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The Oyashio region east of northern Japan has experienced frequent marine heatwaves (MHWs) since 2010, and in the summer and fall of 2022, sea surface temperature hit a record high as of that year. This study examined the impact of the 2022/23 MHW on dissolved oxygen (DO) by analyzing observations from a vessel and biogeochemical Argo floats. It was found that warm saline water from the Kuroshio Current intruded at ~ 42°N in July. DO anomalies from the climatology above a depth of 200 m were negatively correlated with the temperature anomalies at the same depth, while the opposite was true for deeper depths. In the density coordinate, DO and temperature anomalies exhibited a strong negative correlation when the potential density ( σ θ ) was less than ~ 27.0 kg m −3 . Thus, it was demonstrated that subsurface DO anomalies could be statistically predicted from temperature and salinity fields using this relationship. Notably, DO anomalies could be divided into components related to isopycnal mixing and density-surface heaving. This decomposition revealed a dynamical process, whereby the intrusion of the Kuroshio water, which is lighter than the Oyashio water, pushed down the density surfaces, causing oxygenation. Meanwhile, isopycnal mixing tended to mitigate the increase of DO concentration since DO concentration was smaller in the south than in the north on an isopycnal surface of σ θ  < 27.0 kg m −3 . This study clarified that, during the 2022/23 MHW, deoxygenation occurred near the surface owing the warming, whereas the DO concentration increased in the subsurface layer.

PurposeThis study aimed to evaluate the relationship between sleep quality as assessed using the Pittsburgh Sleep Quality Index (PSQI) and the index of diffusivity along the perivascular space (ALPS index), a possible indirect indicator of glymphatic system activity.Materials and methodsThis study included the diffusion magnetic resonance imaging (MRI) data of 317 people with sleep disruption and 515 healthy controls (HCs) from the Human Connectome Project (WU-MINN HCP 1200). The ALPS index was calculated automatically based on diffusion tensor image analysis (DTI)-ALPS of diffusion MRI. The ALPS index of the sleep disruption and HC groups was compared using general linear model (GLM) analysis with covariates, such as age, sex, level of education, and intracranial volume. In addition, to confirm the relationship between sleep quality and the ALPS index in the sleep disruption group as well as evaluate the effect of each PSQI component on the ALPS index, correlation analyses between the ALPS indices and PSQI scores of all the components and between the ALPS index and each PSQI component was performed using GLM analysis with the abovementioned covariates, respectively.ResultsThe ALPS index was significantly lower in the sleep disruption group than in the HC group (p = 0.001). Moreover, the ALPS indices showed significant negative correlations with the PSQI scores of all the components (false discovery rate [FDR]-corrected p < 0.001). Two significant negative correlations were also found between the ALPS index and PSQI component 2 (sleep latency, FDR-corrected p < 0.001) and 6 (the use of sleep medication, FDR-corrected p < 0.001).ConclusionOur findings suggest that glymphatic system impairment contributes to sleep disruption in young adults.

Stimulator of interferon genes (STING) triggers the type I interferon and inflammatory responses against a variety of DNA pathogens, which is essential to limiting viral infection and replication. STING activates the downstream kinase TBK1 at the trans-Golgi network (TGN) and is degraded at lysosomes through a process called lysosomal microautophagy. Impaired STING targeting to lysosomes results in the prolonged inflammatory signal, which may be associated with a variety of neurodegenerative and autoinflammatory diseases. Thus, development of methods to quantify STING degradation helps understand the mechanism of lysosomal microautophagy and its related diseases. Here we report a quantitative method to monitor STING degradation with two luciferases, firefly luciferase (FLuc) and Nanoluciferase (NLuc). The expression plasmid is composed of FLuc, a P2A self-cleavage site, and NLuc-tagged STING. FLuc intensity reflects the total amount of translated protein, serving as an internal control, while NLuc intensity corresponds to the amount of STING. Comparison of the NLuc/FLuc ratios at different time points after STING stimulation revealed the kinetics of decay of STING levels in live cells. This method should provide a useful complement to western blotting and fluorescence-activated cell sorter (FACS) analysis presently used to monitor STING degradation.Key words: innate immunity, STING, membrane traffic, lysosomal degradation, luciferase

PurposeThe method of diffusion tensor image analysis along the perivascular space (DTI-ALPS) was gathering attention to evaluate the brain’s glymphatic function or interstitial fluid dynamics. However, to the best knowledge, no study was conducted on the reproducibility of these automated methods for ALPS index values. Therefore, the current study evaluated the ALPS index reproducibility based on DTI-ALPS using two major automated calculation techniques in scan and rescan of the same subject on the same day.Materials and methodsThis study included 23 participants, including 2 with Alzheimer’s disease, 15 with mild cognitive impairment, and 6 with cognitive normals. Scan and rescan data of diffusion magnetic resonance images were obtained, as well as automatically index for ALPS (ALPS index) and ALPS index maintaining tensor vector orientation information (vALPS index) with region of interest on the template fractional anisotropy map calculated by FSL software.These ALPS indices were compared in terms of scan and rescan reproducibility.ResultsThe absolute difference in ALPS-index values between scan and rescan was larger in the ALPS index than in the vALPS index by approximately 0.6% as the relative difference. Cohen’s d for the left and right ALPS indices between methods were 0.121 and 0.159, respectively.ConclusionThe vALPS index based on DTI-ALPS maintaining tensor vector orientation information has higher reproducibility than the ALPS index. This result encourages a multisite study on the ALPS index with a large sample size and helps detect a subtle pathological change in the ALPS index.

Carnosine (β-alanyl-l-histidine) is an imidazole dipeptide present at high concentrations in skeletal muscles, where it plays a beneficial role. However, oral intake of carnosine or β-alanine to increase skeletal muscle carnosine levels has disadvantages such as low efficiency and side effects. Therefore, we proposed homocarnosine (γ-aminobutyryl-l-histidine) as a novel alternative imidazole peptide for skeletal muscle based on its structural similarity to carnosine. To induce endogenous homocarnosine synthesis in skeletal muscles, mice were fed a basal diet mixed with 0, 0.5, 2, or 5% γ-aminobutyric acid (GABA) for 6 weeks. As expected, in the control group (0% GABA), GABA and homocarnosine were present in trace concentrations. Skeletal muscle homocarnosine levels were significantly increased in the 2% and 5% GABA intake groups (tenfold, P < 0.01 and 53-fold, P < 0.01; respectively) relative to those of the control group, whereas 0.5% GABA intake induced no such effect. GABA intake had no effect on the levels of carnosine, anserine, and β-alanine. Vigabatrin (inhibitor of GABA transaminase (GABA-T)) administration to mice receiving 2% GABA intake for 2 weeks led to GABA-T inhibition in the liver. Subsequently, a 43-fold increase in circulating GABA levels and a tendency increase in skeletal muscle homocarnosine levels were observed. Therefore, skeletal muscle homocarnosine synthesis can be induced by supplying its substrate GABA in tissues. As GABA availability is tightly regulated by GABA-T via GABA degradation, inhibitors of GABA or β-alanine degradation could be novel potential interventions for increasing skeletal muscle imidazole dipeptides.

Stimulator of interferon genes (STING) is critical for the type I interferon responses to pathogen- or self-derived cytosolic DNA. STING signalling is terminated by ESCRT-driven lysosomal microautophagy. How STING is directly encapsulated by lysosomes has not yet been understood. Here we show that two lysosomal components, a phosphoinositide PI(3,5)P 2 and CHMP4B (a subunit of ESCRT-III subcomplex) are essential for STING encapsulation by lysosomes. Liposome sedimentation assay reveals that CHMP4B binds to PI(3,5)P 2 . The forced recruitment of the catalytic core of Pikfyve (a lipid kinase generating PI(3,5)P 2 ) to early endosomes, recruits a fraction of CHMP4B to early endosomes. CHMP4B mutant, defective in the binding to PI(3,5)P 2 , cannot restore the microautophagic degradation of STING or the resolution of the STING signalling in cells depleted of Chmp4b . Our results reveal a molecular mechanism that terminates innate immune signalling at the lysosomal membrane. Inhibition of Pikfyve, a kinase generating PI(3,5)P2, abolishes CHMP4B (an ESCRT-III subunit) recruitment to lysosomes, and leads to an accumulation of STING vesicles and sustained signaling. Our results reveal a lysosomal PI(3,5)P2/CHMP4B axis that terminates innate immune signaling.

PurposeThis study aimed to evaluate the along the perivascular space (ALPS) index based on the diffusion tensor image ALPS (DTI-ALPS) in corticobasal degeneration with corticobasal syndrome (CBD-CBS) and investigate its correlation with motor and cognitive functions.Materials and methodsThe data of 21 patients with CBD-CBS and 17 healthy controls (HCs) were obtained from the 4-Repeat Tauopathy Neuroimaging Initiative and the Frontotemporal Lobar Degeneration Neuroimaging Initiative databases. Diffusion magnetic resonance imaging was performed using a 3-Tesla MRI scanner. The ALPS index based on DTI-ALPS was automatically calculated after preprocessing. The ALPS index was compared between the CBD-CBS and HC groups via a general linear model analysis, with covariates such as age, sex, years of education, and intracranial volume (ICV). Furthermore, to confirm the relation between the ALPS index and the motor and cognitive score in CBD-CBS, the partial Spearman’s rank correlation coefficient was calculated with covariates such as age, sex, years of education, and ICV. A p value of < 0.05 was considered as statistically significant in all statistical analyses.ResultsThe ALPS index of CBD-CBS was significantly lower than that of HC (Cohen’s d =  − 1.53, p < 0.005). Moreover, the ALPS index had a significant positive correlation with the mini mental state evaluation score (rs = 0.65, p < 0.005) and a significant negative correlation with the unified Parkinson’s Disease Rating Scale III score (rs =  − 0.75, p < 0.001).ConclusionThe ALPS index of patients with CBD-CBS, which is significantly lower than that of HCs, is significantly associated with motor and cognitive functions.

Purpose In the 2016 WHO Classification of Lymphoid Tissue Neoplasms, co-expression of MYC and BCL2 is newly designated as double expressor lymphoma. Patients with primary central nervous system lymphoma with double expressor (DE-PCNSL) have been reported to have a higher risk of recurrence and a worse prognosis than those with PCNSL without double expressor (non-DE-PCNSL). The aim of this study was to determine whether DE-PCNSL has characteristic clinical and MR imaging features compared to non-DE-PCNSL. Methods This study included 36 immunocompetent patients with PCNSL, including 16 with double expressor and 20 without double expressor. The enhancement pattern and the values of apparent diffusion coefficient (ADC), relative cerebral blood volume (rCBV), leakage-corrected rCBV, and K2 at enhancing lesions were compared between the DE-PCNSL and non-DE-PCNSL groups. The mean and minimum values from the ROI on ADC maps were designated as ADC mean and ADC min , respectively. The data of rCBV, leakage-corrected rCBV and K2 were obtained from dynamic susceptibility contrast (DSC) perfusion MRI. The Kaplan-Meier method was used to estimate progression-free survival (PFS) differences. Results DE-PCNSL was significantly more common in women (12 of 16 patients, 75%) compared to non-DE-PCNSL (7 of 20 patients, 35%; P  =.02). The rCBV ratio and leakage-corrected rCBV ratio were significantly lower in DE-PCNSL compared to non-DE-PCNSL ( P  =.02 and P  =.03, respectively). There was no significant difference in the enhancement pattern and ADC mean , ADC min and K2 values between the two groups. DE-PCNSL tended to have a shorter PFS than non-DE-PCNSL, although the difference was not significant. Conclusion rCBV and leakage-corrected rCBV may help differentiate double-expressor from non-double-expressor subtypes in PCNSL.

Multiple reports have identified smoking as a risk factor for long COVID; however, few have distinguished among tobacco product types. We conducted a cross-sectional study using data from an internet-based survey administered in February 2023 to examine the association between 12 persistent symptoms and smoking status in participants with a history of COVID-19. A total of 28,250 participants were included, of whom 5,068 had a history of COVID-19. Among current tobacco users with a history of COVID-19, the odds ratios for persistent symptoms were significantly elevated for four symptoms—arthralgia, chest pain, dyspnea, and dysosmia—compared to never smokers. For subgroup analysis, current tobacco users were categorized into three groups: combustible cigarette (CC), heated tobacco product (HTP), and dual users. Among dual users, the odds ratios were significantly elevated for five symptoms: arthralgia, chest pain, dyspnea, dysgeusia, and dysosmia. CC users showed significantly higher odds for chest pain, dyspnea, and fatigue, while HTP users for dyspnea and sexual dysfunction. Smoking in individuals with a history of COVID-19 associates the prevalence of persistent symptoms, and its impact may vary by smoking type. Separately analyzing smoking subgroups allows for a more accurate understanding of the relationship between persistent symptoms and smoking behavior.

Abstract Background: Transbronchial cryobiopsy enables high-quality sample collection around the probe tip. Meanwhile, existing cryoprobes have less flexibility and a higher risk of bleeding. The ultrathin cryoprobe with a 1.1-mm diameter addresses these problems and allows specimens to be directly retrieved through the working channel of a thin bronchoscope. Objective: This study evaluated the diagnostic utility and safety of non-intubated cryobiopsy using an ultrathin cryoprobe added to conventional biopsy for diagnosing peripheral pulmonary lesions (PPLs). Methods: The data of patients who underwent conventional biopsy followed by non-intubated cryobiopsy to retrieve specimens through the thin bronchoscope’s working channel for diagnosing PPLs at Osaka Metropolitan University Hospital from July 2021 to June 2022 were retrospectively collected. They were analyzed to evaluate the diagnostic utility and safety of adding non-intubated cryobiopsy to conventional biopsy for PPLs. The characteristics of PPLs that obtain additional diagnostic benefits from cryobiopsy over conventional biopsy were also investigated. Results: The analysis included 113 patients. The diagnostic yields of conventional biopsy and non-intubated cryobiopsy were 70.8% and 82.3%, respectively (p = 0.009). The total diagnostic yield was 85.8%, higher than conventional biopsy alone (p < 0.001). Although one moderate bleeding occurred, no severe complications developed. The additional diagnostic benefits of non-intubated cryobiopsy over conventional biopsy were demonstrated when the radial endobronchial ultrasound (R-EBUS) showed “adjacent to” (60.3% vs. 82.8%, p = 0.017). Conclusions: Non-intubated cryobiopsy using an ultrathin cryoprobe has high diagnostic utility and safety for diagnosing PPLs, with additional diagnostic benefits over conventional biopsy depending on the R-EBUS image.