A septin requirement differentiates autonomous and contact-facilitated T cell proliferation.

T cell proliferation is initiated by T cell antigen receptor (TCR) triggering, soluble growth factors or both. In characterizing T cells lacking the septin cytoskeleton, we found that successful cell division has discrete septin-dependent and septin-independent pathways. Septin-deficient T cells failed to complete cytokinesis when prompted by pharmacological activation or cytokines. In contrast, cell division was not dependent on septins when cell-cell contacts, such as those with antigen-presenting cells, provided a niche. This septin-independent pathway was mediated by phosphatidylinositol-3-OH kinase activation through a combination of integrins and costimulatory signals. We were able to differentiate between cytokine- and antigen-driven expansion in vivo and thus show that targeting septins has strong potential to moderate detrimental bystander or homeostatic cytokine-driven proliferation without influencing expansion driven by conventional antigen-presentation.

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory.

Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundant in tumor tissues. Here, hypothesizing that tumor Tregs would clonally expand after they are activated by tumor-associated antigens to suppress antitumor immune responses, we performed single-cell analysis on tumor Tregs to characterize them by T cell receptor clonotype and gene-expression profiles. We found that multiclonal Tregs present in tumor tissues predominantly expressed the chemokine receptor CCR8. In mice and humans, CCR8+ Tregs constituted 30 to 80% of tumor Tregs in various cancers and less than 10% of Tregs in other tissues, whereas most tumor-infiltrating conventional T cells (Tconvs) were CCR8- CCR8+ tumor Tregs were highly differentiated and functionally stable. Administration of cell-depleting anti-CCR8 monoclonal antibodies (mAbs) indeed selectively eliminated multiclonal tumor Tregs, leading to cure of established tumors in mice. The treatment resulted in the expansion of CD8+ effector Tconvs, including tumor antigen-specific ones, that were more activated and less exhausted than those induced by PD-1 immune checkpoint blockade. Anti-CCR8 mAb treatment also evoked strong secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that elimination of tumor-reactive multiclonal Tregs was sufficient to induce memory-type tumor-specific effector Tconvs. Despite induction of such potent tumor immunity, anti-CCR8 mAb treatment elicited minimal autoimmunity in mice, contrasting with systemic Treg depletion, which eradicated tumors but induced severe autoimmune disease. Thus, specific removal of clonally expanding Tregs in tumor tissues for a limited period by cell-depleting anti-CCR8 mAb treatment can generate potent tumor immunity with long-lasting memory and without deleterious autoimmunity.

The ectoenzyme E-NPP3 negatively regulates ATP-dependent chronic allergic responses by basophils and mast cells.

Crosslinking of the immunoglobulin receptor FcεRI activates basophils and mast cells to induce immediate and chronic allergic inflammation. However, it remains unclear how the chronic allergic inflammation is regulated. Here, we showed that ecto-nucleotide pyrophosphatase-phosphodiesterase 3 (E-NPP3), also known as CD203c, rapidly induced by FcεRI crosslinking, negatively regulated chronic allergic inflammation. Basophil and mast cell numbers increased in Enpp3(-/-) mice with augmented serum ATP concentrations. Enpp3(-/-) mice were highly sensitive to chronic allergic pathologies, which was reduced by ATP blockade. FcεRI crosslinking induced ATP secretion from basophils and mast cells, and ATP activated both cells. ATP clearance was impaired in Enpp3(-/-) cells. Enpp3(-/-)P2rx7(-/-) mice showed decreased responses to FcεRI crosslinking. Thus, ATP released by FcεRI crosslinking stimulates basophils and mast cells for further activation causing allergic inflammation. E-NPP3 decreases ATP concentration and suppresses basophil and mast cell activity.

Expression Analyses of Rich2/Arhgap44, a Rho Family GTPase-Activating Protein, during Mouse Brain Development.

Rho family small GTPases, such as Rho, Rac, and Cdc42, play essential roles during brain development, by regulating cellular signaling and actin cytoskeletal reorganization. Rich2/Arhgap44, a Rac- and Cdc42-specific GTPase-activating protein, has been reported to be a key regulator for dendritic spine morphology and synaptic function. Given the essential roles of Rac and Cdc42 in brain development, Rich2 is supposed to take part in brain development. However, not only the molecular mechanism involved but also the expression profile of Rich2 during neurodevelopment has not yet been elucidated. In this study, we carried out expression analyses of Rich2 by focusing on mouse brain development. In immunoblotting, Rich2 exhibited a tissue-dependent expression profile in the young adult mouse, and the expression was increased during brain development. In immunohistochemical analyses, Rich2 was observed in the cytoplasm of cortical neurons at postnatal day (P) 0 and then came to be enriched in the nucleus with moderate distribution in neuropils at P7. Later at P30, a complex immunostaining pattern of Rich2 was observed; Rich2 was distributed in the nucleus, cytoplasm, and neuropils in many cortical neurons, whereas other neurons frequently displayed little expression. In the hippocampus at P7, Rich2 was distributed mainly in the cytoplasm of excitatory neurons in the cornu ammonis regions, while it was moderately detected in the nucleus in the dentate granule cells. Notably, Rich2 was distributed in excitatory synapses of the cornu ammonis 1 region at P30. Biochemical fractionation analyses also detected Rich2 in the postsynaptic density. Taken together, Rich2 is found to be expressed in the central nervous system in a developmental stage-dependent manner and may be involved in synapse formation/maintenance in cortical neurons.

Importance of the relative epicardial connection locations and right-sided pulmonary vein isolation line for successful pulmonary vein isolation.

INTRODUCTION: The presence of an epicardial connection (EC) decreases the success rate of pulmonary vein isolation (PVI); however, the effect of designing isolation lines has not been evaluated. We sought to clarify the effects of designing an anterior line for right-sided PVI considering the presence and location of the EC. METHODS: Seventy-four consecutive patients who underwent initial catheter ablation for atrial fibrillation were retrospectively included in this study. The presence of the EC was determined by the left atrial (LA) activation map during right atrial pacing, and patients were divided into EC-positive (n = 23, 31%) and EC-negative (n = 51, 69%) groups. EC-positive patients were further subdivided based on the EC location: on-the-line group, (EC on the PVI line, n = 11); inside-line group (EC on the pulmonary vein [PV] side, n = 10); and outside-line group (EC on the LA side, n = 2). The PVI parameters were compared among the three groups. RESULTS: The success rates of the first-pass isolation were comparable between the EC-negative and EC-positive groups (70.6% vs. 60.9%, ns), but the success rate was significantly higher in the on-the-line group than in the inside-line group (91% vs. 20%, p = 0.002). First-pass isolation was successful in both patients in the outside-line group. Additional carina ablation was required only in the inside-line group. CONCLUSIONS: The association between the EC site and the right-sided PV anterior isolation line affected the success rate of first-pass isolation. For successful right-sided PVI, it is important to consider the EC site when designing the PVI line.

The Safety and Strategies for Reinitiating Electroconvulsive Therapy After ECT-Induced Takotsubo Cardiomyopathy: A Case Report and Systematic Review.

OBJECTIVES: Takotsubo cardiomyopathy (TCM) is a life-threatening complication of electroconvulsive therapy (ECT). We report the case of a 66-year-old woman who was rechallenged with ECT after ECT-induced TCM. Moreover, we have made a systematic review to assess the safety of and strategies for reinitiating ECT after TCM. METHODS: We searched for published reports on ECT-induced TCM since 1990 in MEDLINE (PubMed), Scopus, Cochrane Library, ICHUSHI, and CiNii Research. RESULTS: A total of 24 ECT-induced TCM cases were identified. Patients who developed ECT-induced TCM were predominantly middle-aged and older women. There was no specific trend in anesthetic agents used. Seventeen (70.8%) cases developed TCM by the third session in the acute ECT course. Eight (33.3%) cases developed ECT-induced TCM despite the use of ß-blockers. Ten (41.7%) cases developed cardiogenic shock or abnormal vital signs related to cardiogenic shock. All cases recovered from TCM. Eight (33.3%) cases tried to receive ECT retrial. The duration until ECT retrial was between 3 weeks and 9 months. The most common preventive measures during ECT retrial were related to ß-blockers; however, the type, dose, and route of administration of ß-blockers varied. In all cases, ECT could be reperformed without TCM recurrence. CONCLUSIONS: Electroconvulsive therapy-induced TCM is more likely to cause cardiogenic shock than nonperioperative cases; nevertheless, it has good prognosis. Cautious reinitiation of ECT after TCM recovery is possible. Further studies are required to determine preventive measures for ECT-induced TCM.

[Staged Hybrid Repair of Extensive Thoracic Aortic Aneurysm with Right Aortic Arch and Isolated Left Subclavian Artery:Report of a Case].

A 69-year-old male was referred to our hospital due to extensive thoracic aortic aneurysm with right aortic arch and isolated left subclavian artery. We chose staged hybrid repair to avoid the risk of spinal cord injury and bilateral recurrent nerve paralysis. First, ascending aorta replacement with elephant trunk and reconstruction of the cervical branches were underwent. Second, we performed the thoracic endovascular aortic repair for aortic arch and descending aortic aneurysm. The postoperative course was satisfactory and, computed tomography (CT) showed successful aortic repair without any type of endoleak. He was discharged on the ninth day after the second operation. To our knowledge, this is the first report of surgical repair for an aortic aneurysm with right aortic arch and isolated subclavian artery.

Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease.

OBJECTIVE: The relationship between autoimmune diseases and the gut microbiome has been intensively studied, and several autoimmunity-associated bacterial taxa have been identified. However, much less is known about the roles of the gut virome in autoimmune diseases. METHODS: Here, we performed a whole gut virome analysis based on the shotgun sequencing of 476 Japanese which included patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis and healthy control subjects. RESULTS: Our case-control comparison of the viral abundance revealed that crAss-like phages, which are one of the main components of a healthy gut virome, significantly decreased in the gut of the patients with autoimmune disease, specifically the patients with RA and SLE. In addition, Podoviridae significantly decreased in the gut of the patients with SLE. To understand how these viruses affected the bacteriome, we performed a quantitative virus-bacterium association analysis and clustered regularly interspaced short palindromic repeat-based virus-bacterium interaction analysis. We identified a symbiosis between Podoviridae and Faecalibacterium. In addition, multiple bacterial targets of crAss-like phages were identified (eg, Ruminococcus spp). CONCLUSION: Our data suggest that the gut virome can affect our body either directly or via bacteria. Our analyses have elucidated a previously missing part of the autoimmunity-associated gut microbiome and presented new candidates that contribute to the development of autoimmune diseases.

Comparison of Cryoballoon and Contact Force-Sensing Radiofrequency Ablation for Persistent Atrial Fibrillation in Clinical Practice.

BACKGROUND: Outcomes of cryoballoon ablation for persistent atrial fibrillation (AF) are unclear, especially in Japanese patients, so the effectiveness and safety of cryoballoon ablation in clinical practice were retrospectively compared with those of contact force-sensing radiofrequency (CFRF) ablation including the high-power protocol.Methods and Results:Consecutive patients with persistent AF were reviewed, and 253 and 265 patients who underwent cryoballoon and CFRF ablation, respectively, were enrolled. The primary endpoint was atrial arrhythmia recurrence. The secondary endpoints were periprocedural complications and repeat ablation. The rate of additional left atrial (LA) ablation after pulmonary vein isolation (PVI) was similar between groups (68.8% cryoballoon vs. 74.0% CFRF, P=0.19). Freedom from atrial arrhythmia recurrence was comparable between groups over a follow-up of 25.5±12.5 months (72.3% cryoballoon vs. 69.8% CFRF; adjusted hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.59-1.21, P=0.36). Outcomes were similar in the subgroups of PVI alone and PVI plus additional LA ablation. LA posterior wall isolation, absence of defragmentation, and low creatine clearance, but not catheter selection, were associated with the primary endpoint. Periprocedural complications (adjusted HR 0.73, 95% CI 0.34-1.54, P=0.41) and repeat ablation (adjusted HR 1.11, 95% CI 0.71-1.74, P=0.64) were similar for both procedures. CONCLUSIONS: Cryoballoon ablation for persistent AF in Japanese clinical practice had acceptable outcomes comparable to those of advanced CFRF ablation.

Clinical features and prognosis of patients with and without diabetes mellitus undergoing endovascular aortic aneurysm repair.

BACKGROUND: This study aimed to compare the clinical features and prognoses of patients with and without diabetes mellitus (DM) who underwent endovascular repair for aortic aneurysm (AA). METHODS: We analyzed the clinical database of a prospective multicenter study, registering 929 patients who underwent their first endovascular AA repair in Japan between January 2016 and June 2018. The baseline characteristics and prognoses (including all-cause mortality and cardiovascular events) after repair were compared between the DM and non-DM groups. Prognoses were also compared between the groups after propensity score matching. RESULTS: In total, 226 patients (24.3%) had DM. Compared with non-DM patients, DM patients had higher pack-years of smoking (P = 0.011), higher body mass index (P = 0.009), lower high-density lipoprotein cholesterol levels (P = 0.038), higher triglyceride levels (P = 0.025), and lower left ventricular ejection fraction (P = 0.005). Meanwhile, the low-density lipoprotein cholesterol and blood pressure levels showed no significant intergroup difference (all P > 0.05). DM patients had a higher prevalence of myocardial infarction (P = 0.016), history of coronary revascularization (P = 0.015), and lower extremity artery disease (P = 0.019). Lesion characteristics and procedures were similar between the groups (all P > 0.05). DM patients had a higher risk of all-cause mortality and cardiovascular events than non-DM patients (both P < 0.001). Subsequent propensity score matching also demonstrated that DM patients had a significantly lower rate of overall survival (P = 0.001) and freedom from cardiovascular events (P = 0.010). The Kaplan-Meier estimates at 1 year for the overall survival were 85.6% (95% confidence interval [CI], 80.9% to 90.5%) and 94.3% (95% CI, 91.7% to 97.0%) for patients with and without DM, respectively. The corresponding estimates for freedom from cardiovascular events were 79.8% (95% CI, 74.5% to 85.5%) and 87.7% (95% CI, 84.2% to 91.3%), respectively. CONCLUSIONS: Among patients undergoing endovascular AA repair, those with DM had more cardiovascular risk factors. DM patients had a higher incidence rate of all-cause mortality and cardiovascular events. Matching analysis indicated that DM per se would be a risk factor for poor prognoses after AA repair.

Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia.

Colonic epithelial cells are covered by thick inner and outer mucus layers. The inner mucus layer is free of commensal microbiota, which contributes to the maintenance of gut homeostasis. In the small intestine, molecules critical for prevention of bacterial invasion into epithelia such as Paneth-cell-derived anti-microbial peptides and regenerating islet-derived 3 (RegIII) family proteins have been identified. Although there are mucus layers providing physical barriers against the large number of microbiota present in the large intestine, the mechanisms that separate bacteria and colonic epithelia are not fully elucidated. Here we show that Ly6/PLAUR domain containing 8 (Lypd8) protein prevents flagellated microbiota invading the colonic epithelia in mice. Lypd8, selectively expressed in epithelial cells at the uppermost layer of the large intestinal gland, was secreted into the lumen and bound flagellated bacteria including Proteus mirabilis. In the absence of Lypd8, bacteria were present in the inner mucus layer and many flagellated bacteria invaded epithelia. Lypd8(-/-) mice were highly sensitive to intestinal inflammation induced by dextran sulfate sodium (DSS). Antibiotic elimination of Gram-negative flagellated bacteria restored the bacterial-free state of the inner mucus layer and ameliorated DSS-induced intestinal inflammation in Lypd8(-/-) mice. Lypd8 bound to flagella and suppressed motility of flagellated bacteria. Thus, Lypd8 mediates segregation of intestinal bacteria and epithelial cells in the colon to preserve intestinal homeostasis.

Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Focal Intimal Disruption Size at Multidetector CT and Disease Progression in Type B Aortic Intramural Hematoma.

Background Recent imaging techniques show that patients with aortic intramural hematoma (IMH) have various sizes of focal intimal disruptions (FIDs) that may affect clinical outcomes. Purpose To evaluate the relationship between size of FIDs detected at multidetector CT and disease progression in patients with type B IMH. Materials and Methods This retrospective study analyzed consecutive patients with type B IMH who underwent multidetector CT at admission within 24 hours after symptom onset from January 2011 to March 2017. FID was defined as a focal contrast material-filled pouch projecting outside of the aorta lumen with a communicating orifice greater than 3 mm. Large FID was defined as an FID of at least 10 mm in length and width and at least 5 mm in depth. Aorta-related events were defined as a composite of aortic rupture, surgical or endovascular aortic repair, progressive aortic enlargement, and development of aortic dissection. Results Seventy-six patients (mean age, 72 years ± 11 [standard deviation]; 54 men) were evaluated. Fifty patients (66%; 50 of 76) had 91 FIDs. Twenty-eight patients had large FIDs and 22 patients had small FIDs. Aorta-related events occurred in 15 of 28 patients with large FIDs, two of 22 patients with small FIDs, and four of 26 patients with no FID. Patients with large FIDs showed lower aorta-related event-free survival rates than did patients with small FIDs or no FID (small FIDS, 63% ± 10 vs 90% ± 7 at 3 years, respectively [P = .001]; and no FIDS, 63% ± 10 vs 84% ± 7 at 3 years, respectively [P = .005]). Multivariable analysis showed that a maximum aortic diameter of at least 40 mm (hazard ratio, 4.8; 95% CI: 1.8, 12.6; P = .001) and large FID (hazard ratio, 3.2; 95% CI: 1.1, 8.9; P = .03) were the independent predictors of aorta-related events. Conclusion A large portion of patients with B-intramural hematoma (IMH) had focal intimal disruption (FID) detected at CT at admission. Large FIDs were associated with disease progression of IMH. © RSNA, 2021 See also the editorial by Raptis and Braverman in this issue. Online supplemental material is available for this article.

Anti-AQP4 autoantibodies promote ATP release from astrocytes and induce mechanical pain in rats.

BACKGROUND: Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain. METHODS: We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases. RESULTS: Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. CONCLUSION: Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.

Cervical Vestibular Evoked Myogenic Potentials That Are Absent at 500 Hz But Present at 1000 Hz Are Characteristic of Endolymphatic Hydrops-Related Disease.

OBJECTIVES: It remains unclear whether the dominance of 1000 Hz responses over responses at 500 Hz in cervical vestibular evoked myogenic potentials (cVEMPs) are characteristic of endolymphatic hydrops (EH), due to the presence of patients with absent responses at both frequencies. The purpose of the present study is to examine whether the dominant cVEMP responses at 1000 Hz over 500 Hz are characteristic findings of EH-related diseases among patients who show various cVEMP findings. DESIGN: We retrospectively reviewed the medical records of 470 consecutive patients who underwent cVEMP testing with short-tone bursts at both 500 Hz and 1000 Hz. We categorized the cVEMP responses of these 470 patients into the following five groups: (group 1) present responses at both frequencies bilaterally, (group 2) present responses at 500 Hz but absent at 1000 Hz on at least one side, (group 3) absent responses at 500 Hz but present at 1000 Hz on at least one side, (group 4) absent responses at both frequencies on one side and present at both frequencies on the other side, and (group 5) absent responses at both frequencies bilaterally. We compared the proportion of EH-related diseases between each group and the other four groups and then investigated any increased or decreased disease incidence in each group. RESULTS: In group 3, the proportion of EH-related disease was significantly higher (p < 0.01), and the incidence of an EH-related disease was greatly increased (standard residual value > 3). CONCLUSIONS: cVEMPs that are absent at 500 Hz and present at 1000 Hz may be characteristic of EH-related disease.

PCP-dependent transcellular regulation of actomyosin oscillation facilitates convergent extension of vertebrate tissue.

Oscillatory flows of actomyosin play a key role in the migration of single cells in culture and in collective cell movements in Drosophila embryos. In vertebrate embryos undergoing convergent extension (CE), the Planar Cell Polarity (PCP) pathway drives the elongation of the body axis and shapes the central nervous system, and mutations of the PCP genes predispose humans to various malformations including neural tube defects. However, the spatiotemporal patterns of oscillatory actomyosin contractions during vertebrate CE and how they are controlled by the PCP signaling remain unknown. Here, we address these outstanding issues using a combination of in vivo imaging and mathematical modeling. We find that effective execution of CE requires alternative oscillations of cortical actomyosin across cell membranes of neighboring cells within an optimal frequency range. Intriguingly, temporal and spatial clustering of the core PCP protein Prickle 2 (Pk2) is correlated to submembranous accumulations of F-actin, and depletion of Pk2 perturbs the oscillation of actomyosin contractions. These findings shed light on the significance of temporal regulation of actomyosin contraction by the PCP pathway during CE, in addition to its well-studied spatial aspects.

Septin-dependent remodeling of cortical microtubule drives cell reshaping during epithelial wound healing.

Wounds in embryos heal rapidly through contraction of the wound edges. Despite well-recognized significance of the actomyosin purse string for wound closure, roles for other cytoskeletal components are largely unknown. Here, we report that the septin cytoskeleton cooperates with actomyosin and microtubules to coordinate circumferential contraction of the wound margin and concentric elongation of wound-proximal cells in Xenopus laevis embryos. Microtubules reoriented radially, forming bundles along lateral cell cortices in elongating wound-proximal cells. Depletion of septin 7 (Sept7) slowed wound closure by attenuating the wound edge contraction and cell elongation. ROCK/Rho-kinase inhibitor-mediated suppression of actomyosin contractility enhanced the Sept7 phenotype, whereas the Sept7 depletion did not affect the accumulation of actomyosin at the wound edge. The cortical microtubule bundles were reduced in wound-proximal cells in Sept7 knockdown (Sept7-KD) embryos, but forced bundling of microtubules mediated by the microtubule-stabilizing protein Map7 did not rescue the Sept7-KD phenotype. Nocodazole-mediated microtubule depolymerization enhanced the Sept7-KD phenotype, suggesting that Sept7 is required for microtubule reorganization during cell elongation. Our findings indicate that septins are required for the rapid wound closure by facilitating cortical microtubule reorganization and the concentric elongation of surrounding cells.

Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase.

BACKGROUND: Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS. METHODS: We adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-ß (n = 38) in all of relapsing-remitting multiple sclerosis (RRMS) patients enrolled in this study. RESULTS: Sema4A KO recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a significant reduction in the clinical score compared to the WT recipient mice. However, Sema4A KO recipient mice showed similar disease activity to the WT recipient mice when transferred with Th1-skewed encephalitogenic T cells. Bone marrow chimeric study indicated that Sema4A expressed on hematopoietic cells, but not the CNS resident cells, are responsible for augmenting Th17-mediated neuroinflammation. Additionally, in contrast to comparable IFN-γ levels, IL-17A is significantly higher in RRMS patients with high Sema4A level than those with low Sema4A patients with high Sema4A levels showed earlier disease onset, more severe disease activity and IFN-ß unresponsiveness than those with low Sema4A levels. CONCLUSIONS: Sema4A is involved not only in the Th cell priming but also in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase, which could contribute to the higher disease activity observed in RRMS patients with high serum Sema4A levels.

Association between serum folate levels and schizophrenia based on sex.

AIM: Sex differences in serum folate concentrations are well known, but no studies have investigated the association between serum folate levels and schizophrenia based on sex. With this study in a Japanese population, we examined the difference in serum folate levels between patients with schizophrenia and non-psychiatric controls stratified by sex. The relations among serum folate levels, plasma total homocysteine (tHcy), and serum vitamin B6 (pyridoxal) levels were also examined using data from our previous studies. METHODS: The serum folate concentrations of 482 patients diagnosed with schizophrenia and 1350 non-psychiatric control subjects were measured. We conducted an analysis of covariance to examine the differences in serum folate levels between the two groups based on sex. Spearman's rank correlation was used to evaluate the relations among folate, tHcy, and vitamin B6 levels. RESULTS: In the control group, serum folate concentrations were higher in women than in men. Lower levels of serum folate were observed in both male and female patients with schizophrenia. An inverse correlation between serum folate and plasma tHcy and a weak positive correlation between serum folate and vitamin B6 were observed in the combined cohort. CONCLUSION: Our findings suggest that: (i) a low serum folate level may be associated with schizophrenia regardless of sex; and (ii) folate administration may be beneficial for the treatment of schizophrenia. In schizophrenic patients with low serum folate levels, folate administration might result in improvements in high tHcy and an increase in low vitamin B6 levels.