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Ultrahigh-energy density (UHED) states greater than 1 Gbar pressure are typically observed under extreme conditions, such as in the core of an inertial confinement fusion implosion. A novel alternative approach for generating volumetric UHED states is to use nanowire arrays irradiated with a femtosecond ultrahigh-intensity laser. In this paper, we present an experimental investigation on laser absorption and energy transport in nanowire arrays irradiated with a picosecond kilojoule petawatt laser. The laser–target interactions were studied by measuring the x-ray emission and escaping hot electrons from a bare Cu foil and a foil with a nanowire array grown on its surface. The measured Cu-Kα and He-α emissions from the nanowire array were higher than those from the flat foil. In addition, hot electrons observed from the front surface of the nanowire array were enhanced. On the other hand, despite the stronger Kα emission from the nanowire array and the enhancement of hot electrons escaping from the front surface of the nanowire array, the number of hot electrons observed from the rear side of the flat foil target was slightly lower than that of the flat foil. A comparison of the experimental results with the results of a two-dimensional particle-in-cell simulation code suggested that the magnetic fields generated around the periodic nanowire array trap hot electrons, improving the electron-to-target energy coupling and efficiently producing UHED states.

We demonstrate a significantly simplified experimental approach for investigating liquid metallic hydrogen, which is crucial to understand the internal structure and evolution of giant planets. Plastic samples were shockcompressed and then probed by short pulses of X-rays generated by free electron lasers. By comparison with ab initio simulations, we provide indirect evidence for the creation of elemental hydrogen in shock-compressed plastics at ∼150GPa and ∼5,000K and thus in a regime where hydrogen is predicted to be metallic. Being the most common form of condensed matter in our solar system, and ostensibly the simplest of all elements, hydrogen is the model case for many theoretical studies and we provide a new possibility to benchmark models for conditions with extreme pressures and temperatures. Moreover, this approach will also allow to probe the chemical behavior of metallic hydrogen in mixture with other elements, which, besides its importance for planetary physics, may open up promising pathways for the synthesis of new materials.

Abstract Magnetic reconnection is a universal process in space, astrophysical, and laboratory plasmas. It alters magnetic field topology and results in energy release to the plasma. Here we report the experimental results of a pure electron outflow in magnetic reconnection, which is not accompanied with ion flows. By controlling an applied magnetic field in a laser produced plasma, we have constructed an experiment that magnetizes the electrons but not the ions. This allows us to isolate the electron dynamics from the ions. Collective Thomson scattering measurements reveal the electron Alfvénic outflow without ion outflow. The resultant plasmoid and whistler waves are observed with the magnetic induction probe measurements. We observe the unique features of electron-scale magnetic reconnection simultaneously in laser produced plasmas, including global structures, local plasma parameters, magnetic field, and waves.

Laser–plasma interaction and hot electrons have been characterized in detail in laser irradiation conditions relevant for direct-drive inertial confinement fusion. The experiment was carried out at the Gekko XII laser facility in multibeam planar target geometry at an intensity of approximately $3\times {10}^{15}$ W/cm2. Experimental data suggest that high-energy electrons, with temperatures of 20–50 keV and conversion efficiencies of $\eta

Laser plasma instabilities, such as stimulated Raman scattering (SRS) and two-plasmon decay (TPD), are basic phenomena in intense laser science and applications. In direct-drive inertial confinement fusion (ICF) where a fuel capsule is imploded by high-power lasers, SRS and TPD are generally problematic because hot electrons (HEs) generated by SRS and TPD cause fuel preheating, whereas HEs with acceptable energy are expected to contribute to ablation pressure enhancement. In all cases, it is necessary to clarify the occurrence of SRS, TPD, and subsequent HE generation. The ablator of a fuel capsule in direct-drive ICF typically consists of carbon with a variable amount of hydrogen (H). We investigated the H effects in the ablator on SRS, TPD, and HEs under direct-drive ICF conditions at the GEKKO laser facility in planer geometry. The experimental results showed an increase in SRS, TPD, and HEs when H was present in the ablator. The analysis indicated that the variations in plasma inhomogeneity and plasma temperature obtained by H addition were insufficient to explain the observed results. Thus, the enhancement is mainly attributed to the high ion acoustic wave damping driven by the H ions into the plasmas, suggesting that Langmuir decay instability caused SRS saturation, whereas other mechanisms, such as cavitation, could overwhelm the TPD saturation. These results suggest that a suitable choice of H concentration in the ablator is critical for mitigating and controlling the extent of SRS, TPD, and HEs to achieve robust and efficient implosion in direct-drive ICF.

Turbulence effects explored use macroscale systems in general. Here the authors generate a turbulent plasma using laser irradiation of a solid target and study the dynamics of the plasma flow at the micron-scale by using scattering of an XFEL beam.

The interaction between a molecular cloud and an external agent (e.g., a supernova remnant, plasma jet, radiation, or another cloud) is a common phenomenon throughout the Universe and can significantly change the star formation rate within a galaxy. This process leads to fragmentation of the cloud and to its subsequent compression and can, eventually, initiate the gravitational collapse of a stable molecular cloud. It is, however, difficult to study such systems in detail using conventional techniques (numerical simulations and astronomical observations), since complex interactions of flows occur. In this paper, we experimentally investigate the compression of a foam ball by Taylor–Sedov blast waves, as an analog of supernova remnants interacting with a molecular cloud. The formation of a compression wave is observed in the foam ball, indicating the importance of such experiments for understanding how star formation is triggered by external agents.

Abstract Water, methane, and ammonia are commonly considered to be the key components of the interiors of Uranus and Neptune. Modelling the planets’ internal structure, evolution, and dynamo heavily relies on the properties of the complex mixtures with uncertain exact composition in their deep interiors. Therefore, characterising icy mixtures with varying composition at planetary conditions of several hundred gigapascal and a few thousand Kelvin is crucial to improve our understanding of the ice giants. In this work, pure water, a water-ethanol mixture, and a water-ethanol-ammonia “synthetic planetary mixture” (SPM) have been compressed through laser-driven decaying shocks along their principal Hugoniot curves up to 270, 280, and 260 GPa, respectively. Measured temperatures spanned from 4000 to 25000 K, just above the coldest predicted adiabatic Uranus and Neptune profiles (3000–4000 K) but more similar to those predicted by more recent models including a thermal boundary layer (7000–14000 K). The experiments were performed at the GEKKO XII and LULI2000 laser facilities using standard optical diagnostics (Doppler velocimetry and optical pyrometry) to measure the thermodynamic state and the shock-front reflectivity at two different wavelengths. The results show that water and the mixtures undergo a similar compression path under single shock loading in agreement with Density Functional Theory Molecular Dynamics (DFT-MD) calculations using the Linear Mixing Approximation (LMA). On the contrary, their shock-front reflectivities behave differently by what concerns both the onset pressures and the saturation values, with possible impact on planetary dynamos.

Abstract High resolution X-ray imaging is crucial for many high energy density physics (HEDP) experiments. Recently developed techniques to improve resolution have, however, come at the cost of a decreased field of view. In this paper, an innovative experimental detector for X-ray imaging in the context of HEDP experiments with high spatial resolution, as well as a large field of view, is presented. The platform is based on coupling an X-ray backligther source with a Lithium Fluoride detector, characterized by its large dynamic range. A spatial resolution of 2 µm over a field of view greater than 2 mm2 is reported. The platform was benchmarked with both an X-ray free electron laser (XFEL) and an X-ray source produced by a short pulse laser. First, using a non-coherent short pulse laser-produced backlighter, reduced penumbra blurring, as a result of the large size of the X-ray source, is shown. Secondly, we demonstrate phase contrast imaging with a fully coherent monochromatic XFEL beam. Modeling of the absorption and phase contrast transmission of X-ray radiation passing through various targets is presented.

We present new diagnostics for use in optical laser pump - X-ray Free Electron Laser (XFEL) probe experiments to monitor dimensions, intensity profile and focusability of the XFEL beam and to control initial quality and homogeneity of targets to be driven by optical laser pulse. By developing X-ray imaging, based on the use of an LiF crystal detector, we were able to measure the distribution of energy inside a hard X-ray beam with unprecedented high spatial resolution (∼1 μm) and across a field of view larger than some millimetres. This diagnostic can be used in situ, provides a very high dynamic range, has an extremely limited cost, and is relatively easy to be implemented in pump-probe experiments. The proposed methods were successfully applied in pump-probe experiments at the SPring-8 Angstrom Compact free electron LAser (SACLA) XFEL facility and its potential was demonstrated for current and future High Energy Density Science experiments.

The development of small sized laser operating above room temperature is important in the realization of optical integrated circuits. Recently, micro-lasers consisting of photonic crystals (PhCs) and whispering gallery mode cavities have been demonstrated. Optically pumped laser devices could be easily designed using photonic crystal-slab waveguides (PhC-WGs) with an air-bridge type structure. In this study, we observe lasing at 1.3μm from two-photon pumped InAs-quantum-dots embedded GaAs PhC-WGs above room temperature. This type of compact laser shows promise as a new light source in ultra-compact photonics integrated circuits.

To evaluate the influences of air temperature change on ski activities, the changes in the numbers of skiers visiting seven ski areas in Japan were predicted in conjunction with climate change. First, having built a model for predicting snow depth based on the budgets of water and heat using the air temperature and precipitation data collected nationwide, we demonstrated good agreement between the predicted and observed snow depths (p < 0.01 and the ratios for more than 81% cases ranged from 0.5 to 2). Second, the relationship between the number of skiers and the depth of snow at one of the seven ski areas was analyzed statistically on a daily basis. In addition, we did the same on a monthly basis at six other ski areas and compared the observed and predicted numbers of skiers (p < 0.01 and the ratios for more than 94% cases ranged from 0.5 to 2). Using this model and the relationship between daily snow depth and number of skiers, the changes in skier numbers in the seven ski areas were predicted for several scenarios with respect to air temperature changes; e.g. a more than 30% drop in visiting skiers was forecast in almost all ski areas in Japan except northern region (Hokkaido) and/or high altitude regions (center of the Main Island) under the condition of a 3 °C increase in air temperature. The vulnerability of the ski industry and its adaptation to climate change are discussed. [ABSTRACT FROM AUTHOR]

The first laboratory evidence of a radiative shock (RS) decelerating during its free expansion phase in an optically thick medium is presented. A shock is generated in a multilayer solid target under the irradiation of a high-power laser at the GEKKO XII laser facility. The rear surface of the target is connected to a gas cell filled with Xe. Upon breakout, an RS, characterized by low Boltzmann number Bo ≪ 1 and Mihalas number R ≈ 10, is generated. Experimental results reveal that radiative losses through the radiative precursor cause the shock to lose energy and decelerate. A model is developed that describes the shock propagation as a function of time. The model is in agreement with both numerical simulations and experimental results. These results have tremendous consequences for astrophysical systems, such as SN 1987A, where radiative deceleration may play a role in the formation of the observed hotspots in the circumstellar ring. [ABSTRACT FROM AUTHOR]

Laser-driven ramp compression was used to investigate iron characteristics along the isentropic path. The iterative Lagrangian analysis method was employed to analyze the free surface velocity profiles in iron stepped target measured with two VISARs. The onset stress for the α to ε phase transformation was determined from the sudden change in the sound velocity and was found over-pressurized compared to the static and shock results. The derived stress (26 GPa) and strain rate (up to 108 s−1) are consistent with our previous experimental results. The stress–density relations were compared with those from previous ramp experiments and good agreements were found, which experimentally confirms the simulations, showing that iterative Lagrangian analysis can be applied to the ramp-compression data with weak shock. [ABSTRACT FROM AUTHOR]

Magnesium oxide has been experimentally and computationally investigated in the warm-dense solid and liquid ranges from 200 GPa to 1 TPa along the principal Hugoniot. The linear approximation between shock velocity and particle velocity is validated up to a shock velocity of 15 km/s from the experimental data, this suggesting that the MgO B1 structure is stable up to the corresponding shock pressure of ~350 GPa. Moreover, our Hugoniot data, combined with ah initio simulations, show two crossovers between MgO Hugoniot and the extrapolation of the linear approximation line, occurring at a shock pressures of approximately 350 and 650 GPa, with shock temperatures of 8000 and 14 000 K, respectively. These crossover regions are consistent with the solid-solid (B1-B2) and the solid-liquid (B2-melt) phase boundaries predicted by the ah initio calculations. [ABSTRACT FROM AUTHOR]

Copy number variations (CNVs) have emerged as crucial genetic factors influencing a wide spectrum of human health outcomes, with particularly strong associations to psychiatric disorders. This review presents a synthesis of diverse impacts of psychiatric disorder-associated CNVs on neurodevelopment, brain function, and physical health across the lifespan. Large-scale studies have revealed that CNV carriers exhibit an increased risk for psychiatric disorders, cognitive deficits, sleep disturbances, neurological disorders, and other physical conditions, including cardiovascular diseases, diabetes, and renal disease, highlighting the wide-ranging impact of CNVs beyond the brain. Neuroimaging studies reveal substantial CNV effects on brain structure, from cortical and subcortical alterations to white matter microstructure, with effect sizes often exceeding those observed in idiopathic psychiatric disorders. Cellular and animal models have begun to elucidate dynamic CNV effects on neurodevelopment, neuronal function, and cellular energy metabolism, while revealing complex CNV-environment interactions and cell type-specific responses, particularly in studies of 22q11.2 deletion syndrome. This review also explores the complex interplay between psychiatric and physical health conditions in CNV carriers, and how these interactions contribute to adverse socioeconomic outcomes, including reduced educational attainment and income levels, creating a feedback loop that further impacts health outcomes. Finally, this review also highlights research limitations and proposes key priorities for clinical implementation, including the need for longitudinal studies, standardized guidelines for CNV result reporting and genetic counseling, and integrated care networks, providing a foundation for advancing the field of precision psychiatry., (Copyright © 2024. Published by Elsevier Inc.)

Patients with epilepsy often require long-term treatment with antiseizure medications, and their impact on daily activities, particularly driving, is of significant concern. The recently published "Guideline for Evaluating Effects of Psychotropic Drugs on the Performance to Drive a Motor Vehicle" in Japan provides a framework that can be referred to for not only the evaluation of new drugs but also the reevaluation of approved drugs. This study conducted a literature review regarding the effects of carbamazepine, valproate, lamotrigine, lacosamide, and levetiracetam, which are frequently prescribed for epilepsy, on driving performance following the guideline's tiered evaluation approach. Analyses of pharmacological, pharmacodynamic, and adverse events suggested that these drugs primarily affect arousal function. Driving studies showed that acute administration of carbamazepine, but not chronic monotherapy with carbamazepine, valproate, lamotrigine, and levetiracetam, significantly impairs driving performance. Epidemiological studies have not identified a definitive association between these drugs and traffic accidents. Initial administration of these five antiseizure medications may affect driving performance, warranting special attention, but the influence appears to diminish with continued use. Nevertheless, while long-term administration of these five drugs may not have a clinically meaningful effect on driving performance, safe driving is not guaranteed for each individual patient, and appropriate individualized guidance is important in clinical practice., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

We report a case of a 61-year-old female with 22q11.2 deletion syndrome (22q11.2DS) and a novel heterozygous nonsense variant in MAP1A, identified through whole-genome sequencing (WGS). The patient presented with intellectual developmental disorder, treatment-resistant schizophrenia (SCZ), and multiple congenital anomalies. Despite aggressive pharmacotherapy, she experienced persistent auditory hallucinations and negative symptoms. WGS revealed a 3 Mb deletion at 22q11.2 and a nonsense variant in MAP1A (c.4652T>G, p.Leu1551*). MAP1A, encoding microtubule-associated protein 1A, is crucial for axon and dendrite development and has been implicated in autism spectrum disorder and SCZ. The MAP1A variant may contribute to the severe psychiatric phenotype, as it is thought to influence synaptic plasticity, a process also affected by 22q11.2 deletion. This case highlights the importance of WGS in identifying additional pathogenic variants that may explain phenotypic variability in 22q11.2DS. Thus, WGS can lead to a better understanding of the genetic architecture of 22q11.2DS. However, further studies are needed to elucidate the role of secondary genetic contributors in the diverse clinical presentations of 22q11.2DS., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: This study was approved by the Institutional Review Board of Yokohama City University Faculty of Medicine. After obtaining written informed consent, peripheral blood leukocytes were collected from the patients and their parents., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Atherosclerosis can develop in adult patients with congenital heart disease (CHD) and should be given attention. Endothelial function is well known as a predictor of the development of atherosclerosis but has not been well investigated in patients with repaired CHD. This study aimed to clarify the endothelial function and its relationship with clinical backgrounds and parameters in adolescents with various types of repaired CHDs. Endothelial function was evaluated using peripheral arterial tonometry (PAT). The reactive hyperemia index (RHI) was evaluated and compared between adolescents with repaired CHD and those in the control group. The relationship between the clinical background and parameters was also investigated in patients with repaired CHD. Forty-eight patients with repaired CHD (age 14.0 ± 3.3 years) and 114 healthy volunteers were included in this study. Patients with repaired CHD comprised 16 with repaired non-cyanotic CHD, 14 with repaired tetralogy of Fallot, and 18 who underwent the Fontan procedure. RHI in the repaired CHD group was significantly lower than in the control group. There was no significant correlation between the RHI and blood biochemical markers, such as uric acid, creatine, and brain natriuretic peptide levels. The RHI was significantly higher in patients taking angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) than in those not taking them. Endothelial function was impaired in adolescents with repaired CHD compared to that in the control group. Microvascular endothelial dysfunction developed even in adolescents with simple non-cyanotic CHD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis., Methods: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS)., Results: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS., Conclusion: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Pain is a complex phenomenon that involves sensory, emotional, and cognitive components. The posterior insula cortex (pIC) has been shown to integrate multisensory experience with emotional and cognitive states. However, the involvement of the pIC in the regulation of affective behavior in pain remains unclear. Here, we investigate the role of pain-related pIC neurons in the regulation of anxiety-like behavior during acute pain. We combined a chemogenetic approach with targeted recombination in active populations (TRAP) in mice. Global chemogenetic inhibition of pIC neurons attenuates chemically-induced mechanical hypersensitivity without affecting pain-related anxiety-like behavior. In contrast, inhibition of pain-related pIC neurons reduces both mechanical hypersensitivity and pain-related anxiety-like behavior. The present study provides important insights into the role of pIC neurons in the regulation of sensory and affective pain-related behavior., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To identify risk factors for mental distress and investigate whether the factors were different between men and women during the coronavirus disease 2019 (COVID-19), using KOKOROBO data, which is an online platform that aims to facilitate access to mental health services., Methods: We used baseline data on KOKOROBO users 13 years of age or older in Japan who accessed it from October 11, 2021, to April 6, 2023, excluding those receiving treatment for mental health problems. Global severity, based on the most severe measure on Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Insomnia Severity Index (ISI), was analyzed using multivariable logistic regression with baseline characteristics for each gender, and for under 30 and 30 years of age or older in women. We conducted the same analysis of suicidal ideation for each gender., Results: In the 686 men and 1274 women, 117 (17.1%) and 100 (7.8%) had minimal global severity respectively, and the rest suffered from mental distress to some extent. For women, ages under 30 years (adjusted OR (aOR): 0.352, 95%CI: 0.231-0.539, P < 0.001), marriage (aOR: 0.453, 95%CI: 0.274-0.746, P = 0.002), and concerns about COVID-19 infection were associated with global severity, while having children (aOR: 0.509, 95% CI: 0.284-0.909, P = 0.023) and decrease of going out during the COVID-19 pandemic had a protective effect on global severity and suicidal ideation for men, respectively. Living with family was a risk factor for mental distress in unmarried women over 30 years of age. Less communication with family or others and responding to the questionnaire late at night (00:00-05:59) were associated with severe global severity in both genders., Conclusions: Age, living arrangement, marriage, having children, concerns about COVID-19 infection, and lifestyle changes during the COVID-19 pandemic had gender-specific effects on mental distress, while frequent communication and regular life rhythm maintained mental health in both genders. Young women and, unmarried middle-aged women living with their families tended to experience mental distress during the COVID-19 pandemic., Trial Registration: The Ethics Committee of the National Center of Neurology and Psychiatry approved this study (approval number B2020141) on April 15, 2021., (© 2024. The Author(s).)

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aim: Genome-wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD-associated loci., Methods: The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders., Results: A meta-analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10 -8 ) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over-represented in categories including long-term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling., Conclusion: The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Hereditary coproporphyria (HCP) is caused by a partial deficiency of coproporphyrinogen oxidase during heme biosynthesis. Givosiran is approved for the treatment of acute hepatic porphyria. We herein report the case of a 47-year-old woman with HCP. Monthly givosiran administration improved her subjective symptoms and reduced her δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels to the normal range. However, givosiran was discontinued after six months due to a decreased renal function. The patient's ALA and PBG levels remained within the normal ranges, and her HCP-related symptoms resolved more than 2 years after the discontinuation of givosiran.

Background: This study aimed to investigate the microstructural and mechanical properties of semitendinosus tendon graft tissues during anterior cruciate ligament reconstruction and the clinical outcomes in skeletally immature and mature patients., Methods: Twenty-two patients who underwent primary anterior cruciate ligament reconstruction using a hamstring tendon graft were analyzed and divided into skeletally immature (n = 7) and mature groups (n = 15) based on magnetic resonance imaging findings of the epiphyseal plate of the distal femur. Tissue samples were collected from the mid-portion of the semitendinosus tendon. The collagen fibril diameter, maximum stress, and strain at maximum stress point in the semitendinosus tendon tissues were calculated for comparison of the microstructural and mechanical properties between the two groups. Postoperative outcomes were also assessed between the two groups., Results: The mean and 60th and 80th percentiles of fibril diameters in the skeletally immature group were significantly smaller than those in the mature group (65.9 ± 13.0, 73.5 ± 19.3, and 91.3 ± 27.4 nm in the skeletally immature group; and 90.3 ± 14.7, 94.0 ± 18.4, and 125.3 ± 19.9 nm in the skeletally immature group; p = 0.001, 0.024, and 0.004, respectively). Additionally, the strain at maximum stress was higher in the skeletally immature group (237.2 ± 102.4% vs. 121.5 ± 51.9%, p = 0.024). However, there was no difference in maximum stress between the skeletally immature and mature groups (19.9 ± 14.3 MPa vs. 24.5 ± 23.4 MPa, p = 0.578). Strain was negatively correlated with the mean fibril diameter and the 60th and 80th percentiles of fibril diameters, whereas stress was positively correlated with the mean fibril diameter. The skeletally immature group had a higher pivot shift test-positive rate than the mature group at the last follow-up (p = 0.023)., Conclusion: Semitendinosus tendon graft tissues differed microstructurally and mechanically between skeletally immature and mature patients., Level of Evidence: Level Ⅳ., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Aim: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population., Methods: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%., Results: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05)., Conclusion: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

The development of lipid nanoparticles (LNPs) has enabled the clinical application of small interfering ribonucleic acid (siRNA)-based therapies. Accordingly, various unique ionizable lipids have been explored for efficient siRNA delivery. However, safety concerns related to the structure of ionizable lipids have been raised. Here, we developed a pH-responsive dipeptide-conjugated lipid (DPL) for efficient, high safety siRNA delivery. We synthesized a DPL library by varying the dipeptide sequence and established a strong correlation between the knockdown efficiency of the DPL-based LNPs and the dipeptide sequence. The LNPs prepared with a DPL containing arginine (R) and glutamic acid (E) (DPL-ER) exhibited the highest knockdown efficiency. In addition, the DPL-ER-based LNPs with relatively long lipid tails (DPL-ER-C22:C22) exhibited a higher knockdown efficiency than those with short ones (DPL-ER-18:C18). The zeta potential of the DPL-ER-C22:C22-based LNPs increased as the pH decreased from 7.4 (physiological condition) to 5.5 (endosomal condition). Importantly, the DPL-ER-C22:C22-based LNPs exhibited a higher knockdown efficiency than the LNPs prepared using commercially available ionizable lipids. These results suggest that the DPL-based LNPs are safe and efficient siRNA delivery carriers., Competing Interests: Declaration of competing interest The authors have no competing interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aberrant salience processing has been proposed as a pathophysiological mechanism underlying psychiatric symptoms in patients with schizophrenia. The gaze trajectories of individuals with schizophrenia have been reported to be abnormal when viewing an image, suggesting anomalous visual salience as one possible pathophysiological mechanism associated with psychiatric diseases. This study was designed to determine whether visual salience is affected in individuals with schizophrenia, and whether this abnormality is unique to patients with schizophrenia. We examined the gaze behaviors of 1012 participants recruited from seven institutes (550 healthy individuals and 238, 41, 50 and 133 individuals with schizophrenia, bipolar disorder, major depressive disorder and autism spectrum disorder, respectively) when they looked at stationary images as they liked, i.e., free-viewing condition. We used an established computational model of salience maps derived from low-level visual features to measure the degree to which the gaze trajectories of individuals were guided by visual salience. The analysis revealed that the saliency at the gaze of individuals with schizophrenia were higher than healthy individuals, suggesting that patients' gazes were guided more by low-level image salience. Among the low-level image features, orientation salience was most affected. Furthermore, a general linear model analysis of the data for the four psychiatric disorders revealed a significant effect of disease. This abnormal salience processing depended on the disease and was strongest in patients with schizophrenia, followed by patients with bipolar disorder, major depressive disorder, and autism spectrum disorder, suggesting a link between abnormalities in salience processing and strength/frequency for psychosis of these disorders., (© 2024. The Author(s).)

Candidatus Patescibacteria, also known as candidate phyla radiation (CPR), including the class-level uncultured clade JAEDAM01 (formerly a subclass of Gracilibacteria/GN02/BD1-5), are ubiquitous in activated sludge. However, their characteristics and relationships with other organisms are largely unknown. They are believed to be episymbiotic, endosymbiotic or predatory. Despite our understanding of their limited metabolic capacity, their precise roles remain elusive due to the difficulty in cultivating and identifying them. In previous research, we successfully recovered high-quality metagenome-assembled genomes (MAGs), including a member of JAEDAM01 from activated sludge flocs. In this study, we designed new probes to visualize the targeted JAEDAM01-associated MAG HHAS10 and identified its host using fluorescence in situ hybridization (FISH). The FISH observations revealed that JAEDAM01 HHAS10-like cells were located within dense clusters of Zoogloea, and the fluorescence brightness of zoogloeal cells decreased in the vicinity of the CPR cells. The Zoogloea MAGs possessed genes related to extracellular polymeric substance biosynthesis, floc formation and nutrient removal, including a polyhydroxyalkanoate (PHA) accumulation pathway. The JAEDAM01 MAG HHAS10 possessed genes associated with type IV pili, competence protein EC and PHA degradation, suggesting a Zoogloea-dependent lifestyle in activated sludge flocs. These findings indicate a new symbiotic relationship between JAEDAM01 and Zoogloea., (© 2024 The Author(s). Environmental Microbiology Reports published by John Wiley & Sons Ltd.)

1q21.1 deletion has been identified as a risk factor related to not only mental disorders such as schizophrenia, but also congenital heart defects. However, at human cellular and molecular levels, it is still not known how this variant affects brain and heart development and contributes to the onset of these diseases. Here, we generated induced pluripotent stem cells (iPSCs) from a patient with 1q21.1 deletion. The iPSCs expressed stemness markers and exhibited the ability to differentiate into three germ layers in vitro. These iPSCs will be useful tools to understand the pathophysiology of mental disorders and heart defects in humans., 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 © 2024. Published by Elsevier B.V.)

Background: This study aimed to assess anxiety, depression and quality of life (QoL) in patients with head and neck cancer undergoing laryngectomy using comprehensive self-reported questionnaires for a period of up to 5 years., Methods: This prospective observational study enrolled 150 consecutive patients with locally advanced head and neck cancer who underwent laryngectomy at Nagoya University Hospital between 2007 and 2020. Anxiety, depression and QoL were assessed at baseline (preoperative) and at 3, 6, 12, 24, 36, 48 and 60 months after surgery using two brief self-reported questionnaires, such as the eight-item Short Form Health Survey (SF-8) and the Hospital Anxiety and Depression Scale (HADS)., Results: The surgical procedures were total laryngectomy, pharyngo-laryngectomy and pharyngo-laryngo-oesophagectomy in 97 (65%), 41 (27%) and 12 (8%) patients, respectively. All eight items of the SF-8 were significantly worse than those of the normal population at baseline and at 3 months after surgery. However, general health, vitality, mental health and bodily pain improved to normal levels within 1 year after surgery and were maintained for 5 years. In this study, 35% of patients were categorised as potential cases of depression, and 35% were potential cases of anxiety. During the follow-up period, the proportion of patients with anxiety gradually decreased after surgery. Further analysis revealed that the SF-8 and HADS scores and trends in 89 patients without tumour recurrence were similar to those in the total enrolled 150 patients., Conclusion: Anxiety, depression and QoL in laryngectomised patients improved at 1 year after surgery and were maintained for up to 5 years., What This Paper Adds: What is already known on the subject Laryngectomy is associated with prolonged functional and psychological effects and has a major impact on patient quality of life (QoL). Several prospective studies evaluating the QoL in laryngectomised patients have been reported, in which significant deterioration in social functioning was found even 1 year after surgery. What this paper adds to existing knowledge One year is not a sufficient period for laryngectomised patients to return to normal life and spend their time in a social community. A recent review showed that most studies on QoL in laryngectomised patients were conducted under 1 year after the procedure, and there were not enough studies of sufficient quality. This is the first long-term prospective observational study of Japanese patients with head and neck cancer who underwent laryngectomy up to 5 years after surgery. What are the potential or actual clinical implications of this work? Our long-term observational study showed that the scores for anxiety, depression and QoL in laryngectomised patients improved at 1 year after surgery and were maintained for up to 5 years. Clinicians should recognize the importance of psychosocial risk factors in their QoL and multidisciplinary management, including social and psychological support, is essential for long-term laryngectomised survivors., (© 2024 Royal College of Speech and Language Therapists.)

Objectives: We investigated the background of patients who underwent contact laser vaporization of the prostate (CVP) surgery and the learning curve of the operators., Methods: A total of 207 patients who underwent CVP surgery for benign prostatic hyperplasia between August 2018 and March 2023 were included in this study. Patient background, perioperative results, pre- and postoperative urinary flow tests, and complications were collected retrospectively., Results: We enrolled 12 doctors who were divided into expert (five doctors) and novice (seven doctors) groups based on the number of TURP experiences before CVP. The median patient age was 73 years (51-92 years) and prostate volume was 56 cc (15-190 cc) with no difference between the expert and novice groups. Complications included urinary retention (eight cases), hematuria (four), urinary tract infection (four), intraoperative perforation (two), and postoperative stricture (one). Both cases of intraoperative perforation occurred in the novice group. The expert group had a significantly shorter operative time (38 vs. 66 min) and a higher operative efficacy of prostate volume divided by operative time (1.43 vs. 0.88 cc/min). Postoperatively, IPSS, quality of life scores, and postvoid residual urine volume decreased, and maximal flow rate increased; however, there was no significant difference between the groups. The expert group showed stable operative time and operative efficacy after about five to eight cases, while the novice group showed stable after about 15 cases., Conclusions: Our findings suggest that CVP was safely performed at our hospital, and operators with limited experience in TURP can achieve stable perioperative results., (© 2024 The Japanese Urological Association.)

GNAO1 encodes G protein subunit alpha O1 (Gαo). Pathogenic variations in GNAO1 cause developmental delay, intractable seizures, and progressive involuntary movements from early infancy. Because the functional role of GNAO1 in the developing brain remains unclear, therapeutic strategies are still unestablished for patients presenting with GNAO1-associated encephalopathy. We herein report that siRNA-mediated depletion of Gnao1 perturbs the expression of transcripts associated with Rho GTPase signaling in Neuro2a cells. Consistently, siRNA treatment hampered neurite outgrowth and extension. Growth cone formation was markedly disrupted in monolayer neurons differentiated from iPSCs from a patient with a pathogenic variant of Gαo (p.G203R). This variant disabled neuro-spherical assembly, acquisition of the organized structure, and polarized signals of phospho-MLC2 in cortical organoids from the patient's iPSCs. We confirmed that the Rho kinase inhibitor Y27632 restored these morphological phenotypes. Thus, Gαo determines the self-organizing process of the developing brain by regulating the Rho-associated pathway. These data suggest that Rho GTPase pathway might be an alternative target of therapy for patients with GNAO1-associated encephalopathy., (© 2024. The Author(s).)

Background: Secondary carnitine deficiency in patients with anorexia nervosa has been rarely reported. This study aimed to investigate the occurrence of carnitine deficiency in severely malnourished patients with eating disorders during refeeding and assess its potential adverse effects on treatment outcomes., Method: In a cohort study of 56 female inpatients with eating disorders at a single hospital from March 2010 to December 2020, we measured plasma free carnitine (FC) levels and compared to those of a healthy control group (n = 35). The patients were categorized into three groups based on FC levels: FC deficiency (FC< 20 µmol/L), FC pre-deficiency (20 µmol/L ≤ FC< 36 µmol/L), and FC normal (36 µmol/L ≤ FC)., Results: Upon admission, the patients had a median age of 26 years (interquartile range [IQR]: 21-35) and a median body mass index (BMI) of 13.8 kg/m 2 (IQR: 12.8-14.8). Carnitine deficiency or pre-deficiency was identified in 57% of the patients. Hypocarnitinemia was associated with a decline in hemoglobin levels during refeeding (odds ratio [OR]: 0.445; 95% confidence interval [CI]: 0.214-0.926, p = 0.03), BMI at admission (OR: 0.478; 95% CI: 0.217-0.874, p = 0.014), and moderate or greater hepatic impairment at admission (OR: 6.385; 95% CI: 1.170-40.833, p = 0.032)., Conclusions: Hypocarnitinemia, particularly in cases of severe undernutrition (BMI< 13 kg/m 2 at admission) was observed in severely malnourished patients with eating disorders during refeeding, a critical metabolic transition phase. Moderate or severe hepatic impairment at admission was considered a potential indicator of hypocarnitinemia. Although hypocarnitinemia was not associated with any apparent adverse events other than anemia during refeeding, the possibility that carnitine deficiency may be a risk factor for more serious complications during sudden increases in energy requirements associated with changes in physical status cannot be denied. Further research on the clinical significance of hypocarnitinemia in severely malnourished patients with eating disorders is warranted., (© 2024. The Author(s).)