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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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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).)

Background: Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion., Methods: We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas., Results: Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K + channel inhibitors and prostaglandin D 2 (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels., Conclusions: Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K + channels to dilate the nasal mucosal vasculature., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background and Aim: Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model., Material and Methods: Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS + CZ (MCT + CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48 h after MCT administration. Postoperative survival rates were evaluated (n = 9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury., Results: The cumulative 10-day postoperative survival rate was significantly higher in the SOS + CZ group than in the SOS group (88.9% vs 33.3%, P = 0.001). Total SOS scores were significantly lower in the SOS + CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS + CZ group than in the SOS group on POD 1 (86.1 ± 8.2% vs 63.8 ± 9.3%, P = 0.003)., Conclusion: Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., (© 2024. The Author(s).)

Recent genetic studies have found common genomic risk variants among psychiatric disorders, strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis using genome-edited iPS cells with variants on both alleles revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18, which is repressed by ZNF558, and mitophagy activity were increased in ASTN2-deleted neuronal cells. These phenotypes were also detected in neuronal cells differentiated from patient-derived iPS cells with heterozygous ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of psychiatric disorders by regulating mitophagy via ZNF558., (© 2024. The Author(s).)

In December 2022, the Ministry of Health, Labour and Welfare (MHLW) of Japan issued and implemented the guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance. This guideline recommends the use of a tiered approach to assess clinically meaningful driving impairment. It is noted that adverse events cannot be solely explained by pharmacokinetics, as the onset and duration of these events vary. Among these adverse events, those affecting alertness, such as drowsiness caused by psychotropic drugs on driving performance, are more frequently observed during initial treatment stages and dose escalation. Hence, when evaluating the effects of psychotropic drugs on driving performance, it becomes crucial to assess the persistence of clinically meaningful impairment. Therefore, the MHLW guideline, developed by the authors, emphasizes the need to assess the temporal profile of adverse events affecting driving in all clinical trials. Additionally, the guideline states that when conducting driving studies, the timing of multiple dosing should consider not only the pharmacokinetics of the investigational drug but also its tolerance., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity., (© 2024. The Author(s).)

Laser-driven dynamic compression experiments of plastic materials have found surprisingly fast formation of nanodiamonds (ND) via X-ray probing. This mechanism is relevant for planetary models, but could also open efficient synthesis routes for tailored NDs. We investigate the release mechanics of compressed NDs by molecular dynamics simulation of the isotropic expansion of finite size diamond from different P-T states. Analysing the structural integrity along different release paths via molecular dynamic simulations, we found substantial disintegration rates upon shock release, increasing with the on-Hugnoiot shock temperature. We also find that recrystallization can occur after the expansion and hence during the release, depending on subsequent cooling mechanisms. Our study suggests higher ND recovery rates from off-Hugoniot states, e.g., via double-shocks, due to faster cooling. Laser-driven shock compression experiments of polyethylene terephthalate (PET) samples with in situ X-ray probing at the simulated conditions found diamond signal that persists up to 11 ns after breakout. In the diffraction pattern, we observed peak shifts, which we attribute to thermal expansion of the NDs and thus a total release of pressure, which indicates the stability of the released NDs., (© 2024. The Author(s).)

Background: Follow-up is recommended for an asymptomatic unilocular hepatic cystic lesion without wall-thickness and nodular components. A few liver cystic lesions represent biliary cystic neoplasms, which are difficult to differentiate from simple cysts with benign mural nodules on imaging alone., Case Presentation: An 84-year-old woman with a history of simple liver cyst diagnosed one year prior was admitted for evaluation of a developed mural nodule in the cystic lesion. She had no specific symptoms and no abnormalities in blood tests except for carcinoembryonic antigen (5.0 ng/mL) and carbohydrate antigen (43.5 U/mL) levels. Contrast-enhanced computed tomography revealed a well-defined, low-attenuation lesion without a septum that had enlarged from 41 to 47 mm. No dilation of the bile duct was observed. A gradually enhancing mural nodule, 14 mm in diameter, was confirmed. MRI revealed a uniform water-intense cystic lesion with a mural nodule. This was followed by T2-enhanced imaging showing peripheral hypointensity and central hyperintensity. Enhanced ultrasonography revealed an enhanced nodule with a distinct artery within it. A needle biopsy of the wall nodule or aspiration of intracystic fluid was not performed to avoid tumor cell spillage. The possibility of a neoplastic cystic tumor could not be ruled out, so a partial hepatectomy was performed with adequate margins. Pathologically, the cystic lesion contained a black 5 mm nodule consisting of a thin, whitish fibrous wall and dilated vessels lined by CD31 and CD34 positive endothelial cells. The final diagnosis was a rare cavernous hemangioma within a simple liver cyst., Conclusions: Cavernous hemangiomas mimicking well-enhanced mural nodules can arise from simple liver cysts. In less malignant cases, laparoscopic biopsy or percutaneous targeted biopsy of the mural nodules, together with needle ablation, may be recommended to avoid unnecessary surgery., (© 2024. The Author(s).)

Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher's exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (P FDR ) < 0.001), IL-9 (56.64, 20.46 to 92.82, P FDR  < 0.001) and MIP-1b (18.27, 4.96 to 31.57, P FDR  < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (P FDR  < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412., 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 Elsevier Inc. All rights reserved.)

Abstract: Chronic orofacial pain (COP) is relieved by duloxetine (DLX) and frequently causes depressive symptoms. The aim of this study was to confirm effects of DLX on pain and depressive symptoms, and to associate with their effectiveness in platelet serotonin transporter (SERT) expression, which is a target molecule of DLX and plasma serotonin concentration in COP patients with depressive symptoms. We assessed for the severity of pain and depressive symptoms using the Visual Analog Scale (VAS) and 17-item Hamilton Depression Rating Scale (HDRS), respectively. Chronic orofacial pain patients were classified into 2 groups based on their HDRS before DLX-treatment: COP patients with (COP-D) and without (COP-ND) depressive symptoms. We found that the VAS and HDRS scores of both groups were significantly decreased after DLX treatment compared with those before DLX treatment. Upregulation of total SERT and downregulation of ubiquitinated SERT were observed before DLX treatment in both groups compared with healthy controls. After DLX treatment, there were no differences in total SERT of both groups and in ubiquitinated SERT of COP-D patients compared with healthy controls; whereas, ubiquitinated SERT of COP-ND patients remained downregulated. There were positive correlations between changes of serotonin concentrations and of VAS or HDRS scores in only COP-D patients. Our findings indicate that DLX improves not only pain but also comorbid depressive symptoms of COP-D patients. Duloxetine also reduces platelet SERT through upregulation of ubiquitinated SERT. As the result, decrease of plasma serotonin concentrations may be related to the efficacy of DLX in relieving pain and depression in COP patients., (Copyright © 2023 International Association for the Study of Pain.)

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.)

Hepatic artery pseudoaneurysms have been reported to occur in approximately 1% of cases after metal stenting for malignant biliary obstruction. In contrast, only a few cases have been reported as complications after plastic stenting for benign biliary disease. We report a 61-year-old man with cholangitis who presented with a rare complication of hemobilia after implantation of 7 Fr double pigtail plastic biliary stents. No bleeding was observed approximately one month after biliary stent tube removal. Contrast-enhanced CT scan revealed a circularly enhanced lesion (5 mm in diameter) in the arterial phase at the tip of the previously inserted plastic bile duct stent. Color Doppler ultrasonography enhanced the lesion and detected arterial blood flow inside. He was diagnosed with a hepatic artery pseudoaneurysm. However, he had no risk factors such as prolonged catheterization, severe cholangitis, liver abscess, or long-term steroid use. Superselective transarterial embolization using two metal microcoils was successfully completed without damage to the surrounding liver parenchyma. If hemobilia is suspected after insertion of a plastic bile duct stent, immediate monitoring using contrast-enhanced computed tomography or Doppler ultrasonography is recommended., (© 2024. Japanese Society of Gastroenterology.)

Aims/introduction: Glucagon plays an essential role in hepatic glucogenesis by enhancing glycogen breakdown, inducing gluconeogenesis, and suppressing glycogenesis. Moreover, glucagon increases cyclic adenosine monophosphate (cAMP) levels, thereby activating protein kinase A (PKA) and cAMP guanine nucleotide exchange factor (also known as Epac). Although the function of PKA in the liver has been studied extensively, the function of hepatic Epac is poorly understood. The aim of this study was to elucidate the role of Epac in mediating the action of glucagon on the hepatocytes., Materials and Methods: Epac mRNA and protein expression, localization, and activity in the hepatocytes were analyzed by reverse transcription polymerase chain reaction, western blotting, immunofluorescence staining, and Rap1 activity assay, respectively. Additionally, we investigated the effects of an Epac-specific activator, 8-CPT, and an Epac-specific inhibitor, ESI-05, on glycogen metabolism in isolated rat hepatocytes. Further mechanisms of glycogen metabolism were evaluated by examining glucokinase (GK) translocation and mRNA expression of gluconeogenic enzymes., Results: Epac2, but not Epac1, was predominantly expressed in the liver. Moreover, 8-CPT inhibited glycogen accumulation and GK translocation and enhanced the mRNA expression of gluconeogenic enzymes. ESI-05 failed to reverse glucagon-induced suppression of glycogen storage and partially inhibited glucagon-induced GK translocation and the mRNA expression of gluconeogenic enzymes., Conclusions: Epac signaling plays a role in mediating the glucogenic action of glucagon in the hepatocytes., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

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.

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders., (© 2024. The Author(s).)

The human cerebrum contains a large amount of cortico-cortical association fibers. Among them, U-fibers are short-range association fibers located in white matter immediately deep to gray matter. Although U-fibers are thought to be crucial for higher cognitive functions, the organization within U-fiber regions are still unclear. Here we investigated the properties of U-fiber regions in the ferret cerebrum using neurochemical, neuronal tracing, immunohistochemical and electron microscopic techniques. We found that U-fiber regions can be subdivided into two regions, which we named outer and inner U-fiber regions. We further uncovered that outer U-fiber regions have smaller-diameter axons with thinner myelin compared with inner U-fiber regions. These findings may indicate functional complexity within U-fiber regions in the cerebrum., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd and Japan Neuroscience Society. All rights reserved.)

Indoleamine 2,3-dioxygenase 2 (IDO2) is an enzyme of the tryptophan-kynurenine pathway that is constitutively expressed in the brain. To provide insight into the physiological role of IDO2 in the brain, behavioral and neurochemical analyses in IDO2 knockout (KO) mice were performed. IDO2 KO mice showed stereotyped behavior, restricted interest and social deficits, traits that are associated with behavioral endophenotypes of autism spectrum disorder (ASD). IDO2 was colocalized immunohistochemically with tyrosine-hydroxylase-positive cells in dopaminergic neurons. In the striatum and amygdala of IDO2 KO mice, decreased dopamine turnover was associated with increased α-synuclein level. Correspondingly, levels of downstream dopamine D1 receptor signaling molecules such as brain-derived neurotrophic factor and c-Fos positive proteins were decreased. Furthermore, decreased abundance of ramified-type microglia resulted in increased dendritic spine density in the striatum of IDO2 KO mice. Both chemogenetic activation of dopaminergic neurons and treatment with methylphenidate, a dopamine reuptake inhibitor, ameliorated the ASD-like behavior of IDO2 KO mice. Sequencing analysis of exon regions in IDO2 from 309 ASD samples identified a rare canonical splice site variant in one ASD case. These results suggest that the IDO2 gene is, at least in part, a factor closely related to the development of psychiatric disorders., (© 2023 Federation of European Biochemical Societies.)

Aim: Depressive disorder is often evaluated using established rating scales. However, consistent data collection with these scales requires trained professionals. In the present study, the "rater & estimation-system" reliability was assessed between consensus evaluation by trained psychiatrists and the estimation by 2 models of the AI-MADRS (Montgomery-Asberg Depression Rating Scale) estimation system, a machine learning algorithm-based model developed to assess the severity of depression., Methods: During interviews with trained psychiatrists and the AI-MADRS estimation system, patients responded orally to machine-generated voice prompts from the AI-MADRS structured interview questions. The severity scores estimated from two models of the AI-MADRS estimation system, the max estimation model and the average estimation model, were compared with those by trained psychiatrists., Results: A total of 51 evaluation interviews conducted on 30 patients were analyzed. Pearson's correlation coefficient with the scores evaluated by trained psychiatrists was 0.76 (95% confidence interval 0.62-0.86) for the max estimation model, and 0.86 (0.76-0.92) for the average estimation model. The ANOVA ICC rater & estimation-system reliability with the evaluation scores by trained psychiatrists was 0.51 (-0.09 to 0.79) for the max estimation model, and 0.75 (0.55-0.86) for the average estimation model., Conclusion: The average estimation model of AI-MADRS demonstrated substantially acceptable rater & estimation-system reliability with trained psychiatrists. Accumulating a broader training dataset and the refinement of AI-MADRS interviews are expected to improve the performance of AI-MADRS. Our findings suggest that AI technologies can significantly modernize and potentially revolutionize the realm of depression assessments., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Aim: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case-control sample., Method: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD., Results: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit., Conclusion: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., (© 2024. The Author(s).)

Nominally-pure lithium fluoride (LiF) crystals were irradiated with monochromatic hard x-rays of energy 5, 7, 9 and 12 keV at the METROLOGIE beamline of the SOLEIL synchrotron facility, in order to understand the role of the selected x-ray energy on their visible photoluminescence (PL) response, which is used for high spatial resolution 2D x-ray imaging detectors characterized by a wide dynamic range. At the energies of 7 and 12 keV the irradiations were performed at five different doses corresponding to five uniformly irradiated areas, while at 5 and 9 keV only two irradiations at two different doses were carried out. The doses were planned in a range between 4 and 1.4 × 10 3 Gy (10.5 mJ cm -3 to 3.7 J cm -3 ), depending on the x-ray energy. After irradiation at the energies of 7 and 12 keV, the spectrally-integrated visible PL intensity of the F 2 and F 3 + colour centres (CCs) generated in the LiF crystals, carefully measured by fluorescence microscopy under blue excitation, exhibits a linear dependence on the irradiation dose in the investigated dose range. This linear behaviour was confirmed by the optical absorption spectra of the irradiated spots, which shows a similar linear behaviour for both the F 2 and F 3 + CCs, as derived from their overlapping absorption band at around 450 nm. At the highest x-ray energy, the average concentrations of the radiation-induced F, F 2 and F 3 + CCs were also estimated. The volume distributions of F 2 defects in the crystals irradiated with 5 and 9 keV x-rays were reconstructed in 3D by measuring their PL signal using a confocal laser scanning microscope operating in fluorescence mode. On-going investigations are focusing on the results obtained through this z -scanning technique to explore the potential impact of absorption effects at the excitation laser wavelength., (Creative Commons Attribution license.)

Background: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia., Methods: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point)., Results: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste., Conclusion: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste., Trial Registration: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021., (© 2024. The Author(s).)

The pain matrix, which includes several brain regions that respond to pain sensation, contribute to the development of chronic pain. Thus, it is essential to understand the mechanism of causing chronic pain in the pain matrix such as anterior cingulate (ACC), or primary somatosensory (S1) cortex. Recently, combined experiment with the behavior tests and in vivo calcium imaging using fiber photometry revealed the interaction between the neuronal function in deep brain regions of the pain matrix including ACC and the phenotype of chronic pain. However, it remains unclear whether this combined experiment can identify the interaction between neuronal activity in S1, which receive pain sensation, and pain behaviors such as hyperalgesia or allodynia. In this study, to examine whether the interaction between change of neuronal activity in S1 and hyperalgesia in hind paw before and after causing inflammatory pain was detected from same animal, the combined experiment of in vivo fiber photometry system and von Frey hairs test was applied. This combined experiment detected that amplitude of calcium responses in S1 neurons increased and the mechanical threshold of hind paw decreased from same animals which have an inflammatory pain. Moreover, we found that the values between amplitude of calcium responses and mechanical thresholds were shifted to negative correlation after causing inflammatory pain. Thus, the combined experiment with fiber photometry and the behavior tests has a possibility that can simultaneously consider the interaction between neuronal activity in pain matrix and pain induced behaviors and the effects of analgesics or pain treatments.

Here we describe the novel, multi-point Comet Interceptor mission. It is dedicated to the exploration of a little-processed long-period comet, possibly entering the inner Solar System for the first time, or to encounter an interstellar object originating at another star. The objectives of the mission are to address the following questions: What are the surface composition, shape, morphology, and structure of the target object? What is the composition of the gas and dust in the coma, its connection to the nucleus, and the nature of its interaction with the solar wind? The mission was proposed to the European Space Agency in 2018, and formally adopted by the agency in June 2022, for launch in 2029 together with the Ariel mission. Comet Interceptor will take advantage of the opportunity presented by ESA's F-Class call for fast, flexible, low-cost missions to which it was proposed. The call required a launch to a halo orbit around the Sun-Earth L2 point. The mission can take advantage of this placement to wait for the discovery of a suitable comet reachable with its minimum Δ V capability of 600  ms - 1 . Comet Interceptor will be unique in encountering and studying, at a nominal closest approach distance of 1000 km, a comet that represents a near-pristine sample of material from the formation of the Solar System. It will also add a capability that no previous cometary mission has had, which is to deploy two sub-probes - B1, provided by the Japanese space agency, JAXA, and B2 - that will follow different trajectories through the coma. While the main probe passes at a nominal 1000 km distance, probes B1 and B2 will follow different chords through the coma at distances of 850 km and 400 km, respectively. The result will be unique, simultaneous, spatially resolved information of the 3-dimensional properties of the target comet and its interaction with the space environment. We present the mission's science background leading to these objectives, as well as an overview of the scientific instruments, mission design, and schedule., Competing Interests: Competing InterestsThe authors declare no competing interests., (© The Author(s) 2024.)

Aim: Clinical studies reported that patients with schizophrenia are at a higher risk of developing dementia than people without schizophrenia. However, early neuropathological studies have shown that the incidence of Alzheimer's disease (AD) in schizophrenia patients does not differ from that in controls. These inconsistent results may be attributable to the inclusion of non-AD dementia, but there have been few clinicopathological studies in older patients with schizophrenia based on the current neuropathological classification. This study aimed to investigate the neuropathological basis of incident dementia in older patients with schizophrenia., Methods: We systematically examined 32 brains of old patients with schizophrenia using standardized pathological methods. The severity of dementia-related neuropathologies was analyzed using standardized semiquantitative assessments. After excluding patients who fulfilled the neuropathological criteria, clinicopathological variables were compared between patients with and without incident dementia to identify potential differences., Results: Seven patients fulfilled the pathological criteria for AD (n = 3), argyrophilic grain disease (AGD) (n = 2), dementia with Lewy bodies (n = 1), and AGD/progressive supranuclear palsy (n = 1). Among 25 patients for whom a neuropathological diagnosis was not obtained, 10 had dementia, but the clinicopathological findings did not differ from the remaining 15 patients without dementia., Conclusion: Two types of older schizophrenia patient present dementia: patients with co-existing neurodegenerative disease and patients who do not meet pathological criteria based on the current classification. To understand the neurobiological aspects of incident dementia in older patients with schizophrenia, further clinicopathological studies are needed that do not simply analyze incident dementia as a comorbidity of conventional dementia-related neuropathologies., (© 2023 The Authors. Psychiatry and Clinical Neurosciences © 2023 Japanese Society of Psychiatry and Neurology.)

Subjective-objective discrepancies in sleep onset latency (SOL), which is often observed among psychiatric patients, is attributed partly to the definition of sleep onset. Recently, instead of SOL, latency to persistent sleep (LPS), which is defined as the duration from turning out the light to the first consecutive minutes of non-wakefulness, has been utilized in pharmacological studies. This study aimed to determine the non-awake time in LPS that is most consistent with subjective sleep onset among patients with psychiatric disorders. We calculated the length of non-awake time in 30-s segments from lights-out to 0.5-60 min. The root mean square error was then calculated to determine the most appropriate length. The analysis of 149 patients with psychiatric disorders showed that the optimal non-awake time in LPS was 12 min. On the other hands, when comorbid with moderate or severe obstructive sleep apnea (OSA), the optimal length was 19.5 min. This study indicates that 12 min should be the best fit for the LPS non-awake time in patients with psychiatric disorders. When there is comorbidity with OSA, however, a longer duration should be considered. Measuring LPS minimizes discrepancies in SOL and provides important clinical information., (© 2023. The Author(s).)

Background: Sleep disturbances are core symptoms of psychiatric disorders. Although various sleep measures have been developed to assess sleep patterns and quality of sleep, the concordance of these measures in patients with psychiatric disorders remains relatively elusive., Objective: This study aims to examine the degree of agreement among 3 sleep recording methods and the consistency between subjective and objective sleep measures, with a specific focus on recently developed devices in a population of individuals with psychiatric disorders., Methods: We analyzed 62 participants for this cross-sectional study, all having data for polysomnography (PSG), Zmachine, Fitbit, and sleep logs. Participants completed questionnaires on their symptoms and estimated sleep duration the morning after the overnight sleep assessment. The interclass correlation coefficients (ICCs) were calculated to evaluate the consistency between sleep parameters obtained from each instrument. Additionally, Bland-Altman plots were used to visually show differences and limits of agreement for sleep parameters measured by PSG, Zmachine, Fitbit, and sleep logs., Results: The findings indicated a moderate agreement between PSG and Zmachine data for total sleep time (ICC=0.46; P<.001), wake after sleep onset (ICC=0.39; P=.002), and sleep efficiency (ICC=0.40; P=.006). In contrast, Fitbit demonstrated notable disagreement with PSG (total sleep time: ICC=0.08; wake after sleep onset: ICC=0.18; sleep efficiency: ICC=0.10) and exhibited particularly large discrepancies from the sleep logs (total sleep time: ICC=-0.01; wake after sleep onset: ICC=0.05; sleep efficiency: ICC=-0.02). Furthermore, subjective and objective concordance among PSG, Zmachine, and sleep logs appeared to be influenced by the severity of the depressive symptoms and obstructive sleep apnea, while these associations were not observed between the Fitbit and other sleep instruments., Conclusions: Our study results suggest that Fitbit accuracy is reduced in the presence of comorbid clinical symptoms. Although user-friendly, Fitbit has limitations that should be considered when assessing sleep in patients with psychiatric disorders., (©Keita Kawai, Kunihiro Iwamoto, Seiko Miyata, Ippei Okada, Hiroshige Fujishiro, Akiko Noda, Kazuyuki Nakagome, Norio Ozaki, Masashi Ikeda. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 13.12.2023.)

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li + PGS ) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li + Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi + Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li + PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li + PGS was positively associated with lithium treatment response in the ConLi + Gen cohort, in both the categorical (P = 9.8 × 10 - 12 , R 2  = 1.9%) and continuous (P = 6.4 × 10 - 9 , R 2  = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10 - 4 , R 2  = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li + PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment., (© 2023. The Author(s).)

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection., (© 2023. The Author(s).)

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.)

The use of mesenchymal stem/stromal cells (MSCs) has attracted attention in the field of regenerative medicine based on their anti-inflammatory and tissue repair-promoting effects. Bone marrow is widely used as a source of MSCs; however, the performance of bone marrow (BM)-MSCs deteriorates as the cells age along with cell passaging. Recently, it has been reported that MSCs can be generated from induced pluripotent stem cells (iPSCs), which is expected to represent a new source of MSCs. However, few studies have investigated aging in iPSC-derived MSCs (iMSCs) and their functions. In this study, we investigated whether iMSCs overcome cellular senescence compared to that in BM-MSCs. Cellular senescence was quantitatively evaluated by staining iMSCs and BM-MSCs with fluorescein di-β-D-galactopyranoside (FDG) and following flow cytometer analysis. The hepatocyte growth factor (HGF) concentration in the culture supernatant was also measured as a factor in the therapeutic efficacy of nephritis. The iMSCs did not reach their proliferation limit and their morphology did not change even after 10 passages. The FDG positivity of BM-MSCs increased with passaging, whereas that in iMSCs did not increase. The HGF concentration increased with passaging in iMSCs. In conclusion, our results suggest that iMSCs may be less susceptible to senescence than BM-MSCs and may be used in clinical applications., Competing Interests: There are no conflicts of interest to declare.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms., (© 2023. The Author(s).)

The structures, strain fields, and defect distributions in solid materials underlie the mechanical and physical properties across numerous applications. Many modern microstructural microscopy tools characterize crystal grains, domains and defects required to map lattice distortions or deformation, but are limited to studies of the (near) surface. Generally speaking, such tools cannot probe the structural dynamics in a way that is representative of bulk behavior. Synchrotron X-ray diffraction based imaging has long mapped the deeply embedded structural elements, and with enhanced resolution, dark field X-ray microscopy (DFXM) can now map those features with the requisite nm-resolution. However, these techniques still suffer from the required integration times due to limitations from the source and optics. This work extends DFXM to X-ray free electron lasers, showing how the [Formula: see text] photons per pulse available at these sources offer structural characterization down to 100 fs resolution (orders of magnitude faster than current synchrotron images). We introduce the XFEL DFXM setup with simultaneous bright field microscopy to probe density changes within the same volume. This work presents a comprehensive guide to the multi-modal ultrafast high-resolution X-ray microscope that we constructed and tested at two XFELs, and shows initial data demonstrating two timing strategies to study associated reversible or irreversible lattice dynamics., (© 2023. Springer Nature Limited.)