A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model.

Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, from brain inflammation to disturbed innate/adaptive immune in the periphery, are frequently observed in patients with autism; however, the intrinsic mechanisms behind them remain elusive. We hypothesize a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism. It is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development. Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain. We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes. Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.

Suspected Immune Thrombocytopenic Purpura Induced by Lenalidomide for the Treatment of Myelodysplastic Syndrome with Deletion of Chromosome 5q: A Case Report.

Lenalidomide (LEN), one of the key drugs in the treatment of myelodysplastic syndromes (MDS) with 5q deletion, as well as multiple myeloma (MM), has various immunomodulatory effects and has been associated with autoimmune diseases, including immune thrombocytopenic purpura (ITP). A 78-year-old man presented with pancytopenia and was diagnosed with MDS with 5q deletion and other chromosomal abnormalities. Two cycles of LEN therapy (one cycle: 10 mg/day for 21 days) resulted in a transient improvement in anemia, followed by MDS progression with severe thrombocytopenia (4 × 109/L) refractory to platelet transfusions. As other non-immune and alloimmune causes of transfusion-refractory thrombocytopenia were excluded, and the level of platelet-associated immunoglobulin G was extremely high compared with the level before treatment with LEN, the diagnosis of ITP was highly suspected. Despite treatment with prednisolone (PSL), eltrombopag, and repeated platelet transfusions, his platelet count did not increase, and he died of a gastrointestinal hemorrhage. Several cases of ITP induced by LEN used to treat MM had been reported, but the platelet count recovered after administration of PSL in these previous cases. However, we should be mindful of using LEN for patients with MDS because its treatment may become extremely difficult if ITP develops.

Molecular signatures from multi-omics of autism spectrum disorders and schizophrenia.

The genetic and phenotypic heterogeneity of autism spectrum disorder (ASD) impedes the unification of multiple biological hypotheses in an attempt to explain the complex features of ASD, such as impaired social communication, social interaction deficits, and restricted and repetitive patterns of behavior. However, recent psychiatric genetic studies have identified numerous risk genes and chromosome loci (copy number variation: CNV) which enable us to analyze at the single gene level and utilize system-level approaches. In this review, we focus on ASD as a major neurodevelopmental disorder and review recent findings mainly from the bioinformatics of omics studies. Additionally, by comparing these data with other major psychiatric disorders, including schizophrenia (SCZ), we identify unique characteristics of both diseases from multiple enrichment, pathway, and protein-protein interaction networks (PPIs) analyses using susceptible genes found in recent large-scale genetic studies. These unified, systematic approaches highlight unique characteristics of both disorders from multiple aspects and demonstrate how convergent pathways can contribute to an understanding of the complex etiology of such neurodevelopmental and neuropsychiatric disorders.

Anti-Obesity Effects of Matoa (Pometia pinnata) Fruit Peel Powder in High-Fat Diet-Fed Rats.

Fruit peels, pericarps, or rinds are rich in phenolic/polyphenolic compounds with antioxidant properties and potentially beneficial effects against obesity and obesity-related non-communicable diseases. This study investigated the anti-obesity effects of matoa (Pometia pinnata) and salak (Salacca zalacca) fruit peel. Neither matoa peel powder (MPP) nor salak peel powder (SPP) affected the body weight, visceral fat weight, or serum glucose or lipid levels of Sprague-Dawley rats when included as 1% (w/w) of a high-fat diet (HFD). However, MPP significantly decreased the hepatic lipid level. MPP at a dose of 3% (w/w) of the HFD decreased body weight, visceral fat, and serum triglyceride levels as well as the hepatic lipid content. The inhibitory effect of MPP on hepatic lipid accumulation was not enhanced when its concentration was increased from 1% to 3% of the HFD. The anti-obesity effect of matoa was partly explained by the inhibitory effect of the matoa peel extract on fatty acid-induced secretion of ApoB-48 protein, a marker of intestinal chylomicrons, in differentiated Caco-2 cell monolayers. We identified hederagenin saponins that are abundant in MPP as potential anti-obesity substances. These results will contribute towards the development of functional foods with anti-obesity effects using the matoa fruit peel.

Functional significance of rare neuroligin 1 variants found in autism.

Genetic mutations contribute to the etiology of autism spectrum disorder (ASD), a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1) is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

Correction: Functional significance of rare neuroligin 1 variants found in autism.

[This corrects the article DOI: 10.1371/journal.pgen.1006940.].

Behavioral and neuroanatomical analyses in a genetic mouse model of 2q13 duplication.

Duplications of human chromosome 2q13 have been reported in patients with neurodevelopmental disorder including autism spectrum disorder. Nephronophthisis-1 (NPHP1) was identified as a causative gene in the minimal deletion on chromosome 2q13 for familial juvenile type 1 nephronophthisis and Joubert syndrome, an autosomal recessive neurodevelopmental disorder characterized by a cerebellar and brain stem malformation, hypotonia, developmental delay, ataxia, and sometimes associated with cognitive impairment. NPHP1 encodes a ciliary protein, nephrocystin-1, which is expressed in the brain, yet its function in the brain remains largely unknown. In this study, we generated bacterial artificial chromosome-based transgenic mice, called 2q13 dup, that recapitulate human chromosome 2q13 duplication and contain one extra copy of the Nphp1 transgene. To analyze any behavioral alterations in 2q13 dup mice, we conducted a battery of behavioral tests. Although 2q13 dup mice show no significant differences in social behavior, they show deficits in spontaneous alternation behavior and fear memory. We also carried out magnetic resonance imaging to confirm whether copy number gain in this locus affects the neuroanatomy. There was a trend toward a decrease in the cerebellar paraflocculus of 2q13 dup mice. This is the first report of a genetic mouse model for human 2q13 duplication.

Noninvasive Assessment of Oxygen Extraction Fraction in Chronic Ischemia Using Quantitative Susceptibility Mapping at 7 Tesla.

BACKGROUND AND PURPOSE: The oxygen extraction fraction (OEF) is an effective metric to evaluate metabolic reserve in chronic ischemia. However, OEF is considered to be accurately measured only when using positron emission tomography (PET). Thus, we investigated whether OEF maps generated by magnetic resonance quantitative susceptibility mapping (QSM) at 7 Tesla enabled detection of OEF changes when compared with those obtained with PET. METHODS: Forty-one patients with chronic stenosis/occlusion of the unilateral internal carotid artery or middle cerebral artery were examined using 7 Tesla-MRI and PET scanners. QSM images were obtained from 3-dimensional T2*-weighted images, using a multiple dipole-inversion algorithm. OEF maps were generated based on susceptibility differences between venous structures and brain tissues on QSM images. OEF ratios of the ipsilateral middle cerebral artery territory against the contralateral side were calculated on the QSM-OEF and PET-OEF images, using an anatomic template. RESULTS: The OEF ratio in the middle cerebral artery territory showed significant correlations between QSM-OEF and PET-OEF maps (r=0.69; P<0.001), especially in patients with a substantial increase in the PET-OEF ratio of 1.09 (r=0.79; P=0.004), although showing significant systematic biases for the agreements. An increased QSM-OEF ratio of >1.09, as determined by receiver operating characteristic analysis, showed a sensitivity and specificity of 0.82 and 0.86, respectively, for the substantial increase in the PET-OEF ratio. Absolute QSM-OEF values were significantly correlated with PET-OEF values in the patients with increased PET-OEF. CONCLUSIONS: OEF ratios on QSM-OEF images at 7 Tesla showed a good correlation with those on PET-OEF images in patients with unilateral steno-occlusive internal carotid artery/middle cerebral artery lesions, suggesting that noninvasive OEF measurement by MRI can be a substitute for PET.

Rodent models of genetic and chromosomal variations in psychiatric disorders.

Elucidating the molecular basis of complex human psychiatric disorders is challenging due to the multitude of factors that underpin these disorders. Genetic and chromosomal changes are two factors that have been suggested to be involved in psychiatric disorders. Indeed, numerous risk loci have been identified in autism spectrum disorders, schizophrenia, and related psychiatric disorders. Here, we introduce genetic animal models that disturb excitatory-inhibitory balance in the brain and animal models mirroring human chromosomal abnormalities, both of which may be implicated in autism spectrum disorder pathophysiology. In addition, we discuss recent unique translational research using rodent models, such as Cntnap2 knockout mouse, Mecp2 mutant mouse, Pick1 knockout mouse, and neonatal ventral hippocampal lesion rat. By using these models, several types of drugs are administered during the developmental period to see the effect on psychotic symptoms and neural activities in adults. The accumulating evidence from recent animal studies provides an informative intervention strategy as a translational research.

Unique pharmacological property of ISRIB in inhibition of Aß-induced neuronal cell death.

A pharmacological approach to ameliorate Alzheimer's disease (AD) has not yet been established. In the present study, we investigated the pharmacological characteristics of the recently identified memory-enhancing compound, ISRIB for the amelioration of AD. ISRIB potently attenuated amyloid ß-induced neuronal cell death at concentrations of 12.5-25 nM, but did not inhibit amyloid ß production in the HEK293T cell line expressing the amyloid precursor protein (APP). These results suggest that ISRIB possesses the unique pharmacological property of attenuating amyloid ß-induced neuronal cell death without affecting amyloid ß production.

Cerebral Hyperperfusion after Revascularization Inhibits Development of Cerebral Ischemic Lesions Due to Artery-to-Artery Emboli during Carotid Exposure in Endarterectomy for Patients with Preoperative Cerebral Hemodynamic Insufficiency: Revisiting the "Impaired Clearance of Emboli" Concept.

The purpose of the present study was to determine whether cerebral hyperperfusion after revascularization inhibits development of cerebral ischemic lesions due to artery-to-artery emboli during exposure of the carotid arteries in carotid endarterectomy (CEA). In patients undergoing CEA for internal carotid artery stenosis (≥70%), cerebral blood flow (CBF) was measured using single-photon emission computed tomography (SPECT) before and immediately after CEA. Microembolic signals (MES) were identified using transcranial Doppler during carotid exposure. Diffusion-weighted magnetic resonance imaging (DWI) was performed within 24 h after surgery. Of 32 patients with a combination of reduced cerebrovascular reactivity to acetazolamide on preoperative brain perfusion SPECT and MES during carotid exposure, 14 (44%) showed cerebral hyperperfusion (defined as postoperative CBF increase ≥100% compared with preoperative values), and 16 (50%) developed DWI-characterized postoperative cerebral ischemic lesions. Postoperative cerebral hyperperfusion was significantly associated with the absence of DWI-characterized postoperative cerebral ischemic lesions (95% confidence interval, 0.001-0.179; p = 0.0009). These data suggest that cerebral hyperperfusion after revascularization inhibits development of cerebral ischemic lesions due to artery-to-artery emboli during carotid exposure in CEA, supporting the "impaired clearance of emboli" concept. Blood pressure elevation following carotid declamping would be effective when embolism not accompanied by cerebral hyperperfusion occurs during CEA.

Association between BACH2 expression and clinical prognosis in diffuse large B-cell lymphoma.

BACH2, a B cell-specific transcriptional repressor, plays a significant role in B cell maturation. Despite a number of previous studies, the clinicopathological significance of BACH2 expression in diffuse large B cell lymphoma (DLBCL) remains to be established. The present study was performed to validate the significance of BACH2 expression as a predictor of prognosis in DLBCL. A total of 94 DLBCL cases were included in the present study. All were diagnosed between 2008 and 2011, and thorough clinical and pathological investigations were possible, including immunohistochemical analysis of BACH2. Eighteen cases were selected by positive MYC gene alteration (MYC+ group) according to cytogenetic study. The remaining 76 cases were subclassified into germinal center B cell phenotype (GCB group, 38 cases) or non-GCB phenotype (non-GCB group, 38 cases). There were no significant differences between the two groups with regard to clinical characteristics and outcomes. In the GCB group, 21 cases were judged to have high BACH2 expression, with 19 cases in the non-GCB group. In cases with high BACH2 expression in GCB and non-GCB groups, the 3-year overall survival (OS) rate was significantly shorter than that with low expression (71.7% vs 91.3%, P = 0.0256). In the MYC+ group, 15 cases had high BACH2 expression levels. Although overall the MYC+ group showed short survival time (3-year OS 35.0%), 3 out of 4 cases with low BACH2 expression are alive without disease relapse at the time of publication of this paper. In conclusion, BACH2 expression level is a promising predictor of prognosis for DLBCL.

Feasibility of Diffusion-weighted Imaging (DWI) for Assessing Cerebrospinal Fluid Dynamics: DWI-fluidography in the Brains of Healthy Subjects.

PURPOSE: The present study aimed to investigate whether diffusion-weighted imaging (DWI) can qualify and quantify cerebrospinal fluid (CSF) dynamics in the brains of healthy subjects. For this purpose, we developed new DWI-based fluidography and compared the CSF dynamics seen on the fluidography with two apparent diffusion coefficients obtained with different DWI signal models at anatomical spaces filled by CSF. METHODS: DWI with multiple b values was performed for 10 subjects using a 7T MRI scanner. DWI-fluidography based on the DWI signal variations in different motion probing gradient directions was developed for visualizing the CSF dynamics voxel-by-voxel. DWI signals were measured using an ROI in the representative CSF-filled anatomical spaces in the brain. For the multiple DWI signals, the mono-exponential and kurtosis models were fitted and two kinds of apparent diffusion coefficients (ADCC and ADCK) were estimated in each space using the Gaussian and non-Gaussian diffusion models, respectively. RESULTS: DWI-fluidography could qualitatively represent the features of CSF dynamics in each anatomical space. ADCs indicated that the motions at the foramen of Monro, the cistern of the velum interpositum, the quadrigeminal cistern, the Sylvian cisterns, and the fourth ventricle were more drastic than those at the subarachnoid space and anterior horns of the lateral ventricle. Those results seen in ADCs were identical to the findings on DWI-fluidography. CONCLUSION: DWI-fluidography based on the features of DWI signals could show differences of CSF dynamics among anatomical spaces.

Germ-cell-specific transcriptome analysis illuminates the chromatin and ubiquitin pathway in autism spectrum disorders.

Accumulating epidemiological studies have suggested a positive association between advanced paternal age at conception and the increased risk of neurodevelopmental outcomes such as autism spectrum disorder (ASD) in their children. Recent biological studies using human sperm have identified increased de novo mutations in aged fathers, and hyper- or hypomethylation has been identified in the sperm from aged rodents. Dysregulation of DNA methylation in sperm may explain the transgenerational effects on the pathogenesis of ASD. However, compared to these epigenetic changes in the sperm of aged males, the effects of inherited predisposition from germ cells are largely unknown. Here, we use single-cell transcriptome data sets from 13 cell lines, including 12 ASD-associated CNVs models and control, that are performed neural differentiation from mouse embryonic stem cells. This study performed comprehensive bioinformatic analyses such as gene ontology (GO), network, pathway, and upstream regulator analyses. Through these analyses, we identify several susceptible pathways, such as chromatin and ubiquitin, in addition to translational and oxidative phosphorylation. Our results suggest that dysregulation of epigenetic chromosome remodeling and ubiquitin-proteasome pathway in the germ cell is a possible modulator for subsequent differentiated cells, sperm, and egg, as a risk factor for the neurodevelopmental disorder.

Progression of hemolysis in a patient with hereditary spherocytosis after the second dose of COVID-19 mRNA vaccine.

Herein, we report the case of a 22-year-old woman with hereditary spherocytosis (HS) whose condition worsened after administration of the coronavirus disease 2019 (COVID-19), mRNA vaccine 'BNT162b2 Pfizer-BioNTech.' The woman had been diagnosed with HS in 2005, and her condition remained stable until February 2021. In March 2021, she received the first dose of the above vaccine and experienced pain at the injection site. After the second dose in April 2021, she developed fever and general malaise. Investigations revealed progression of hemolysis, which improved after a few days. To the best of our knowledge, this is the first report of progression of hemolysis in a patient with HS after administration of the mRNA vaccine COVID-19, BNT162b2 'Pfizer-BioNTech.'

Animal models of psychiatric disorders that reflect human copy number variation.

The development of genetic technologies has led to the identification of several copy number variations (CNVs) in the human genome. Genome rearrangements affect dosage-sensitive gene expression in normal brain development. There is strong evidence associating human psychiatric disorders, especially autism spectrum disorders (ASDs) and schizophrenia to genetic risk factors and accumulated CNV risk loci. Deletions in 1q21, 3q29, 15q13, 17p12, and 22q11, as well as duplications in 16p11, 16p13, and 15q11-13 have been reported as recurrent CNVs in ASD and/or schizophrenia. Chromosome engineering can be a useful technology to reflect human diseases in animal models, especially CNV-based psychiatric disorders. This system, based on the Cre/loxP strategy, uses large chromosome rearrangement such as deletion, duplication, inversion, and translocation. Although it is hard to reflect human pathophysiology in animal models, some aspects of molecular pathways, brain anatomy, cognitive, and behavioral phenotypes can be addressed. Some groups have created animal models of psychiatric disorders, ASD, and schizophrenia, which are based on human CNV. These mouse models display some brain anatomical and behavioral abnormalities, providing insight into human neuropsychiatric disorders that will contribute to novel drug screening for these devastating disorders.

Ruptured Aneurysm at the Origin of an Anomalous Callosomarginal Artery Arising from the A1 Segment of the Anterior Cerebral Artery-A Case Report.

Aneurysms of the A1 segment of the anterior cerebral artery tend to develop in combination with various vascular anomalies of the A1 segment. Arterial branches that originate from the A1 segment and perfuse cortical regions are known to be rare. In this report, we describe a 48-year-old woman who presented with a ruptured aneurysm at the origin of an anomalous cortical artery arising from the A1 segment, for which microsurgical neck clipping was performed. Intraoperatively, the anomalous artery was seen to originate from the A1 segment, running into the interhemispheric fissure. An aneurysm was located at the bifurcation of the anomalous artery and the A1 segment. Postoperative angiography showed that the anomalous artery has branched into the fronto-orbital artery and the frontopolar artery and terminated as the anterior internal frontal arteries. We report a rare case of an aneurysm arising from an anomalous callosomarginal artery that arose from the A1 segment and perfused the cortical region. It is of significance to recognize that an aneurysm can develop at the origin of an anomalous artery that arises from the A1 segment.

Camurati-Engelmann disease combined with transethmoidal meningoencephalocele: illustrative case.

BACKGROUND: Camurati-Engelmann disease (CED) is a rare disorder characterized by progressive cranial hyperostosis and diaphyseal sclerosis of the long bones. Chronic intracranial hypertension gradually occurs due to progressive cranial vault hyperostosis. OBSERVATIONS: A 57-year-old man who had been diagnosed with CED at 9 years old suddenly developed cerebrospinal fluid rhinorrhea. A bone defect of the right cribriform plate and protrusion of brain tissue from the right cribriform plate into the right nasal cavity were identified. The patient underwent endoscopic resection of the meningoencephalocele combined with the bath-plug procedure. After surgery, cerebrospinal fluid rhinorrhea disappeared. LESSONS: Chronic intracranial hypertension due to progressive cranial vault hyperostosis in CED may cause a bone defect and meningoencephalocele in the anterior skull base, resulting in cerebrospinal fluid rhinorrhea.

PET With 11C-Methyl-l-Methionine as a Predictor of Consequential Outcomes at the Time of Discontinuing Temozolomide-Adjuvant Chemotherapy in Patients With Residual IDH-Mutant Lower-Grade Glioma.

PURPOSE: The aim of this study was to clarify whether PET with 11C-methyl-l-methionine (11C-met PET) can predict consequential outcomes at the time of discontinuing temozolomide (TMZ)-adjuvant chemotherapy in patients with residual isocitrate dehydrogenase gene (IDH)-mutant lower-grade glioma. PATIENTS AND METHODS: Among 30 patients showing residual lesions of IDH-mutant lower-grade glioma, we compared the tumor-to-normal brain tissue ratio of standardized uptake values (SUVT/N) from 11C-met PET at the time of discontinuing TMZ-adjuvant chemotherapy with putative predictive factors including age, Karnofsky Performance Scale, number of courses of adjuvant therapy, residual tumor size, and promotor methylation status of O6-methylguanine-DNA methyl-transferase gene (MGMT). For each factor, progression-free survival (PFS) was compared between groups divided by cutoff values, determined to predict tumor relapse using receiver operating characteristic curves for each factor. Univariate and multivariate analyses were conducted using log-rank testing and Cox regression analysis, respectively. In addition, PFS was compared between patients grouped by combined findings from multiple predictors identified from univariate and multivariate analyses. RESULTS: Univariate and multivariate analyses identified SUVT/N from 11C-met PET and MGMT methylation status as independent predictors of outcomes after TMZ discontinuation. When comparing 3 groups assigned by the combination of MGMT and SUVT/N findings, PFS differed significantly among groups. CONCLUSIONS: The present study suggested that 11C-met PET at the time of discontinuing TMZ-adjuvant chemotherapy allows prediction of outcomes at least comparable to MGMT methylation status in patients with residual IDH-mutant lower-grade glioma. Further, 11C-met PET allows more precise prediction of outcomes by assessment in combination with MGMT findings.

Active recovery effects on local oxygenation level during intensive cycling bouts.

We hypothesised that the oxygen supply to the fatigued muscles is improved after the recovery with exercise caused by aerobic metabolism in the slow twitch fibres during the recovery period. Ten males performed a 30 s maximum cycling (1st Exercise), followed by a 20 min rest interval (Interval Rest) in which participants were either sitting (No Exercise) or low intensive cycling (Active). Then they again underwent a 30 s bout of maximum cycling (2nd Exercise). The total work of the 2nd Exercise was higher in Active compared to No Exercise (297 ± 14 vs 276 ± 23 J · kg(-1), P < 0.01). After Interval Rest, the muscle oxygenation level (P < 0.05) and blood lactate concentration (P < 0.05) were lower in Active compared to No Exercise. In Active, the total work was higher in the 2nd Exercise than the 1st Exercise (297 ± 14 vs 277 ± 23 J · kg(-1), P < 0.01), and muscle oxygenation levels during the 2nd Exercise were also higher at 10 (P < 0.05) and 15 (P < 0.01) s after the beginning of the exercise. It was suggested that active recovery exercise would manage to increase the muscle oxygenation level, and improve the performance during the 2nd Exercise accompanied with blood lactate control.