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In the ventricular-subventricular-zone (V-SVZ) of the postnatal mammalian brain, immature neurons (neuroblasts) are generated from neural stem cells throughout their lifetime. These V-SVZ-derived neuroblasts normally migrate to the olfactory bulb through the rostral migratory stream, differentiate into interneurons, and are integrated into the preexisting olfactory circuit. When the brain is injured, some neuroblasts initiate migration toward the lesion and attempt to repair the damaged neuronal circuitry, but their low regeneration efficiency prevents functional recovery. Elucidation of the molecular basis of neuroblast migration toward lesions is expected to lead to the development of new therapeutic strategies for brain regenerative medicine. Here, we show gene expression profiles of neuroblasts migrating in the peri-injured cortex compared with those migrating in the V-SVZ using photo-isolation chemistry, a method for spatial transcriptome analysis. Differentially expressed gene analysis showed that the expression levels of 215 genes (97 upregulated and 118 downregulated genes) were significantly different in neuroblasts migrating in the peri-injured cortex from those migrating in the V-SVZ. Gene Ontology analysis revealed that in neuroblasts migrating in the peri-injured cortex, expression of genes involved in regulating migration direction and preventing cell death was upregulated, while the expression of genes involved in cell proliferation and maintenance of the immature state was downregulated. Indeed, neuroblasts migrating in the peri-injured cortex had significantly lower Cyclin D2 mRNA and Ki67 protein expression levels than those in the V-SVZ. In the injured brain, amoeboid microglia/macrophages expressed transforming growth factor- β (TGF- β ), and neuroblasts migrating in the peri-injured cortex expressed TGF- β receptors. Experiments using primary cultured neuroblasts showed that application of TGF- β significantly decreased proliferating cells labeled with BrdU. These data suggest that the proliferative activity of neuroblasts migrating toward lesions is suppressed by TGF- β secreted from cells surrounding the lesion. This is the first comprehensive study characterizing the gene expression profiles of neuroblasts migrating in the peri-injured cortex.

Two new fungicides, flutianil and pyriofenone were introduced into the Japanese market in 2013 and 2014, to control powdery mildew on cucumber. Isolates of Podosphaera xanthii, the causal agent of powdery mildew, were collected in Ibaraki Prefecture, Japan, between 2017 and 2019 from cucumber greenhouses with a history of flutianil and pyriofenone usage. They were then tested for sensitivity to both fungicides by the leaf disc test. First, the sensitivity of three baseline reference isolates to each fungicide was determined. Minimum inhibitory concentrations values were 0.0063 μg/ml for flutianil and 10 μg/ml for pyriofenone, while 50% effective concentration (EC50) values of these fungicides were 0.00013–0.00035 μg/ml and 0.39–0.70 μg/ml, respectively. To determine the current sensitivity of P. xanthii in detail, 23 single-spore isolates were then sampled from five greenhouses and tested. Nineteen isolates showed high resistance (Flu-HR/Pyr-HR) with EC50 values of >100 μg/ml for flutianil and > 1000 μg/ml for pyriofenone. The low sensitivity of Flu-HR/Pyr-HR isolates was stable even after 46 subcultures on fungicide-untreated cotyledons. Additionally, two isolates showed moderate resistance (Flu-MR/Pyr-MR) to flutianil (EC50: mean 0.8 μg/ml) and pyriofenone (mean 58.7 μg/ml). The results from foliar inoculation tests on potted cucumber plants confirmed low efficacies of flutianil and pyriofenone against resistant isolates. Among a total of 122 isolates sampled from 13 greenhouses, 89 isolates (73.0%) were categorized as Flu-HR/Pyr-HR and two isolates (1.6%) as Flu-MR/Pyr-MR. This is the first report on flutianil resistance in any pathogen.

Objective Heart failure (HF) is a common and highly morbid cardiovascular disorder. Oxidative stress worsens HF, and uric acid (UA) is a useful oxidative stress marker. The novel anti-hyperuricemic drug febuxostat is a potent non-purine selective xanthine oxidase inhibitor. The present study examined the UA-lowering and prognostic effects of febuxostat in patients with HF compared with conventional allopurinol. Methods This multicenter, randomized trial included 263 patients with chronic HF who were randomly assigned to two groups and received allopurinol or febuxostat (UA >7.0 mg/dL). All patients were followed up for 3 years after enrollment. Results There were no significant differences in baseline clinical characteristics between the two groups. The UA level was significantly decreased after 3 years of drug administration compared with the baseline in both groups. Urine levels of the oxidative stress marker 8-hydroxy-2′-deoxyguanosine were lower in the febuxostat group than in the allopurinol group (11.0 ± 9.6 vs. 22.9 ± 15.9 ng/mL), and the rate of patients free from hospitalization due to worsening HF tended to be higher in the febuxostat group than in the allopurinol group (89.0% vs. 83.0%). Conclusions Febuxostat is potentially more effective than allopurinol for treating patients with chronic HF and hyperuricemia. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/; ID: 000009817).

Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro , and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.

Background: When integrating visual and somatosensory processing into the subjective postural vertical using the Romberg test, patients with hemiplegic can be sorted into either post-stroke or pushers with unilateral spatial neglect (USN). This study aimed to clarify the characteristics of the integrated processing of the integrated subjective postural vertical (ISPV) with open or closed eyes in patients with hemiplegic and/or pusher with USN. Methods: This cross-sectional study included 91 patients with hemiplegic and 45 with pusher and USN. The outcomes included the ratio and sum of SPV with the eyes closed and open. Statistical analyses were performed using the parametric and/or non-parametric Wilcoxon rank-sum test, Mann–Whitney U test, or chi-square test after the Shapiro–Wilk test. Results: The outcomes in the 91 patients with hemiplegic were as follows: moderate-to-severe ISPV with ratio, 1.64°; ISPV sum (ISPVS), 9.41°. The outcomes in the 45 patients with pusher and USN were as follows: moderate-to-severe, ISPV: 1.35°, and ISPVS: 13.96°. No significant differences were observed between the two groups in terms of demographic data or ISPV. However, the number of patients with pusher syndrome was significantly higher in the ISPVS group than in stroke patients with hemiplegic. Conclusions: Adaptation occurs by integrating sensory modalities, and the pusher behavior in patients with USN is characterized by the specific pathophysiology of a two-modality disorder with visual and somatosensory deficits. This study provides key insights into the pathophysiological characteristics of patients with pusher syndrome and USN.

This study aimed to perform a comparative analysis of postoperative results between lumbar degenerative spondylolisthesis (LDS) treated with oblique lateral interbody fusion (OLIF) and transforaminal lumbar interbody fusion (TLIF) from the Chiba spine surgery registry database. Sixty-five patients who underwent single-level OLIF (O group) for LDS with ≥ 3 years’ follow-up were retrospectively reviewed. The control group comprised 78 patients who underwent single-level TLIF (T group). The analyzed variables included global alignment, radiological parameters of fused segments, asymptomatic and symptomatic ASD incidence, clinical outcomes at 3 years postoperatively using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire data, visual analogue scale scores for low back pain, lower extremity pain, and lower extremity numbness. There was no significant change in global alignment between the two groups. The rate of improvement in anterior intervertebral disc height was not significantly different between the groups at 1-month postoperatively. However, at the final evaluation, the anterior intervertebral disc height and incidence of asymptomatic ASD were significantly higher in the O group. There was no significant difference in symptomatic ASD, reoperation cases, or clinical results between groups. Thus, single-level OLIF can maintain the corrected disc height, but as it has no effect on global alignment, its benefit is limited.

Throughout life, new neurons generated in the ventricular–subventricular zone take the long journey to the olfactory bulb. The intracellular mechanisms that precisely control the neurons’ migration speed, enabling their well-organized movement, remain unclear. Rho signalling is known to affect the morphology and movement of various cell types, including neurons. Here we identify Gem-interacting protein (Gmip), a RhoA-specific GTPase-activating protein, as a key factor in saltatory neuronal migration. RhoA is activated at the proximal leading process of migrating neurons, where Gmip is also localized and negatively regulates RhoA. Gmip controls the saltatory movement of neurons that regulate their migration speed and ‘stop’ positions in the olfactory bulb, thereby altering the neural circuitry. This study demonstrates that Gmip serves as a brake for the RhoA-mediated movement of neuronal somata, and highlights the significance of speed control in the well-organized neuronal migration and the maintenance of neuronal circuits in the postnatal brain. In the postnatal mouse brain, RhoA signalling regulates the saltatory movement of new neurons migrating from the ventricular–subventricular zone to the olfactory bulb. Here the authors show that a RhoA-specific GTPase-activating protein, Gmip, serves as a brake for RhoA-mediated saltatory movement of new neurons during migration.

The objective of this study is to enhance the inhibition of ice growth in the aqueous solution of a polypeptide, which is inspired by winter flounder antifreeze protein. We carried out measurements on unidirectional freezing of the polypeptide solution. The thickness of the solution was 0.02 mm, and the concentration of polypeptide was varied from 0 to 2 mg/mL. We captured successive microscopic images of ice/solution interfaces, and measured the interface velocity from the locations of tips of the pectinate interface in the images. We also simultaneously measured the temperature by using a small thermocouple. The ice/solution interface temperature was defined by the temperature at the tips. It was found that the interface temperature was decreased with an increasing concentration of polypeptide. To try varying the activity of the polypeptide, we preheated the polypeptide solution and cooled it before carrying out the measurements. Preheating for 1-5 hours was found to cause a further decrease in the interface temperature. Furthermore, wider regions of solution and ice with inclined interfaces in the pectinate interface structure were observed, compared with the case where the solution was not preheated. Thus, the ice growth inhibition was enhanced by this preheating. To investigate the reason for this enhancement, we measured the conformation and aggregates of polypeptide in the solution. We also measured the local concentration of polypeptide. It was found that the polypeptide aggregates became larger as a result of preheating, although the polypeptide conformation was unchanged. These large aggregates caused both adsorption to the interface and the wide regions of supercooled solution in the pectinate interface structure.

Introduction Clarifications regarding the recovery process of the subjective postural vertical (SPV) and activities of daily living in stroke patients are required to help clinicians determine treatment plans. Therefore, we aimed to investigate the characteristics of the longitudinal recovery process of SPV and activities of daily living after stroke. Methods Overall, 109 patients with stroke were enrolled. Clinical assessments included the SPV and total functional independence measure (FIM), initially and after 1 month. The mean and standard deviation of SPV indicated the directional and variability errors, respectively. Participants were categorized as follows: nondeviation group comprised directional and variability errors within the standard values, deviation of variability errors group comprised directional errors within the standard value and variability errors greater than the standard value, and deviation of both directional and variability errors group comprised directional and variability errors greater than the standard values. In addition, a two‐way analysis of variance was performed for initial pre‐ and post‐SPV, and pre‐ and posttotal FIM scores (p < .05). Results The deviation of variability errors group, and deviation of both directional and variability errors group, had larger SPV variability errors than did the nondeviation group. Furthermore, the deviation of variability errors group showed a significant improvement in variability errors after 1 month. There was a correlation between the initial SPV with eyes opened variability error and total FIM after 1 month in Pusher patients with unilateral spatial neglect in the deviation of both directional and variability errors group. Conclusions SPV with eyes opened variability errors and initial FIM score may influence the independence of activities of daily living after 1 month in the recovery of patients with stroke with Pusher and unilateral spatial neglect.  

Background According to most of the commonly used classification systems for subaxial spine injuries, unilateral and minimally displaced facet fractures without any sign of a spinal cord injury would be directed to non-operative management. However, the failure rate of non-operative treatment varies from 20 to 80%, and no consensus exists with regard to predictors of failure after non-operative management. Case presentation Case 1 is a patient with a unilateral facet fracture. The patient had only numbness in the right C6 dermatome but failed non-operative treatment, which resulted in severe spinal cord injury. Case 2 is a patient who had a similar injury pattern as case 1 but presented with immediate instability and underwent fusion surgery. Both patients had a minimally displaced unilateral facet fracture accompanied by disc injury and blunt vertebral artery injury, which are possible signs indicating significant instability. Conclusions This is the first report of an isolated unilateral facet fracture that resulted in catastrophic spinal cord injury. These two cases illustrate that an isolated minimally displaced unilateral facet fracture with disc injury and vertebral artery injury were associated with significant instability that can lead to spinal cord injury.