A phase 1 study of dimdazenil to evaluate the pharmacokinetics, food effect and safety in Chinese healthy subjects

Background and objective: As a partial positive allosteric modulator of the gamma-aminobutyric acid A (GABAA) receptor, dimdazenil was used for the treatment of insomnia with the potential to alleviate associated side effects compared to full agonists. The objective of this trial is to assess the safety, tolerability, food effect and pharmacokinetics following single and multiple doses of dimdazenil in Chinese healthy subjects.Methods: In this phase 1 trial, 36 healthy subjects aged ≥18 years were assigned to receive a single dose of 1.5, 2.5, or 5 mg dimdazenil, with each dose cohort consisting of 12 subjects, and 14 subjects were assigned to receive a multiple 2.5 mg daily dose of dimdazenil for 5 days. Safety, tolerability, and pharmacokinetic characteristics were evaluated.Results: Of the 50 subjects enrolled and 49 completed the trial, the incidences of treatment-emergent adverse events (AEs) in the single-dose groups of 1.5, 2.5, and 5 mg were 16.7%, 58.3% and 66.7% respectively, while 61.5% in the multiple-dose group. There were no serious AEs, deaths, AEs leading to discontinuation or AEs of requiring clinical intervention in any treatment groups. The most treatment-emergent AEs were dizziness (n = 4, 8.2%), hyperuricemia (n = 2, 6.1%), upper respiratory tract infection (n = 2, 6.1%), diastolic blood pressure decreased (n = 2, 6.1%), blood TG increased (n = 2, 6.1%) and RBC urine positive (n = 2, 6.1%). All AEs were mild-to-moderate and transient, and no severe AEs were documented in any study phase. The PK profile of dimdazenil and its active metabolite Ro46-1927 was linear across 1.5–5 mg oral doses in humans. The median Tmax for dimdazenil was in the range of 0.5–1.5 h, and the apparent terminal t1/2z ranged from 3.50 to 4.32 h. Taking Dimdazenil with food may delay Tmax and decrease Cmax, without affecting the total exposure (AUC). No relevant accumulations of dimdazenil and Ro 46–1927 were observed in multiple-dose group.Conclusion: Dimdazenil was generally well tolerated in healthy Chinese subjects after single and 5 days-multiple dosing. The pharmacokinetic properties of dimdazenil are compatible with a drug for the treatment of insomnia.Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR2020197

Modeling nonlinear stress-strain model for sulfate dry-wet cycle erosion of concrete: considerations for the initial compaction stage

Abstract Sulfate dry-wet cycle erosion significantly affects the mechanical properties of concrete. Investigating the uniaxial compressive stress-strain relationship under these conditions is essential for developing accurate constitutive models. This study analyzes the uniaxial stress-strain curves of concrete subjected to dry-wet cycles in 5% and 15% sulfate solutions. The results show that the initial compaction phase in the stress-strain relationship is particularly pronounced under increasing sulfate concentrations and cycle counts. The concrete experiences an extended compaction phase, which accounts for up to 35.71% of the total strain process. This finding challenge traditional constitutive models, which struggle to accurately describe this phase. To address this issue, the study develops a nonlinear stress-strain model for concrete, incorporating the initial damage caused by sulfate dry-wet cycle erosion, based on Weibull statistical damage mechanics principles. The research indicates that the effects of sulfate concentration and cycle count are predominantly reflected in the pronounced nonlinearity of the skeleton strain function’s opening size (a) and shape characteristics (b), modeled using a fourth-degree polynomial. The model demonstrates an excellent fit to experimental data with an R 2 value of 0.99989, showing that the proposed nonlinear stress-strain relationship effectively captures the uniaxial mechanical behavior of concrete under sulfate dry-wet cycle erosion and provides a robust framework for developing constitutive models in such environments

Mechanical and damage characteristics study of concrete under repeated sulfate erosion

The mechanical properties of concrete structures change under repeated sulfate salt erosion, a transformation observable through the evolving energy characteristics during compression. This study conducts uniaxial compression tests on ordinary concrete under repeated sulfate solution and pure water erosion, referencing uniaxial compression tests on concrete with admixtures under sulfate solution erosion, comparing and analyzing their mechanical properties and energy conversion characteristics. Findings indicate: (1) Repeated sulfate erosion increases the nonlinearity of the concrete’s stress-strain curve, especially during the initial compaction phase. Regardless of peak strength, both the energy dissipation curve and damage variables defined by dissipated energy show consistent trends. This suggests that sulfate salts react within the concrete, generating new substances that fill pores, temporarily increasing the elastic modulus while degrading the original structure, ultimately leading to brittle failure. (2) Considering repair effectiveness, protection of repair products, and the evolution of dissipated energy, peak strength variations, and SEM images of internal microcracks, the optimal timing for self-healing in ordinary concrete is suggested to be after 14 wet-dry cycles. (3) Under repeated sulfate salt erosion, the stress-strain relationship of ordinary concrete significantly deviates from traditional damage constitutive models, especially during initial compaction phase. Constitutive models based on damage variable evolution and dissipated energy show better agreement with experimental results in this phase

Chromosome-level genome assembly of tree sparrow reveals a burst of new genes driven by segmental duplications

AbstractThe creation of new genes is a major force of evolution. Despite as an important mechanism that generated new genes, segmental duplication (SD) has yet to be accurately identified and fully characterized in birds because the repetitive complexity leads to misassignment and misassembly of sequence. In addition, SD may lead to new gene copies, which makes it possible to test the “out of testis” hypothesis which suggests genes are frequently born with testis-specific expression. Using a high-quality chromosome-level assembly, we performed a systematic analysis and presented a comprehensive landscape of SDs in tree sparrow (Passer montanus). We detected co-localization of newly expanded genes and long terminal repeat retrotransposons (LTR-RTs), both of which are derived from SDs and enriched in microchromosomes. The newly expanded genes are mostly found in eight families includingC2H2ZNF, OR, PIM, PAK, MROH, HYDIN, HSFandITPRIPL. The large majority of new members of these eight families have evolved to pseudogenes, whereas there still some new copies preserved transcriptional activity. Among the transcriptionally active new members, new genes from different families with diverse structures and functions shared a similar testis-biased expression pattern, which is consistent with the “out of testis” hypothesis. Through a case analysis of the high-quality genome assembly of tree sparrow, we reveal that the SDs contribute to the formation of new genes. Our study provides a comprehensive understanding of the emergence, expression and fate of duplicated genes and how the SDs might participate in these processes and shape genome evolution.</jats:p

Impact of Water&ndash;Cement Ratio on Concrete Mechanical Performance: Insights into Energy Evolution and Ultrasonic Wave Velocity

The water&ndash;cement ratio significantly affects the mechanical properties of concrete with changes in porosity serving as a key indicator of these properties, which are correlated with the ultrasonic wave velocity and energy evolution. This study conducts uniaxial compression tests on concrete with varying water&ndash;cement ratios, analyzing energy evolution and ultrasonic wave velocity variations during the pore compaction stage and comparing damage variables defined by dissipated energy and ultrasonic wave velocity. The results indicate the following findings. (1) Higher water&ndash;cement ratios lead to more complete hydration, lower initial porosity, and a less pronounced pore compaction stage, but they deteriorate mechanical properties. (2) In the pore compaction stage, damage variables defined by dissipated energy are more regular than those defined by ultrasonic wave velocity, showing a nearly linear increase with stress (D = 0~0.025); ultrasonic wave variables fluctuate within &minus;0.06 to 0.04 due to diffraction caused by changes in the pore medium. (3) In the pre-peak stress stage, damage variables defined by ultrasonic wave velocity show a distinct threshold. When the stress ratio exceeds about 0.3, the damage variable curve&rsquo;s growth shows clear regularity, significantly reflecting porosity changes. In conclusion, for studying porosity changes during the pore compaction stage, damage variables defined by dissipated energy are more effective

Chromosome-level genome assembly of tree sparrow reveals a burst of new genes driven by segmental duplications

The creation of new genes is a major force of evolution. Despite as an important mechanism that generated new genes, segmental duplication (SD) has yet to be accurately identified and fully characterized in birds because the repetitive complexity leads to misassignment and misassembly of sequence. In addition, SD may lead to new gene copies, which makes it possible to test the “out of testis” hypothesis which suggests genes are frequently born with testis-specific expression. Using a high-quality chromosome-level assembly, we performed a systematic analysis and presented a comprehensive landscape of SDs in tree sparrow (Passer montanus). We detected co-localization of newly expanded genes and long terminal repeat retrotransposons (LTR-RTs), both of which are derived from SDs and enriched in microchromosomes. The newly expanded genes are mostly found in eight families including C2H2ZNF, OR, PIM, PAK, MROH, HYDIN, HSF and ITPRIPL. The large majority of new members of these eight families have evolved to pseudogenes, whereas there still some new copies preserved transcriptional activity. Among the transcriptionally active new members, new genes from different families with diverse structures and functions shared a similar testis-biased expression pattern, which is consistent with the “out of testis” hypothesis. Through a case analysis of the high-quality genome assembly of tree sparrow, we reveal that the SDs contribute to the formation of new genes. Our study provides a comprehensive understanding of the emergence, expression and fate of duplicated genes and how the SDs might participate in these processes and shape genome evolution.</jats:p

A staging table of embryonic development for a viviparous (live-bearing) lizard

As the only viviparous reptile in China that has both temperature-dependent sex determination (TSD) and genetic-dependent sex determination (GSD) mechanisms, Eremias multiocellata is considered as an ideal species for studying the sex determination mechanism in viviparous lizards. However, studies on embryonic stage of viviparous lizards and morphological characteristics of each stage are limited. In the present study, the embryonic development process of E. multiocellata is divided into 15 stages (stages 28–42) according to the morphology of embryos. Embryos sizes are measured and continuous dynamic variation of some key features, including limbs, genitals, eyes, pigments, and brain scales are color imaged by a stereoscopic microscope. Furthermore, based on these morphological characteristics, we compare the similarities and differences in the embryonic development of E. multiocellata with other squamate species. Our results not only identified the staging table of E. multiocellata with continuous changes of external morphological characteristics but also developed a staging scheme for an important model species that provides a necessary foundation for study of sex determination in a viviparous lizard.</jats:p

DataSheet1_A phase 1 study of dimdazenil to evaluate the pharmacokinetics, food effect and safety in Chinese healthy subjects.pdf

Background and objective: As a partial positive allosteric modulator of the gamma-aminobutyric acid A (GABAA) receptor, dimdazenil was used for the treatment of insomnia with the potential to alleviate associated side effects compared to full agonists. The objective of this trial is to assess the safety, tolerability, food effect and pharmacokinetics following single and multiple doses of dimdazenil in Chinese healthy subjects.Methods: In this phase 1 trial, 36 healthy subjects aged ≥18 years were assigned to receive a single dose of 1.5, 2.5, or 5 mg dimdazenil, with each dose cohort consisting of 12 subjects, and 14 subjects were assigned to receive a multiple 2.5 mg daily dose of dimdazenil for 5 days. Safety, tolerability, and pharmacokinetic characteristics were evaluated.Results: Of the 50 subjects enrolled and 49 completed the trial, the incidences of treatment-emergent adverse events (AEs) in the single-dose groups of 1.5, 2.5, and 5 mg were 16.7%, 58.3% and 66.7% respectively, while 61.5% in the multiple-dose group. There were no serious AEs, deaths, AEs leading to discontinuation or AEs of requiring clinical intervention in any treatment groups. The most treatment-emergent AEs were dizziness (n = 4, 8.2%), hyperuricemia (n = 2, 6.1%), upper respiratory tract infection (n = 2, 6.1%), diastolic blood pressure decreased (n = 2, 6.1%), blood TG increased (n = 2, 6.1%) and RBC urine positive (n = 2, 6.1%). All AEs were mild-to-moderate and transient, and no severe AEs were documented in any study phase. The PK profile of dimdazenil and its active metabolite Ro46-1927 was linear across 1.5–5 mg oral doses in humans. The median Tmax for dimdazenil was in the range of 0.5–1.5 h, and the apparent terminal t1/2z ranged from 3.50 to 4.32 h. Taking Dimdazenil with food may delay Tmax and decrease Cmax, without affecting the total exposure (AUC). No relevant accumulations of dimdazenil and Ro 46–1927 were observed in multiple-dose group.Conclusion: Dimdazenil was generally well tolerated in healthy Chinese subjects after single and 5 days-multiple dosing. The pharmacokinetic properties of dimdazenil are compatible with a drug for the treatment of insomnia.Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR20201978</p