1-2-3-4-6-8 and 24 hours post-dose. 51% were male; mean age was 34 years. 65% were HIV-positive with a mean CD4 count of 268 cells/μL. Anti-tuberculosis drugs were administered as fixed-dose combinations (rifampicin150mg/isoniazid75mg/pyrazinamide400mg/ethambutol275mg) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampicin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analysed by non-compartmental methods and analysis of variance of log-transformed summary parameters. Pharmacokinetic parameters were: rifampicin Cmax 4.129 (2.474-5.596)μg/mL, AUC0-24 21.32 (13.57-28.60)μg/mL*h, half-life 2.45 (1.86-3.08)h; isoniazid Cmax 3.97 (2.979-4.544)μg/mL, AUC0-24 22.5 (14.75-34.59)μg/mL*h, half-life 3.93 (3.18-4.73)h.; pyrazinamide Cmax 34.21 (30.00-41.60)μg/mL, AUC0-24 386.6 (320.0-463.7)μg/mL*h, half-life 6.821 (5.71-8.042)h; ethambutol Cmax 2.278 (1.694-3.098)μg/mL, AUC0-24 20.41 (16.18-26.27)μg/mL*h, half-life 7.507 (6.517-8.696)h. Isoniazid PK data analysis suggested that around two-thirds were slow acetylators. Dose, weight and weight-adjusted dose were not significant predictors of PK exposure probably due to weight-banded dosing. In this first pharmacokinetic study of tuberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with other studies for all first line drugs except for rifampicin, for which Cmax and AUC0-24 were notably lower. Contrary to some earlier observations, HIV status did not significantly affect AUC of any of the drugs. Increasing the dose of rifampicin could be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in half-life of isoniazid of 41% (p=0.022). Possible competitive interactions between isoniazid and sulphamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further