Previous work from this laboratory has demonstrated that withdrawal from the neuroactive steroid 3alpha,5alpha-THP (3alpha-hydroxy-5alpha-pregnan-20-one) after 3-week exposure to its parent compound, progesterone (P), increases anxiety and produces benzodiazepine (BDZ) insensitivity in female rats. These events were linked to upregulation of the alpha4 subunit of the GABA(A) receptor (GABAR) in the hippocampus [Brain Res. 507 (1998) 91; Nature 392 (1998) 926; J. Neurosci. 18 (1998) 5275]. The present study investigates the role of shorter term hormone treatment on alpha4 subunit levels as well as relevant behavioral and pharmacological end-points related to GABAR function. After 2-3 days of P exposure, two- to threefold increases in alpha4 protein levels were observed, which declined to control values after 5-6 days of hormone exposure. This effect was due to the GABA-modulatory metabolite of P, 3alpha,5alpha-THP. alpha4 upregulation was inversely correlated with BDZ potentiation of GABA-gated current, assessed using whole cell patch clamp techniques on acutely isolated hippocampal pyramidal cells. A near total BDZ insensitivity was observed by 2-3 days of hormone exposure in association with the maximal increase in alpha4 levels. Up-regulation of the alpha4 GABAR subunit was also reflected by an increase in anxiety in the elevated plus maze. A significant decrease in open arm entries was observed after 72-h exposure to P, an effect which recovered by 6 days of P treatment. As demonstrated in vitro, alpha4 upregulation also resulted in a relative insensitivity to the anxiolytic actions of BDZ. These results suggest that short-term exposure to 3alpha,5alpha-THP produces changes in GABAR subunit composition similar to those that occur after chronic exposure and withdrawal from the steroid.

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Background Anti-IL23p19 inhibitors are emerging as promising treatment options for ulcerative colitis (UC). Mirikizumab (miri) is a humanized, IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key mediator in the pathogenesis of inflammatory bowel diseases. We assessed the induction efficacy and safety of miri with a Phase 3, multi-center, randomized, parallel-arm, double-blind, placebo (PBO)-controlled trial (LUCENT 1; NCT03518086) in patients with moderately to severely active UC (Modified Mayo Score 4–9 points and centrally read Mayo endoscopic subscore ≥2) who had inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, biologic therapies, or tofacitinib. Methods Adult patients (N=1281) were randomized in a 3:1 ratio to receive blinded intravenous administration of 300 mg miri or PBO every 4 weeks for 12 weeks. Randomization was stratified by biologic failure status, baseline (BL) corticosteroid use, BL disease activity as measured by modified Mayo score, and world region. The primary objective was to test the hypothesis that miri was superior to PBO in inducing clinical remission at Week 12. Key secondary objectives were clinical response, endoscopic remission, symptomatic remission, clinical response in biologic-failed patients, histologic-endoscopic mucosal improvement, and improvement in bowel urgency at Week 12 (see Figure for endpoint definitions). Mixed Model for Repeated Measures was used to assess urgency; the Cochran-Mantel-Haenszel test, with missing data imputed as nonresponse, was used to assess all other outcomes. Results BL characteristics were balanced across the two treatment groups. A significantly greater proportion of patients treated with miri achieved clinical remission at Week 12 (Miri: 24.2%; PBO: 13.3%; Δ=11.1 [99.875%CI: 3.2, 19.1]; p=0.00006). Miri-treated patients achieved all key secondary endpoints, including a significantly greater average reduction in bowel urgency severity compared to PBO (p<0.00001). The frequencies of treatment-emergent adverse events in miri-treated patients were similar to PBO. There were numerically fewer serious adverse events (Miri: 27 [2.8%], PBO: 17 [5.3%]) and discontinuations due to adverse events (Miri: 15 [1.6%], PBO: 23 [7.2%]) in miri-treated patients compared to PBO. There were 2 colon malignancies in the miri arm (0.2%) and no deaths during the treatment period. Conclusion In this phase 3 UC study, 300mg miri IV demonstrated statistically significant and clinically meaningful improvements vs PBO in all primary and key secondary endpoints across clinical, endoscopic, histologic, and symptomatic measures, with an acceptable safety profile.

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Nanosecond pulses were employed to study hot-electron transport in a nominally undoped Al 0.33 Ga 0.67 N/AlN/{Al 0.1 Ga 0.9 N/GaN} heterostructure where the mobile electrons are spread in a composite {Al 0.1 Ga 0.9 /GaN} dual channel exhibiting a camelback electron density profile at high electric fields. The highest velocity of ∼1.6×10 7 cm s −1 was obtained at electric field of 160 kV cm −1 in the channel with the electron density of 0.8 × 10 13 cm −2 owing to its proximity to the LO-phonon-plasmon resonance.