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Lissencephaly is a rare brain malformation characterized by abnormal neuronal migration during cortical development. In this study, we performed a comprehensive genetic analysis using next-generation sequencing in 12 unsolved Japanese lissencephaly patients, in whom PAFAH1B1, DCX, TUBA1A, and ARX variants were excluded using the Sanger method. Exome sequencing (ES) was conducted on these 12 patients, identifying pathogenic variants in CEP85L, DYNC1H1, LAMC3, and DCX in four patients. Next, we performed genome sequencing (GS) on eight unsolved patients, and structural variants in PAFAH1B1, including an inversion and microdeletions involving several exons, were detected in three patients. Notably, these microdeletions in PAFAH1B1 could not to be detected by copy number variation (CNV) detection tools based on the depth of coverage methods using ES data. The density of repeat sequences, including Alu sequences or segmental duplications, which increase the susceptibility to structural variations, is very high in some lissencephaly spectrum genes (PAFAH1B1, TUBA1A, DYNC1H1). These missing CNVs were due to the limitations of detecting repeat sequences in ES-based CNV detection tools. Our study suggests that a combined approach integrating ES with GS can contribute to a higher diagnostic yield and a better understanding of the genetic landscape of the lissencephaly spectrum., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

This study introduces a compact, portable femtosecond fibre laser system designed for synchronization with SPring-8 synchrotron X-ray pulses in a uniform filling mode. Unlike traditional titanium-sapphire mode-locked lasers, which are fixed installations, our system utilizes fibre laser technology to provide a practical alternative for time-resolved spectroscopy, striking a balance between usability, portability and cost-efficiency. Comprehensive evaluations, including pulse characterization, timing jitter and frequency stability tests revealed a centre wavelength of 1600 nm, a pulse energy of 4.5 nJ, a pulse duration of 35 fs with a timing jitter of less than 9 ps, confirming the suitability of the system for time-resolved spectroscopic studies. This development enhances the feasibility of experiments that combine synchrotron X-rays and laser pulses, offering significant scientific contributions by enabling more flexible and diverse research applications., (open access.)

In animal species that have the capability of regenerating tissues and limbs, cell proliferation is enhanced after wound healing and is essential for the reconstruction of injured tissue. Although the ability to induce cell proliferation is a common feature of such species, the molecular mechanisms that regulate the transition from wound healing to regenerative cell proliferation remain unclear. Here, we show that upon injury, InhibinβA and JunB cooperatively function for this transition during Xenopus tadpole tail regeneration. We found that the expression of inhibin subunit beta A (inhba) and junB proto-oncogene (junb) is induced by injury-activated TGF-β/Smad and MEK/ERK signaling in regenerating tails. Similarly to junb knockout (KO) tadpoles, inhba KO tadpoles show a delay in tail regeneration, and inhba/junb double KO (DKO) tadpoles exhibit severe impairment of tail regeneration compared with either inhba KO or junb KO tadpoles. Importantly, this impairment is associated with a significant reduction of cell proliferation in regenerating tissue. Moreover, JunB regulates tail regeneration via FGF signaling, while InhibinβA likely acts through different mechanisms. These results demonstrate that the cooperation of injury-induced InhibinβA and JunB is critical for regenerative cell proliferation, which is necessary for re-outgrowth of regenerating Xenopus tadpole tails., (© 2024. The Author(s).)

Atopic dermatitis (AD) is an allergic skin disease, triggered by excessive type 2 immune reactions. Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that induces type 2 immune response through dendritic cell activation. Therefore, TSLP inhibitors may serve as novel antiallergic drugs. Hypoxia-inducible factor (HIF) activation in the epithelia contributes to several homeostatic phenomena, such as re-epithelialization. However, the effects of HIF activation on TSLP production and immune activation in the skin remain unclear. In this study, we found that selective HIF prolyl hydroxylase inhibitors (PHD inhibitors), which induce HIF activation, suppressed TSLP production in a mouse ovalbumin (OVA) sensitization model. PHD inhibitors also suppressed the production of tumor necrosis factor-alpha (TNF-α), which is a major inducer of TSLP production, in this mouse model and in a macrophage cell line. Consistent with these findings, PHD inhibitors suppressed OVA-specific IgE levels in the serum and OVA-induced allergic responses. Furthermore, we found a direct suppressive effect on TSLP expression in a human keratinocyte cell line mediated by HIF activation. Taken together, our findings suggest that PHD inhibitors exert antiallergic effects by suppressing TSLP production. Controlling the HIF activation system has therapeutic potential in AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: To assess the health-related quality of life (HRQOL) of children with daytime urinary incontinence (DUI) based on pre- and post-treatment self-reports and parent proxy-reports., Methods: The study population comprised 117 children with at least one episode of DUI per week and their caregivers as well as 999 healthy children (control group). The Pediatric Quality of Life Inventory 4.0 (PedsQL) questionnaire was administered to assess the HRQOL of children. To assess the degree of improvement in HRQOL, we categorized children into two groups: group A achieved complete response (CR) to treatment within 12 months and group B did not achieve CR within 12 months. CR was defined as the complete resolution of symptoms or alleviation of symptoms to < 1 DUI episode/month., Results: Valid responses were collected from 84 children [53 boys and 31 girls; mean age: 7.9 ± 1.5 years (range, 6-12)]. Sixty-two patients (73.8%) were classified into group A and 22 (26.1%) into group B. Based on self-reports, significant post-treatment improvement was observed in the scores of all PedsQL items (mean total score: 82.2 ± 11.3 vs. 87.2 ± 9.8; P = 0.003). Group A showed significant improvement in the scores of all PedsQL items after achievement of CR based on child self-reports; however, this was improvement not observed in group B., Conclusions: To the best of our knowledge, this is the first study to demonstrate the complete resolution of DUI with treatment for improving the HRQOL of these children.

Background: Acute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8(-/-)), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system., Methodology/principal Findings: Caspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNFα (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8(-/-) mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging., Conclusions: Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma.