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A contribution of epigenetic modifications to B cell tolerance has been proposed but not directly tested. Here we report that deficiency of ten–eleven translocation (Tet) DNA demethylase family members Tet2 and Tet3 in B cells led to hyperactivation of B and T cells, autoantibody production and lupus-like disease in mice. Mechanistically, in the absence of Tet2 and Tet3, downregulation of CD86, which normally occurs following chronic exposure of self-reactive B cells to self-antigen, did not take place. The importance of dysregulated CD86 expression in Tet2- and Tet3-deficient B cells was further demonstrated by the restriction, albeit not complete, on aberrant T and B cell activation following anti-CD86 blockade. Tet2- and Tet3-deficient B cells had decreased accumulation of histone deacetylase 1 (HDAC1) and HDAC2 at the Cd86 locus. Thus, our findings suggest that Tet2- and Tet3-mediated chromatin modification participates in repression of CD86 on chronically stimulated self-reactive B cells, which contributes, at least in part, to preventing autoimmunity. Ten–eleven translocation (Tet) enzymes oxidize 5-methylcytosine, facilitating DNA demethylation. Kurosaki and colleagues show that B cell–specific loss of Tet2 and Tet3 leads to lupus-like autoimmunity in mice, in part through increased B cell expression of CD86 and enhanced activation of CD4 + T cells.

Active inference offers a unified framework in which agents can exhibit both goal-directed and epistemic behaviors. However, implementing policy search in high-dimensional continuous action spaces presents challenges in terms of scalability and stability. Our previously proposed model, T-GLean, addressed this issue by enabling efficient goal-directed planning through low-dimensional latent space search, further reduced by conditioning on prior habituated behavior. However, the lack of an epistemic term in minimizing expected free energy limited the agent’s ability to engage in information-seeking behavior that can be critical for attaining preferred outcomes. In this study, we present EFE-GLean, an extended version of T-GLean that overcomes this limitation by integrating epistemic value into the planning process. EFE-GLean generates goal-directed policies by inferring low-dimensional future posterior trajectories while maximizing expected information gain. Simulation experiments using an extended T-maze task—implemented in both discrete and continuous domains—demonstrate that the agent can successfully achieve its goals by exploiting hidden environmental information. Furthermore, we show that the agent is capable of adapting to abrupt environmental changes by dynamically revising plans through simultaneous minimization of past variational free energy and future expected free energy. Finally, analytical evaluations detail the underlying mechanisms and computational properties of the model.

Microvascular decompression (MVD) has proven efficacy in trigeminal neuralgia (TN) and hemifacial spasm (HFS). This study utilized computational fluid dynamics (CFD) to investigate the impact of MVD on wall shear stress (WSS) of responsible arteries (RAs) at the neurovascular contact (NVC). A total of 21 cases (10 TN, 11 HFS) were analyzed, involving RAs at NVC validated through intraoperative photographs. Hemodynamic parameters (WSS, vessel diameter, flow rate, pressure drop) was calculated using CFD for the RAs based on 3D silent-magnetic resonance angiograms. The NVC was segmented into NVC-proximal, NVC-site, and NVC-distal portions using simulated 3D CFD images that correlated with surgical observations. WSS ratios of NVC-site to NVC-proximal (NVC-site/proximal) was calculated both before and after MVD. Prior to MVD, WSS in the RA at the NVC displayed a peaked curve with a maximum at NVC-site; however, post MVD, it presented a smooth curve without peaks. The WSS ratio exhibited a significant decrease after MVD. The impact of MVD on WSS of RAs at NVC was evaluated in both TN and HFS cases. Analyzing the hemodynamics of RAs through CFD and identifying WSS peaks at NVC portions before MVD provided a more detailed and localized understanding of the morphologically depicted NVC.

BackgroundCritical coronavirus disease 2019 (COVID-19) has a high fatality rate, especially in hemodialysis (HD) patients, with this poor prognosis being caused by systemic hyperinflammation; cytokine storms. Steroid pulse therapy or tocilizumab (TCZ) have insufficient inhibitory effects against cytokine storms in critical cases. This study evaluated the clinical effects and safety of combining steroid pulse therapy and TCZ.MethodsFrom September 2020 to May 2021, 201 patients with COVID-19 were admitted to our hospital. Before February 2021, patients with an oxygen demand exceeding 8 L/min were intubated and treated with standard therapy (dexamethasone and antiviral therapy). After February 2021, patients underwent high-flow nasal cannula oxygen therapy and were treated with TCZ (8 mg/kg) and methylprednisolone (mPSL) (500 mg/day [≤ 75 kg], 1000 mg/day [> 75 kg]) for 3 days. We compared background characteristics, laboratory findings, and prognosis between non-HD and HD patients and between patients who received and did not receive TCZ and mPSL pulse therapy.ResultsAmong non-HD patients, the TCZ + mPSL pulse group had significantly higher survival rates and lower secondary infection rates (p < 0.05), than the standard therapy group. All HD patients in the standard therapy group with oxygen demand exceeding 8 L/min died. Contrastingly, all patients in the TCZ + mPSL pulse group survived, with their oxygen demand decreasing to 0–1 L/min within 3 weeks post-administration.ConclusionTCZ combined with mPSL pulse therapy improved the survival rate without significant adverse events in critical HD and non-HD patients with COVID-19 by strongly suppressing systemic hyperinflammation.

We demonstrate the lateral optical confinement of GaN-based vertical-cavity surface-emitting lasers (GaN-VCSELs) with a cavity containing a curved mirror that is formed monolithically on a GaN wafer. The output wavelength of the devices is 441–455 nm. The threshold current is 40 mA ( J th  = 141 kA/cm 2 ) under pulsed current injection ( W p  = 100 ns; duty = 0.2%) at room temperature. We confirm the lateral optical confinement by recording near-field images and investigating the dependence of threshold current on aperture size. The beam profile can be fitted with a Gaussian having a theoretical standard deviation of σ  = 0.723 µm, which is significantly smaller than previously reported values for GaN-VCSELs with plane mirrors. Lateral optical confinement with this structure theoretically allows aperture miniaturization to the diffraction limit, resulting in threshold currents far lower than sub-milliamperes. The proposed structure enabled GaN-based VCSELs to be constructed with cavities as long as 28.3 µm, which greatly simplifies the fabrication process owing to longitudinal mode spacings of less than a few nanometers and should help the implementation of these devices in practice.

An isolated single brain metastasis (BM) is an extremely rare manifestation of failure in patients with cecal adenocarcinoma (CAC). Total resection (while preserving function) of a 3-cm BM involving both the primary motor and sensory cortexes presents a conundrum: achieving long-term local control and safety of such a BM is also challenging for stereotactic radiosurgery (SRS). We describe the case of a 3.1-cm BM from CAC in the left parasagittal para-central sulcus region, which was treated using five-fraction SRS with a biologically effective dose (BED) of 81.6 Gy. In the SRS, the gross tumor volume (GTV, 7.14 cm ) was defined based on computed tomography (CT)/T1/T2 matching (enhancing lesion 11.66 cm ), and 98.7% of the GTV (CT/T2 mass) was covered with 43.6 Gy (58% isodose) using volumetric-modulated arcs. The maximum tumor response was partial (19.7% of the prior GTV) and sustained for 15.2 months, leaving minor neurological symptoms. However, the patient developed neurological worsening at six months, attributed to adverse radiation effects with a CT/T1/T2 mismatch, for which medical management, including the addition of bevacizumab (BEV), was effective for one year. Multi-fraction SRS with a high marginal and internal BED and sequential systemic therapy, including BEV, can be a minimally invasive, efficacious, and durable treatment option for a large CAC-BM involving the central sulcus. Early co-administration of BEV following SRS, dose escalation to the GTV boundary, and more than five fractions of SRS may be considered to improve the efficacy and safety further.

The beamline for angle-resolved photoemission spectroscopy (ARPES) with a nano-focused beam (nano-ARPES) is planned as one of the public beamlines in NanoTerasu, the 3-GeV next-generation synchrotron radiation facility at Tohoku, Japan, which is scheduled to start operation in 2024. A 4 m long APPLE-II type undulator provides brilliant soft X-rays with various polarizations (linear horizontal and vertical, and left and right circular) in the energy range of 50-1,000 eV. A collimated plane grating monochromator is adopted as a soft X-ray monochromator because we can select the demagnification factor of grating c f f = cos α /cos β between the high energy-resolution (HR) mode for HR-ARPES experiments and the low divergence mode for high-flux nano-ARPES measurements. This beamline aims to produce the high flux nano-focused beam by using ultrahigh precision reflective mirror optics, not a Fresnel zone plate used as a focusing optics in the previous nano-ARPES station at other synchrotron facilities.

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and its overexpression has been shown to exert anti-tumor effects as a therapeutic target gene in many human cancers. Recently, we demonstrated the anti-glioma effects of an adenoviral vector carrying REIC/Dkk-3 with the super gene expression system (Ad-SGE-REIC). Anti-vascular endothelial growth factor treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. In this study, we examined the effects of Ad-SGE-REIC on glioma treated with bevacizumab. Ad-SGE-REIC treatment resulted in a significant reduction in the number of invasion cells treated with bevacizumab. Western blot analyses revealed the increased expression of several endoplasmic reticulum stress markers in cells treated with both bevacizumab and Ad-SGE-REIC, as well as decreased β-catenin protein levels. In malignant glioma mouse models, overall survival was extended in the combination therapy group. These results suggest that the combination therapy of Ad-SGE-REIC and bevacizumab exerts anti-glioma effects by suppressing the angiogenesis and invasion of tumors. Combined Ad-SGE-REIC and bevacizumab might be a promising strategy for the treatment of malignant glioma.

The optical design of the ultrahigh-resolution RIXS beamline, which is currently developed at NanoTerasu in Japan, is described. The main goal of this beamline is to perform ultrahigh-resolution RIXS measurements with a total energy resolution of <10 meV at 250–1000 eV with E /Δ E >150,000 for both beamline and RIXS spectrometer. To achieve the ultra-high resolution, a 2D-RIXS spectrometer using energy-dispersive X-ray is employed to compensate for lower throughput at higher energy resolution, and the optics of the beamline is optimized for the 2D-RIXS spectrometer. A vertically dispersing in-focus variable-included-angle varied-line-spacing plane grating monochromator is employed for the beamline, with an entrance slit to ensure the ultrahigh resolution. First and second mirrors focus X-ray on entrance slits vertically and horizontally, respectively, and the divergent X-ray is irradiated onto the grating. For the 2D-RIXS spectrometer, there is no exit slit, and the vertically energy-dispersed X-ray is irradiated directly onto a sample. In front of the sample, X-ray is horizontally refocused by a Wolter type-I mirror. The expected horizontal focus size at the sample is ~0.7 μm. The expected photon flux is ~1×10 11 photons/s at 500–1000 eV with a virtual slit width of 2 μm required for E /Δ E >150,000. The height of the dispersed X-ray available in the 2D-RIXS spectrometer is ~120 μm, which allows the use of a remarkably high flux of ~6×10 12 photons/s, and the beamline will serve as an ultrahigh-resolution and high-efficiency RIXS facility.

Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5-aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance.