Activation triggers the exchange of subunits in Ca2+/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.DOI: http://dx.doi.org/10.7554/eLife.13405.001

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Background Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one‐third of PKD patients are attributed to proline‐rich transmembrane protein 2 (PRRT2) mutations. Objective We aimed to explore the potential causative gene for PKD. Methods A cohort of 196 PRRT2‐negative PKD probands were enrolled for whole‐exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case–control analysis, was applied to identify the candidate genes. Another 325 PRRT2‐negative PKD probands were subsequently screened with Sanger sequencing. Results Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A‐related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A‐positive and PRRT2‐positive groups. Conclusions We consolidated mutations in TMEM151A causing PKD with the aid of case–control analysis of a large‐scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A‐related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A‐related PKD. © 2021 International Parkinson and Movement Disorder Society

There is no randomized controlled trial to compare the effectiveness and safety of mechanical thrombectomy (MT) to intravenous thrombolysis in patients with posterior circulation occlusion (PCO). Hence, we firstly performed a meta-analysis to investigate the outcomes of MT in PCO and then compared these outcomes to anterior circulation occlusion (ACO) to provide fundamental data to further studies. Methods: We searched the PubMed, EMBASE, and Cochrane Library from dates of inception to June 2019 for relevant studies. Outcomes including functional independence at 90 days, successful recanalization, mortality, symptomatic intracranial hemorrhage (sICH), and futile recanalization were extracted. Results: Seven studies involving 474 patients with PCO thrombectomy were analyzed. There was a lower rate of functional independence at 90 days and a higher rate of mortality after thrombectomy in PCO versus ACO (odds ratios (OR) 0.72; 95% confidence interval (CI) 0.57-0.90; OR 2.03; 95% CI 1.30-3.18). Recanalization rates were comparable (OR 1.01; 95% CI 0.62-1.65), but a higher futile recanalization rate was found in basilar artery occlusion (BAO) (OR 1.75; 95% CI 1.30-2.37). There was a lower rate of sICH in MT for patients with PCO versus ACO (OR 0.54; 95% CI 0.29-0.99). Conclusions: We found that the outcomes of MT for patients with PCO were poorer than with ACO. On the other hand, MT appears to have lower rates of sICH and to increase successful recanalization. Given the high recanalization rate, MT may serve as an adjunct to standard treatment. The key point to improve outcomes is recognizing reliable factors associated with futile recanalization and optimizing the results of MT. But in view of the different characteristics of posterior circulation stroke and anterior circulation stroke, the results are far from robust. acute ischemic stroke due to large vessel occlusion in the anterior circulation demonstrated an overwhelming benefit of the new generations of mechanical thrombectomy (MT) devices compared to intravenous thrombolysis 2-6) , grounded on which American Heart Association/American Stroke Association guidelines Copyright©2020 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

Uric acid (UA) has been proposed as an important risk factor for cardiovascular and renal morbidity. We conducted an interventional trial to assess effects of altered salt intake on plasma and urine UA levels and the relationship between UA levels and salt sensitivity in humans. Ninety subjects (18–65 years old) were sequentially maintained on a normal diet for 3 days at baseline, a low-salt diet for 7 days (3.0 g/day, NaCl), and a high-salt diet for an additional 7 days (18.0 g/day of NaCl). Plasma UA levels significantly increased from baseline to low-salt diet and decreased from low-salt to high-salt diet. By contrast, daily urinary levels of UA significantly decreased from baseline to low-salt diet and increased from low-salt to high-salt diet. The 24 h urinary sodium excretions showed inverse correlation with plasma UA and positive correlation with urinary UA excretions. Additionally, salt-sensitive subjects presented significantly higher plasma UA changes in comparison to salt-resistant subjects, and a negative correlation was observed between degree of salt sensitivity and plasma UA difference. The present study indicates that variations in dietary salt intake affect plasma and urine UA levels, and plasma UA may be involved in pathophysiological process of salt sensitivity.

In the subacute Parkinson's disease mice model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), injection of HMGB1 competitive inhibitor protein HMGB1 A Box and the Ethyl pyruvate which inhibit the release of HMGB1 from cells, restored the number of dopaminergic neurons and TH+ fibers in the SN and striatum. Our data show that A Box up regulated CD200-CD200R signal of microglia, inhibit the activation of microglia mediated by HMGB1 and the production of TNF-α IL-1β and IL-6 in vivo and in vitro mixed culture system. Microglia overexpressing CD200R produced less inflammatory chemokines and reduced the loss of TH+ neurons. In addition, HMGB1 A Box decreased the level of CCL5 and significantly inhibited the infiltration of almost all T cells including Th17 and the proportion of Th17 in CD4+ T cells. In vitro MPP+ induced model and HMGB1 stimulated mesencephalic cell system, activated microglia induced the differentiation of Naïve T cells to Th17, and A Box significantly inhibited this process. To sum up, our results show that HMGB1 A Box targeting HMGB1, which effectively reduces the activation of microglia in MPTP PD model by restoring CD200-CD200R inhibition signal, inhibit microglia mediated neuroinflammation and the differentiation of T cells to Th17.

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