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Background: Although stimulation of Wnt/β-catenin signaling is an important strategy to treat ischemic stroke, its signaling pathway has not been fully clarified yet. Recently, RSPO3 (R-spondin 3)/LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4) signaling has resolved TLR4 (toll-like receptor 4)-induced inflammation in lung injury; however, whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of RSPO3/LGR4 signaling in the ischemic brain. Methods: BALB/c mice were exposed to permanent distal middle cerebral artery and common carotid artery occlusion. Temporal RSPO3 and LGR4 expressions were examined, and the mice were randomly assigned to receive vehicle or recombinant RSPO3. The underlying mechanisms were investigated using microglial cell lines and primary mixed glia-endothelia-neuron and primary neuronal cultures. Results: In the ischemic brain, RSPO3 and LGR4 were expressed in endothelial cells and microglia/macrophages and neurons, respectively. Stimulation of RSPO3/LGR4 signaling by recombinant RSPO3 recovered neurological deficits with decreased Il1β and iNOS mRNA on day 3 and increased Gap43 on day 9. In cultured cells, LGR4 was expressed in neuron and microglia, whereas RSPO3 promoted nuclear translocation of β-catenin. Neuroprotective effects with reduced expression of inflammatory cytokines were observed in lipopolysaccharide-stimulated glia-endothelium-neuron cultures but not in glutamate-, CoCl 2 -, H 2 O 2 -, or oxygen glucose deprivation-stimulated neuronal cultures, indicating that RSPO3/LGR4 can protect neurons by regulating inflammatory cytokines. LGR4-Fc chimera, which was used to block endogenous RSPO3/LGR4 signaling, increased LPS-induced production of inflammatory cytokines, suggesting that endogenous RSPO3 suppresses inflammation. RSPO3 decreased TLR4-related inflammatory cytokine expression by decreasing TLR4 expression without affecting the M1/M2 phenotype. RSPO3 also inhibited TLR2- and TLR9-induced inflammation but not TLR7-induced inflammation, and promoted neurite outgrowth. Conclusions: RSPO3/LGR4 signaling plays a critical role in regulating TLR-induced inflammation and neurite outgrowth in the ischemic brain. Enhancing this signal will be a promising approach for treating ischemic stroke.

The coronavirus disease 2019 (COVID-19) pandemic has affected the world for over 3 years. Treatment options have improved substantially during this period, including antiviral drugs, antibody drugs, immune-based agents, and vaccination. While these improvements have reduced mortality rates in patients with COVID-19, some patients still develop severe illness. In this review, we aimed to provide an overview of treatments for patients with severe COVID-19 from study reports and clinical experience. We discussed the treatments from two perspectives: respiratory care and drug treatments. In the respiratory care section, we discussed the usefulness of high-flow nasal cannula therapy and non-invasive ventilation as an alternative to invasive ventilation. In the drug treatments section, we focused on three classes for severe COVID-19 treatment: antiviral drugs, immune-based agents, and anticoagulation therapy. We did not discuss antibody drugs and vaccination, as they are not used for severe COVID-19 treatment.

Introduction: Hepato-splanchnic circulation influences the oxygenation of abdominal organs and is important in preventing a reduction in intradialytic blood volume. However, the association between changes in intradialytic hepato-splanchnic circulation and clinical factors remain unknown. Methods: We enrolled 91 hemodialysis (HD) patients (20 with intradialytic hypotension (IDH) and 71 without IDH). During HD, hepatic regional oxygen saturation (rSO2), a marker of hepatic oxygenation reflecting hepato-splanchnic circulation and oxygenation, was monitored. Changes in hepatic rSO2 at the lowest systolic blood pressure (BP) during HD were analyzed to identify associations with clinical factors. Results: Hepatic rSO2 levels were 55.8 ± 15.3% before HD and 53.8 ± 14.9% at the lowest systolic BP; therefore, % changes in hepatic rSO2 were −2.7 ± 11.3%. These values were significantly lower in patients with IDH than in those without IDH (−13.8 ± 9.3% vs 0.4 ± 9.8%, p 2 were independently associated with % changes in systolic BP (standardized coefficient: 0.416) and ultrafiltration rate (−0.206). Furthermore, % changes in mean BP (0.304) were identified as affecting % changes in hepatic rSO2 instead of those in systolic BP. Conclusions: Changes in intradialytic hepatic oxygenation is associated with ultrafiltration rate and changes in systemic BP. Further studies are required to clarify the directionality of the association between changes in hepatic oxygenation and changes in systemic BP during HD.

Because of growing demand in the aircraft industry, research is being conducted around the world to reduce CO2 emissions by electrifying aircraft. The authors are studying a non-contact hybrid aircraft brake that combines an eddy current brake and a magnetorheological fluid brake. This paper presents a basic study of braking and regenerative torque using an axial gap type eddy current brake. The result as that a maximum braking torque of 51.3 mNm was obtained with a three-phase AC power supply when the speed of the conductor disc was 2,000 rpm, the current was 3 A, and the frequency was 10 Hz in the CW direction. The maximum regenerative torque was 48 mNm when the speed of the conductor disc was 2,000 rpm, the current was 3 A, and the frequency was 10 Hz in the CCW direction.

Background: Most studies on stroke have been designed to examine one deficit in isolation; yet, survivors often have multiple deficits in different domains. While the mechanisms underlying multiple-domain deficits remain poorly understood, network-theoretical methods may open new avenues of understanding. Methods: Fifty subacute stroke patients (7±3days poststroke) underwent diffusion-weighted magnetic resonance imaging and a battery of clinical tests of motor and cognitive functions. We defined indices of impairment in strength, dexterity, and attention. We also computed imaging-based probabilistic tractography and whole-brain connectomes. To efficiently integrate inputs from different sources, brain networks rely on a rich-club of a few hub nodes. Lesions harm efficiency, particularly when they target the rich-club. Overlaying individual lesion masks onto the tractograms enabled us to split the connectomes into their affected and unaffected parts and associate them to impairment. Results: We computed efficiency of the unaffected connectome and found it was more strongly correlated to impairment in strength, dexterity, and attention than efficiency of the total connectome. The magnitude of the correlation between efficiency and impairment followed the order attention>dexterity ≈ strength (strength: | r |=.03, P =0.02, dexterity: | r |=.30, P =0.05, attention: | r |=.55, P Conclusions: Attentional impairment is more sensitive to disruption of coordinated networks between brain regions than motor impairment, which is sensitive to disruption of localized networks. Providing more accurate reflections of actually functioning parts of the network enables the incorporation of information about the impact of brain lesions on connectomics contributing to a better understanding of underlying stroke mechanisms.

Extranodal involvement predicts poor outcomes of diffuse large B cell lymphoma (DLBCL), but the impact of the metabolic tumor burden (MTV) of extranodal sites using positron emission tomography has not been clarified. This study aimed to assess the impact of extranodal MTV on overall survival (OS). We retrospectively analyzed 145 newly diagnosed DLBCL patients and verified the prognostic impact of each extranodal and nodal MTV. Multivariate Cox hazards modelling using both extranodal and nodal MTV as covariables identified extranodal MTV as a significant factor for OS (hazard ratio [HR] 1.072, 95% confidence interval [CI] 1.019–1.129, P = 0.008), but not nodal MTV. Multivariate Cox modelling using restricted cubic splines demonstrated that the impact of total MTV depends on the MTV of extranodal sites, not of nodal sites. When both the number and MTV of extranodal involvements were used as covariables, extranodal MTV remained a significant predictor of OS (HR 1.070, 95%CI 1.017–1.127, P = 0.009), but the number of extranodal sites did not. Extranodal MTV potentially had a more significant role on prognosis than nodal MTV. When considering prognostic impacts, the MTV of extranodal involvement is significantly more important than the number.

Invasive Hieracium plant species are invading the Greater Yellowstone Ecosystem. The potential distribution of orange hawkweed (Hieracium aurantiacum) and meadow hawkweed (Hieracium caespitosum) were estimated using habitat susceptibility models to assist land managers’ management of these invasive plants. The objectives of this study were to: (1) develop models describing susceptibility of ecosystems to hawkweed invasion, (2) identify indicator species of orange hawkweed and meadow hawkweed, (3) determine habitat types where these invasive hawkweeds might occur, and (4) create habitat susceptibility maps for management planning and ground surveys. Models were developed using a Mahalanobis distance similarity technique from remotely sensed biotic and abiotic variables, as well as known location data for orange and meadow hawkweed. Ground validation was conducted to assess model weaknesses and subsequent model modification. Indicator plant species were identified as surrogates to determine the likelihood of hawkweed presence during ground survey. Transect data collected from areas susceptible to invasion also were used to determine habitat types where hawkweed might occur. The best model included eight variables: north–south aspect, east–west aspect, slope, NDVI, NDWI, blue spectral band, green spectral band, and precipitation. High susceptibility (65 + % likelihood of suitable habitat) consisted of 66,000 ha for meadow hawkweed and 35,000 ha for orange hawkweed, 5.0% and 2.7% of the study area, respectively. Meadow hawkweed and orange hawkweed had seven and three indicator plant species, respectively. Predicted hawkweed habitat susceptibility encompassed nine habitat types, ranging from xeric sagebrush steppe to wet forests and they overlapped except at the xeric habitat type. Habitat susceptibility models save costs and allow survey prioritization to those areas most susceptible to invasion.

Background. Percutaneous rupture of lumbar facet cysts (LFC) is the only nonsurgical treatment which is effective in directly reducing cysts. However, this is not yet a common procedure, and its effectiveness, including the associated complications, remains unclear. Therefore, this study aimed to evaluate the clinical outcomes of percutaneous rupture for LFC and elucidate whether this minimally invasive procedure could become an alternative to surgeries for cases resistant to conservative treatments. Methods. This study investigated 57 symptomatic patients with LFC for whom conservative treatments were ineffective and underwent percutaneous rupture of the LFC. All patients were followed up for >2 years posttreatment. Clinical evaluations (visual analogue scale (VAS) and recovery rate calculated using the Japanese Orthopedic Association (JOA) scores) and radiographic evaluations (size of LFC based on magnetic resonance imaging (MRI)) were performed from pretreatment to the final follow-up examination. Results. Successful LFC rupture, without hospitalization and general anesthesia, was achieved in 48 patients. No severe complications occurred during treatment through the last observation. Satisfactory clinical results with significant improvements in the VAS and JOA scores were obtained (VAS: pre/posttreatment: 80.7 mm/11.2 mm, JOA: pre/posttreatment: 15.6 points/26.7 points, and recovery rate: 82.3%). A significant reduction in the LFC was also observed in all cases based on the posttreatment MRI findings. No successful rupture cases required subsequent surgical treatments, although four cases of LFC recurrence required additional percutaneous rupture treatment. Conclusions. Percutaneous rupture for LFC is not only a safe and minimally invasive procedure without any severe complications or requirements for hospitalization and general anesthesia but also a beneficial procedure that can eliminate the need for surgery in cases resistant to conservative treatments.

Intradialytic exercise improves physical function. However, malnutrition may be an essential factor affecting the effectiveness of exercise to improve physical function. Few studies of the relationship between malnutrition and the effectiveness of intradialytic exercise to improve physical function exist. Therefore, this study investigated malnutrition at the beginning of intradialytic exercise and how it affects the subsequent improvement in physical function.Patients who performed intradialytic exercise for 12 months were enrolled in this study. A Geriatric Nutritional Risk Index of 91.2 was defined as malnutrition. Patients were assigned to 2 groups using propensity score matching to adjust for confounding factors. Physical function outcomes were handgrip strength, isometric knee extension strength, short physical performance battery, and 10-m walking speed; these were compared at baseline, 3 months, 6 months, and 12 months. The 2 groups were further divided into another 2 groups as per whether the nutritional status had improved after 12 months; therefore, a total of 4 groups were analyzed.After matching, the data of 154 patients in each group were analyzed. During the intragroup comparison, isometric knee extension strength, short physical performance battery, and 10-m walking speed improved significantly in both groups after intradialytic exercise was started compared with before intradialytic exercise was started. However, there was no significant improvement in handgrip strength in the malnutrition group. There were no significant differences in any of the physical function measurements or changes from the baseline values among the 4 groups divided as per subsequent recovery of the nutritional status.Malnutrition may not impact the effectiveness of intradialytic exercise to improve lower-leg physical function. Its effect on the improvement of handgrip strength requires further investigation.

Identification and functional characterization of disease-associated genetic traits are crucial for understanding the pathogenesis of hematologic malignancies. Various in vitro and in vivo models, including cell lines, primary cells, and animal models, have been established to examine these genetic alterations. However, their nonphysiologic conditions, diverse genetic backgrounds, and species-specific differences often limit data interpretation. To evaluate somatic mutations in myeloproliferative neoplasms (MPNs), we used CRISPR/Cas9 combined with the piggyBac transposon system to establish isogenic induced pluripotent stem (iPS) cell lines with or without JAK2V617F mutation, a driver mutation of MPNs. We induced hematopoietic stem/progenitor cells (HSPCs) from these iPS cells and observed phenotypic differences during hematopoiesis using fluorescence-activated cell sorting analysis. HSPCs with pathogenic mutations exhibited cell-autonomous erythropoiesis and megakaryopoiesis, which are hallmarks in the bone marrow of patients with MPNs. Furthermore, we used these HSPCs as a model to validate therapeutic compounds and showed that interferon alpha selectively inhibited erythropoiesis and megakaryopoiesis in mutant HSPCs. These results demonstrate that genome editing is feasible for establishing isogenic iPS cells, studying genetic elements to understand the pathogenesis of MPNs, and evaluating therapeutic compounds against MPNs.