Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. ...Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.
Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) ...and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)–dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain–like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine ...implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS.
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•Caspase-8 activation is defective in pathological samples from MS patients•Insoluble aggregates of RIPK1 and RIPK3 form in human MS cortical lesions•The RIPK1 kinase inhibitor 7N-1 blocks demyelination induced by cuprizone and EAE
Using both animal models and human tissue, Ofengeim et al. provide evidence for the involvement of RIPK1 and necroptosis in mediating the deleterious processes in multiple sclerosis (MS) and provide a link between this disease and other neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Objectives To evaluate the outcome of ketogenic diets (KDs) in patients with glucose transport type 1 deficiency syndrome (GLUT1DS) in Japan. Methods A nationwide survey for GLUT1DS was ...conducted by sending questionnaires to board-certified pediatric neurologists nationwide to obtain clinical and laboratory data. Results Among 39 patients whose diagnosis was confirmed molecularly or by the 3- O -methylglucose uptake assay, 31 were treated with KDs for longer than 1 month. Seventeen patients (55%) were on the modified Atkins diet, 11 (35%) were on the classic KD, and 3 were on the medium-chain triglyceride (MCT) diet. The median values and ranges of serum β-hydroxybutyrate levels in patients on the modified Atkins diet, classic KD and MCT diet were 2.5 mM (0.75–4.1), 1.7 mM (0.23–3.5) and 2.6 mM (1.5–3.0), respectively. The KDs were effective on seizures (80%), aggravation after fasting (80%) and ataxia (79%). Thus, ataxia was as responsive as seizures. Two patients on the classic KD with a ketogenic ratio as low as 1:1 showed improvement in neurological symptoms. The development or intelligence quotient measured using the same psychological scales before and after the KDs in 9 patients did not show a significant improvement; the median quotients before and after the diets were 40 (12–91) and 46 (12–67). Conclusion The KDs were most effective on seizures, transient aggravation after fasting and ataxia. The efficacy on intellectual development was equivocal. The modified Atkins diet was more commonly used for GLUT1DS in this study, and its ketogenicity was equivalent to the classic KD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The study aimed to investigate the role of molecular analysis of SLC2A1 in the diagnostic workup of glucose transporter 1 deficiency syndrome (Glut1DS). During 2006–2020, we received 100 requests for ...SLC2A1 variant analysis of patients clinically suspected for Glut1DS. Pathogenic variants were detected in 37 patients, among whom 11 were familial cases. Most patients presented with epilepsy (n = 31; 84%), movement disorders (MD) (n = 28; 76%), and intellectual disabilities (ID) (n = 29; 78%). Moreover, paroxysmal dyskinesias (PD) (n = 10; 27%) were more frequently seen in familial cases (55%) than in sporadic cases (15%) (p < .05). The Glut1DS patients with ID typically had either epilepsy or MD. The presence of MD, particularly when associated with epilepsy or ID, indicated Glut1DS (p < .05). The cerebrospinal fluid (CSF) glucose levels were at or below the 10th percentile in all 32 SLC2A1-positive patients but only in 16 of 52 (31%) SLC2A1-negative patients (p < .05). Thus, CSF analysis is an essential tool in the diagnostic workup of Glut1DS. SLC2A1 molecular analysis should be performed in patients with a family history of Glut1DS or with at least one of the following clinical features, such as epilepsy, MD, and PD with or without ID, and low CSF glucose level. This would help in precise molecular diagnosis of the disease and facilitate effective treatment and appropriate genetic counseling.
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•There is a phenotypic overlap between Glut1DS and other neurological diseases.•Movement disorders were associated with epilepsy or intellectual disabilities.•CSF analysis is an essential tool in the diagnostic workup of Glut1DS.•All SLC2A1-positive patients displayed hypoglycorrhachia.•Absence of SLC2A1 variants does not exclude Glut1DS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
As mindfulness practices become mainstream, it is increasingly common for participants in mindfulness-based interventions (MBI) to have previous meditation experience. The primary aim of ...this study was to assess whether the impacts of a mindfulness-based stress reduction (MBSR) program on a variety of self-report measures differed for novice meditators (NM) and regular meditators (RM).
Methods
A total of 158 Japanese participants in 10 cohorts completed questionnaires before and after an 8-week community-based MBSR program. The questionnaire consisted of Five Facet Mindfulness Questionnaire (FFMQ), Self-Compassion Scale (SCS), Total Mood Disturbance (TMD) from Profile of Mood States 2, Mental Component Summary (MCS) and Physical Component Summary (PCS) of the 12-Item Short Form Health Survey (2nd version), and Perceived Stress Scale (PSS). Baseline scores and pre-post change scores were compared for RM (participants who had reported meditating ≥ 45 min/week prior to MBSR) and NM (< 45 min/week).
Results
At baseline, RM (38.0% of the sample) had significantly higher scores than NM on FFMQ, SCS, and MCS, and lower scores on TMD and PSS (i.e., less mood disturbance and less stress). Post-program, both groups showed significant improvements in all measures except PCS, with NM’s post-MBSR scores comparable to RM’s baseline scores. A significant Group (NM vs. RM) × Time (pre- vs. post-) interaction was observed only for FFMQ.
Conclusions
Regular meditators, who show greater self-compassion and better mental health than novice meditators at baseline, can benefit from MBSR to a similar extent in measures of self-compassion and other aspects of well-being.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective: Dural arteriovenous fistula (dAVF) is an abnormal vascular communication between the meningeal artery and vein at the dura mater, with frequent recruitment of collateral arterial pedicles. ...In recent years, Onyx embolization has become the mainstay intervention for dAVF at various locations, although an unfavorable vascular anatomy often limits effective obliteration of the lesion. Balloon assistance may facilitate curable occlusion of the abnormal shunt with Onyx while preserving the patency of the affected sinus, even in complicated dAVFs.Methods: We retrospectively reviewed the clinical and angiographic findings of patients with dAVF treated endovascularly in our institution between September 2018 and August 2019. Based on the detailed analysis of individual angioarchitecture, we defined complicated dAVF as lesions for which a complete cure is considered difficult to achieve with simple transarterial Onyx embolization alone, primarily due to a high flow and/or diffuse shunt with or without drainage to the functioning but compromised sinus. We evaluated the preoperative symptoms, anatomical classification, endovascular procedure, radiologic results, and clinical outcomes of these patients.Results: Five patients met our criteria, all of whom were treated with balloon-assisted Onyx embolization (two superior sagittal sinus dAVF, two transverse–sigmoid sinus dAVF, and one torcular dAVF). In four cases, Onyx was injected from a tiny branch of the middle meningeal artery under balloon occlusion of the collateral arteries or balloon devascularization of the competitive inflow. In three cases, balloon sinus protection was performed to prevent the inadvertent occlusion of the vital venous outflow with Onyx. In one case, for the complementary occlusion of the remnant shunt through the previously coiled but recanalized occipital artery, Onyx was injected from the wire lumen of a dual-lumen balloon catheter to avoid undesirable reflux. The angiographic results were an anatomical cure in four cases and near-complete occlusion in one case. No procedural complications were observed in any cases. The clinical outcome was a complete cure in four cases and improvement in one case.Conclusion: Our cases suggest that balloon devascularization can improve the unfavorable flow environment and simplify the vascular anatomy. Balloon sinus protection can support not only securing the patency of the normal venous outflow but also encourage aggressive intervention. Onyx injection via a dual-lumen balloon catheter can augment the controllability of embolization while preventing reflux. Each of these techniques can facilitate safe and effective Onyx embolization in the treatment of complicated dAVFs, and their combination may further expand the therapeutic horizon.
Abstract Objectives We conducted a nationwide survey of glucose transporter type-1 deficiency syndrome (GLUT-1DS) in Japan in order to clarify its incidence as well as clinical and laboratory ...information. Subjects and methods A questionnaire to survey the number of genetically and clinically confirmed cases of GLUT-1DS was sent to 1018 board-certified pediatric neurologists, which resulted in 57 patients being reported. We obtained the clinical and laboratory data of 33 patients through a secondary questionnaire. Results The age of the 33 patients (male: 15, female: 18) at the time of the study ranged between 3 and 35 years (mean: 13.5 years). The age of these patients at the onset of initial neurological symptoms ranged between the neonatal period and 48 months (mean: 9.4 months). GLUT-1DS was diagnosed at a mean age of 8.4 years (range: 1 year to 33 years). The initial symptom was convulsive seizures, which occurred in 15 cases, and was followed by abnormal eye movements in 7 cases and apneic or cyanotic attacks in 4 cases. The latter two symptoms most frequently occurred early in infancy. Thirty-two patients (97%) exhibited some type of epileptic seizure. Neurological findings revealed that most patients had muscle hypotonia, cerebellar ataxia, dystonia, and spastic paralysis. Mild to severe mental retardation was detected in all 33 cases. Furthermore, paroxysmal episodes of ataxia, dystonia/dyskinesia, and motor paralysis were described in approximately 1/3 of all patients. The factors that frequently aggravated these events were hunger, exercise, fever, and fatigue, in that order. The mean CSF/blood glucose ratio was 0.36 (0.28–0.48). Pathological mutations in the SLC2A1 gene were identified in 28 out of 32 cases (87.5%). Conclusion The results described herein provided an insight into the early diagnosis of GLUT1-DS, including unexplained paroxysmal abnormal eye movements, apneic/cyanotic attacks, and convulsive seizures in infancy, as well as uncommon paroxysmal events (ataxia, atonia, and motor paralysis) in childhood.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Snow crab Chionoecetes opilio catches in the western part of Sea of Japan reached their peak in the 1970s. Since then, the catch has been continuously declining to the present, and fishermen have ...eagerly desired the recovery of its stocks. Therefore, the national government has developed 25 protected areas by 2020 to contribute to the recovery of its stocks.We attempted to verify the effectiveness of the protected areas by conducting surveys of population density of snow crab using crab cage trap. Survey sea areas were Tajima Protected Area 2 (T-2A), Akasaki Protected Area 2 (A-2A), and Hamada Protected Area 1 (H-1A). Tajima Protected Area 2 was found to be effective in protecting over 12th instar males and mature females. Akasaki Protected Area 2 and Hamada Protected Area 1 were also effective in protecting mature females. These protective effects are thought to be due to the water depth of the protected areas. In addition, most of the snow crabs captured were individuals with a carapace width of 60 mm or more. This result suggested that catching characteristics of crab cage trap were strongly influence.
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