Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class "spinal ependymoma" (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

Identification of sulfonylpyrimidines as novel selective aldosterone synthase (CYP11B2) inhibitors.

4-[(5-[2-Methyl-5-(methylsulfonyl)pentan-2-yl]sulfonylpyrimidin-4-yl)amino]benzonitrile 2 was identified as a novel potent aldosterone synthase inhibitor. Compound 2 was found to inhibit human CYP11B2 in the nanomolar range, and showed an aldosterone-lowering effect in a furosemide-treated cynomolgus monkey model. Although human CYP11B2 has the high homology sequence with human CYP11B1, compound 2 showed more than 80 times higher selectivity over human CYP11B1 in vitro.

Mobilizing Citizens' Ears: Aural Training as Civil Defense, 1941-45.

In the mid-twentieth century, the Japanese state trained its citizens to identify the sound of a falling bomb. This article explores the little-studied impact of audio-based military technology on wider society, beyond the military sector and beyond Western contexts. In 1941, Japan's elementary schools-renamed National People's Schools-provided new musical training in perfect pitch to strengthen Japan's national defense efforts in wartime. "Explosive sound training" taught children to identify recorded explosive sounds of enemy aircraft, though ultimately such training could not mitigate widespread destruction. This article argues that the recent discussion of "the story of acoustic defense" can benefit from a much broader historiographical framework, one focused not just on the military frame. In the Japanese case, the story was shaped through the active interactions between the military, society, and educational institutions. A multidisciplinary analytical perspective provides a more critical and nuanced understanding of how modern sound-politics overlapped with exercising wartime power.

Cover Essay: Visual Images in Sound Studies.

This essay discusses the significance of visual images in sound studies. The field of sound studies allows us to focus on hearing and soundscapes in cultural experiences and has challenged the primacy of vision as a framework for social analysis. This issue's cover shows Japanese Emperor Hirohito examining Type 90 Air Sound Detectors (also known as "war tubas") in 1936. From the mid-1930s to the early 1940s, these acoustic locators featured not only in experts' books but also in air-defense and military textbooks and in popular Japanese magazines. Magazines for young people highlighted their visuality rather than their actual functioning, mechanisms, and technicality. This essay demonstrates that the acoustic locator's visuality was instrumental for public relations, while its auditory function served practical military purposes. The image suggests that visuals play a vital role in studying the complex ecologies of sound.

Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models.

OBJECTIVE: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (2.0-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO×hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO×hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [3H]-cholesterol and confirmed significant increases of [3H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a-treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a-immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. CONCLUSIONS: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. In addition, this compound proves that a small-molecule direct LCAT activator can achieve HDL-C elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.

Impact of subcallosal artery origin and A1 asymmetry on surgical outcomes of anterior communicating artery aneurysms.

BACKGROUND: Surgical clipping of anterior communicating artery (ACoA) aneurysms remains challenging due to their complex anatomy. Anatomical risk factors for ACoA aneurysm surgery require further elucidation. The aim of this study is to investigate whether proximity of the midline perforating artery, subcallosal artery (SubCA), and associated anomaly of the ACoA complex affect functional outcomes of ACoA aneurysm surgery. METHODS: A total of 92 patients with both unruptured and ruptured ACoA aneurysms, who underwent surgical clipping, were retrospectively analyzed from a multicenter, observational cohort database. Association of ACoA anatomy with SubCA origin at the aneurysmal neck under microsurgical observation was analyzed in the interhemispheric approach subgroup (n = 56). Then, we evaluated whether anatomical factors associated with SubCA neck origin affected surgical outcomes in the entire cohort (both interhemispheric and pterional approaches, n = 92). RESULTS: In the interhemispheric approach cohort, combination of A1 asymmetry and aneurysmal size ≥ 5.0 mm was stratified to have the highest probability of the SubCA neck origin by a decision tree analysis. Then, among the entire cohort using either interhemispheric or pterional approach, combination of A1 asymmetry and aneurysmal size ≥ 5.0 mm was significantly associated with poor functional outcomes by multivariable logistic regression analysis (OR 6.76; 95% CI 1.19-38.5; p = 0.03) as compared with A1 symmetry group in the acute subarachnoid hemorrhage settings. CONCLUSION: Combination of A1 asymmetry and larger aneurysmal size was significantly associated with SubCA aneurysmal neck origin and poor functional outcomes in ACoA aneurysm surgery. Interhemispheric approach may be proposed to provide a wider and unobstructed view of SubCA for ACoA aneurysms with this high-risk anatomical variant.

Activation of Naturally Occurring Lecithin:Cholesterol Acyltransferase Mutants by a Novel Activator Compound.

Lecithin:cholesterol acyltransferase (LCAT) is a unique plasma enzyme able to esterify cholesterol, and it plays an important role in HDL maturation and promotion of reverse cholesterol transport. Familial LCAT deficiency (FLD; OMIM number 245900) is a rare recessive disease that results from loss-of-function mutations in the LCAT gene and has no cure. In this study, we assessed the in vitro efficacy of a novel small-molecule LCAT activator. Cholesterol esterification rate (CER) and LCAT activity were tested in plasma from six controls and five FLD homozygous carriers of various LCAT mutations at different doses of the compound (0.1, 1, and 10 µg/ml). In control plasma, the compound significantly increased both CER (P < 0.001) and LCAT activity (P = 0.007) in a dose-dependent manner. Both CER and LCAT activity increased by 4- to 5-fold, reaching maximum activation at the dose of 1 µg/ml. Interestingly, Daiichi Sankyo compound produced an increase in CER in two of the five tested LCAT mutants (Leu372--Arg and Val309--Met), while LCAT activity increased in three LCAT mutants (Arg147--Trp, Thr274--Ile and Leu372--Arg); mutant Pro254--Ser was not activated at any of the tested doses. The present findings form the basis for personalized therapeutic interventions in FLD carriers and support the potential LCAT activation in secondary LCAT defects. SIGNIFICANCE STATEMENT: We characterized the pharmacology of a novel small-molecule LCAT activator in vitro on a subset of naturally occurring LCAT mutants. Our findings form the basis for personalized therapeutic interventions for familial LCAT deficiency carriers, who can face severe complications and for whom no cure exists.

Optogenetic Rac1 engineered from membrane lipid-binding RGS-LOV for inducible lamellipodia formation.

We report the construction of a single-component optogenetic Rac1 (opto-Rac1) to control actin polymerization by dynamic membrane recruitment. Opto-Rac1 is a fusion of wildtype human Rac1 small GTPase to the C-terminal region of BcLOV4, a LOV (light-oxygen-voltage) photoreceptor that rapidly binds the plasma membrane upon blue-light activation via a direct electrostatic interaction with anionic membrane phospholipids. Translocation of the fused wildtype Rac1 effector permits its activation by GEFs (guanine nucleotide exchange factors) and consequent actin polymerization and lamellipodia formation, unlike in existing single-chain systems that operate by allosteric photo-switching of constitutively active Rac1 or the heterodimerization-based (i.e. two-component) membrane recruitment of a Rac1-activating GEF. Opto-Rac1 induction of lamellipodia formation was spatially restricted to the patterned illumination field and was efficient, requiring sparse stimulation duty ratios of ∼1-2% (at the sensitivity threshold for flavin photocycling) to cause significant changes in cell morphology. This work exemplifies how the discovery of LOV proteins of distinct signal transmission modes can beget new classes of optogenetic tools for controlling cellular function.

"Clip Anchor-Assisted Coil Embolization" for Endovascular Parent Artery Occlusion of Intracranial Traumatic Aneurysm.

Traumatic cerebral aneurysms are histologically dissecting aneurysms or pseudoaneurysms, thus requiring parent artery occlusion for cure. Combination of endovascular parent artery occlusion and extracranial-intracranial bypass is considered optimal to obtain complete obliteration of the aneurysm and to avoid hemodynamic hypoperfusion. However, endovascular parent artery occlusion of the supraclinoid internal carotid artery (ICA) is at risk of ischemic complications due to distal coil protrusion to adjacent perforating arteries or distal embolism of the thrombi generated in the coil mass. A 20-year-old man presented with progressive left optic neuropathy following motor vehicle accident. Radiological examination revealed left supraclinoid ICA aneurysmal formation with dissecting change. We treated this traumatic supraclinoid ICA aneurysm by combination of endovascular parent artery occlusion and high-flow bypass in the hybrid operating room. An aneurysmal clip was applied on the ICA just distal to the aneurysm prior to coil embolization, and worked as a scaffold for subsequent filling coils and as a blockade for the distal emboli. This "clip anchor-assisted coil embolization" technique resulted in optimal parent artery occlusion for the traumatic aneurysm of the supraclinoid ICA with minimal risks of residual blood flow, intraoperative rupture, and thromboembolic complications.

4-Anilino-pyrimidine, novel aldosterone synthase (CYP11B2) inhibitors bearing pyrimidine structures.

2,2,2-Trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-yl}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol 1 was identified as a novel potent aldosterone synthase inhibitor. Despite large species differences, compound 1 inhibits both human and rodent CYP11B2 in a nano-molar range.

Significance of the Hemorrhagic Site for Recurrent Bleeding: Prespecified Analysis in the Japan Adult Moyamoya Trial.

BACKGROUND AND PURPOSE: The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset. METHODS: The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction. RESULTS: Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01-0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39-6.79) for the anterior group (P=0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60-21.27). CONCLUSIONS: Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

[How Can We Cuddle Up to Dying Patients? Attempts of Cancer Philosophy Clinic and Education].

What is needed to treat problems about how can we cuddle up to dying patients is not scientific thinking but philosophical thinking. Cancer philosophy clinic is a place where both patients and medical staffs think about death and how to live until death. The author tries to manage cancer philosophy clinic with the idea of logotherapy and terminal art. The author also tries to educate medical students and other medical staffs in cancer philosophy.

[Persistent Disturbance of Consciousness after Clipping of an Unruptured Cerebral Aneurysm due to Pseudohypoxic Brain Swelling].

A patient developed persistent disturbance of consciousness after uneventful clipping of an unruptured cerebral aneurysm under general anesthesia. Pseudohypoxic brain swelling (PHBS) was suspected because computerized tomography (CT) and magnetic resonance imaging (MRI) revealed diffuse brain swelling, especially in the bilateral basal ganglia and thalami. Steroid pulse therapy in addition to antiedematous drugs and anticonvulsant improved the consciousness. Anesthesiologists should pay attention to PHBS in a case of persistent disturbance of consciousness after uneventful craniotomy.

Mechanical thrombectomy for cerebrovascular occlusion in a patient with situs inversus.

Situs inversus is a rare congenital abnormality characterized by mirror-image transposition of the major visceral organs and vessels. Few reports have discussed the use of mechanical thrombectomy in acute ischemic stroke with situs inversus. We present such a case, to raise awareness and deepen the knowledge on these cases. A 44-year-old man was admitted to our hospital with sudden-onset dysarthria and left-sided paresis. Computed tomography (CT) angiography revealed situs inversus and occlusion in the internal carotid artery. First, intravenous tissue plasminogen activator was administered, followed by immediate reperfusion with mechanical thrombectomy. We achieved thrombolysis in cerebral infarction grade 3. After the procedure, the patient fully recovered. Prompt diagnosis is crucial for rapid recanalization in patients with vascular anomalies such as situs inversus.

Emerging Roles and Mechanisms of RNA Modifications in Neurodegenerative Diseases and Glioma.

Despite a long history of research, neurodegenerative diseases and malignant brain tumor gliomas are both considered incurable, facing challenges in the development of treatments. Recent evidence suggests that RNA modifications, previously considered as static components of intracellular RNAs, are in fact dynamically regulated across various RNA species in cells and play a critical role in major biological processes in the nervous system. Innovations in next-generation sequencing have enabled the accurate detection of modifications on bases and sugars within various RNA molecules. These RNA modifications influence the stability and transportation of RNA, and crucially affect its translation. This review delves into existing knowledge on RNA modifications to offer a comprehensive inventory of these modifications across different RNA species. The detailed regulatory functions and roles of RNA modifications within the nervous system are discussed with a focus on neurodegenerative diseases and gliomas. This article presents a comprehensive overview of the fundamental mechanisms and emerging roles of RNA modifications in these diseases, which can facilitate the creation of innovative diagnostics and therapeutics for these conditions.

Spin-State Control of Shallow Single NV Centers in Hydrogen-Terminated Diamond.

The ability to control the charge and spin states of nitrogen-vacancy (NV) centers near the diamond surface is of pivotal importance for quantum applications. Hydrogen-terminated diamond is promising for long spin coherence times and ease of controlling the charge states due to the low density of surface defects. However, it has so far been challenging to create negatively charged single NV centers with controllable spin states beneath a hydrogen-terminated surface because atmospheric adsorbates that act as acceptors induce surface holes. In this study, we optically detected the magnetic resonance of shallow single NV centers in hydrogen-terminated diamond through precise control of the nitrogen implantation fluence. Furthermore, we found that the probability of detecting the resonance was enhanced by reducing the surface acceptor density through passivation of the hydrogen-terminated surface with hexagonal boron nitride without air exposure. This control method opens up new opportunities for using NV centers in quantum applications.

Capability of insulator study by photoemission electron microscopy at SPring-8.

The observation method of photoemission electron microscopy (PEEM) on insulating samples has been established in an extremely simple way. Surface conductivity is induced locally on an insulating surface by continuous radiation of soft X-rays, and Au films close to the area of interest allow the accumulated charges on the insulated area to be released to ground level. Magnetic domain observations of a NiZn ferrite, local X-ray absorption spectroscopy of sapphire, high-resolution imaging of a poorly conducting Li0.9CoO2 film surface, and Au pattern evaporation on a fine rock particle are demonstrated. Using this technique, all users' experiments on poorly conducting samples have been performed successfully at the PEEM experimental station of SPring-8.

Sexing of dog sperm by fluorescence in situ hybridization.

Effective preselection of sex has been accomplished in several species of livestock and also in humans using the flow cytometric sperm sorting method. A guaranteed high sorting accuracy is a key prerequisite for the widespread use of sperm sexing. The standard validation method is flow cytometric remeasurement of the DNA content of the sexed sperm. Since this method relies on the same instrument that produced the original sperm separation, it is not truly independent. Therefore, to be able to specifically produce either male or female offspring in the dog, we developed a method of direct visualization of sex chromosomes in a single sperm using fluorescence in situ hybridization (FISH) as a validation method. Denaturation of canine spermatozoa by immersion in 1 M NaOH for 4 min yielded consistent hybridization results with over 97% hybridization efficiency and a good preservation of sperm morphology. There was no significant difference between the theoretical ratio (50:50) and the observed ratio of X- and Y-chromosome-bearing spermatozoa in any of the three dogs. In addition, the mean purities of flow-sorted sex chromosomes in spermatozoa of the three dogs were 90.8% for the X chromosome fraction and 89.6% for the Y chromosome fraction. This sorting was evaluated by using the dual color FISH protocol. Therefore, our results demonstrated that the FISH protocol worked reliably for both unsorted and sexed sperm samples.

[Epidural block for lower limb amputation in a patient with Klippel-Trenaunay-Weber syndrome].

A 23-year-old man with Klippel-Trenaunay-Weber syndrome (KTWS) was scheduled for left lower limb amputation. He had complained of severe lower limb pain. Oral administration of acetaminophen, duloxetine, and morphine did not alleviate the pain. Epidural block was performed preoperatively after confirming there were no abnormal angiomas in the lumbar spinal canal on CT scan. The pain was alleviated by the epidural block. The epidural block was also useful during the operation and postoperative pain management. There were no complications related to the epidural block. KTWS is a rare congenital malformation characterized by the triad of varicose veins, capillary malformations, and bony or soft tissue hypertrophy in affected limbs. Some patients with KTWS have epidural hemangioma and cerebral or spinal cord arteriovenous fistulas. There have been some reports of rupture of epidural hemangioma resulting in progressive paraplegia. When epidural block is scheduled for patients with KTWS, CT scan should be performed to investigate abnormal vessels in the lumbar spinal canal.

Recurrent glioblastoma metastatic to the lumbar vertebra: A case report and literature review: Surgical oncology.

Background: Glioblastoma is a malignant tumor, and its prognosis is as poor as 1.5 to 2 years. Most cases recur within one year even under the standard treatment. The majority of recurrences are local, and in rare cases, metastasize mostly within the centra nervous system. Extradural metastasis of glioma is exceedingly rare. Here, we present a case of vertebral metastasis of glioblastoma. Case presentation: We present a 21-year-old man post total resection of the right parietal glioblastoma, diagnosed with lumbar metastasis. He originally presented with impaired consciousness and left hemiplegia and underwent gross total resection of the tumor. Given the diagnosis of glioblastoma, he was treated with radiotherapy combined with concurrent and adjuvant temozolomide. Six months after tumor resection, the patient presented with severe back pain, and was diagnosed as metastatic glioblastoma on the first lumbar vertebrae. Posterior decompression with fixation and postoperative radiotherapy were conducted. He went on to receive temozolomide and bevacizumab. However, at 3 months after the diagnosis of lumbar metastasis, further disease progression was noted, and his care was transitioned to best supportive care. Comparison on copy number status between primary and metastatic lesions on methylation array analysis revealed more enhanced chromosomal instability including 7p loss, 7q gain and 8 gain in the metastatic lesion. Conclusion: Based upon the literature review and our case, younger age of initial presentation, multiple surgical interventions, and long overall survival seem to be the risk factors of vertebral metastasis. As the prognosis of glioblastoma improves over time, its vertebral metastasis is seemingly more common. Therefore, extradural metastasis should be kept in mind in the treatment of glioblastoma. Further, detailed genomic analysis on multiple paired specimens is mandated to elucidate the molecular mechanisms of vertebral metastasis.