Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole‐exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca²⁺ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca²⁺ levels and store‐operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single‐gene defect, which is consistent with Mendelian‐dominant inheritance.     

A serine proteinase PmClipSP2 contributes to prophenoloxidase system and plays a protective role in shrimp defense by scavenging lipopolysaccharide

Serine proteinases (SPs) participate in various biological processes and play vital role in immunity. In this study, we investigated the function of PmClipSP2 from shrimp Penaeus monodon in defense against bacterial infection. PmClipSP2 was identified as a clip-domain SP and its mRNA increased in response to infection with Vibrio harveyi. PmClipSP2-knockdown shrimp displayed a significantly reduced phenoloxidase (PO) activity and increased susceptibility to V. harveyi infection. Injection of LPS and/or β-1,3-glucan induced a dose-dependent mortality and a significant decrease in the number of total hemocytes, with clear morphological changes in the hemocyte surface, of the PmClipSP2-knockdown shrimp. Recombinant PmClipSP2 was shown to bind to LPS and β-1,3-glucan and to activate PO activity. These results reveal that PmClipSP2 acts as a pattern-recognition protein, binding to microbial polysaccharides and likely activating the proPO system, whilst it may play an essential role in the hemocyte homeostasis by scavenging LPS and neutralizing its toxicity.     

Dendritic cell homeostasis is maintained by nonhematopoietic and T‐cell‐produced Flt3‐ligand in steady state and during immune responses

Lymphoid‐tissue dendritic cells (DCs) are short‐lived and need to be continuously replenished from bone marrow‐derived DC progenitor cells. Fms‐related tyrosine kinase 3 is expressed during cellular development from hematopoietic progenitors to lymphoid‐tissue DCs. Fms‐related tyrosine kinase 3 ligand (Flt3L) is an essential, nonredundant cytokine for DC progenitor to lymphoid tissue DC differentiation and maintenance. However, which cells contribute to Flt3L production and how Flt3L cytokine levels are regulated in steady state and during immune reactions remains to be determined. Here we demonstrate that besides nonhematopoietic cells, WT T cells produce Flt3L and contribute to the generation of both classical DCs (cDCs) and plasmacytoid DCs in Flt3L^?/? mice. Upon stimulation in vitro, CD4⁺ T cells produce more Flt3L than CD8⁺ T cells. Moreover, in vivo stimulation of naïve OT‐II CD4⁺ T cells with OVA leads to increase of pre‐cDCs and cDCs in draining lymph nodes of Flt3L^?/? mice in a partially Flt3L‐dependent manner. Thus, Flt3L‐mediated lymphoid tissue DC homeostasis is regulated by steady‐state T cells as well as by proliferative T cells, fostering local development of lymphoid organ resident DCs.     

运动产生鸢尾素对心肌纤维化的影响

文题释义： 心肌纤维化(myocardial fibrosis,MF)：心脏作为人体全身最重要的器官之一,其主要功能是为血流提供动力,把血液运行至身体各个部分。而心脏的泵血功能有赖于心肌的收缩和舒张能力。心肌纤维化是指心脏成纤维细胞的活化和过度增殖,导致胶原纤维过度积聚, 胶原含量升高和胶原容积增高的病理性变化,此过程会使心肌僵硬度提高,收缩和舒张能力降低。鸢尾素(irisin)：属于一种肌肉因子,它于2012年被首次发现,其主要功能是使白色脂肪组织转化为棕色脂肪,增加产热和能量消耗。运动训练可以升高血液鸢尾素水平,且不同运动方式对其影响结果存有差异,血清鸢尾素通过作用于解偶联蛋白2和线粒体稳态调控氧化应激和炎症反应从而对心肌起保护作用。背景：心肌纤维化是现代医学研究的一个重要议题,与心律失常、慢性心力衰竭等常见心脏疾病密切相关。运动介入对心肌纤维化有显著改善作用,但运动改善心肌纤维化的机制及不同运动类型对心肌纤维化的影响缺乏系统、全面的认识。运动如何触发鸢尾素的产生而对心肌纤维化起作用？这个问题目前尚不清楚。 目的：针对国内外学者有关运动刺激诱导鸢尾素的产生及其对心肌纤维化的影响进行全面综述,揭示其对心肌的保护作用机制,从而为提高心脏功能,预防心律失常、慢性心力衰竭等常见心脏疾病提供理论基础及实践参考。 方法：搜寻ELSEVIER、Web of Science、CNKI资料总库、万方数据、维普中文期刊服务平台及台湾学术文献数据库,检索与运动训练、鸢尾素、心肌纤维化等相关的中英文文献,发表时间截止至2019年8月,根据研究需要确立相应的入选标准,对最终筛选所得的58篇文献进行论述。 结果与结论：①人体试验中已证实长时间及单次运动均可提高肌肉及循环鸢尾素水平,而这一结果也在动物实验中得到较好验证;少数试验结果表明长时运动对血液鸢尾素水平无显著影响;出现不同结果的原因可能是选择的研究对象、运动方式、运动强度、运动频率不同,而具体机制尚不明确;②运动可通过鸢尾素作用于心肌线粒体稳定、能量代谢、氧化应激和炎症反应对心肌起保护作用,从而改善心肌纤维化;③心肌纤维化的发生受神经内分泌的调节和氧化应激及炎症反应的影响,鸢尾素可通过抑制ROS/p38MAPK/NFKB信号通路、内源性活性氧和ROS-NLRP3炎症信号通路、调节解偶联蛋白2的表达和线粒体稳态,从而影响心肌纤维化形成机制里的氧化应激反应和炎症反应过程,因此运动改善心肌纤维化可能和运动提高鸢尾素表达从而对心肌起保护作用有关。 ORCID:0000-0003-0990-2396(尹练)中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

PSGL-1 function in immunity and steady state homeostasis

Summary: The substantial importance of P-selectin glycoprotein ligand 1 (PSGL-1) in leukocyte trafficking has continued to emerge beyond its initial identification as a selectin ligand. PSGL-1 seemed to be a relatively simple molecule with an extracellular mucin domain extended as a flexible rod, teleologically consistent with its primary role in tethering leukocytes to endothelial selectins. The rolling interaction between leukocyte and endothelium mediated by this selectin-PSGL-1 interaction requires branched O-glycan extensions on specific PSGL-1 amino acid residues. In some cells, such as neutrophils, the glycosyltransferases involved in formation of the O-glycans are constitutively expressed, while in other cells, such as T cells, they are expressed only after appropriate activation. Thus, PSGL-1 supports leukocyte recruitment in both innate and adaptive arms of the immune response. A complex array of amino acids within the selectins engage multiple sugar residues of the branched O-glycans on PSGL-1 and provide the molecular interactions responsible for the velcro-like catch bonds that support leukocyte rolling. Such binding of PSGL-1 can also induce signaling events that influence cell phenotype and function. Scrutiny of PSGL-1 has revealed a better understanding of how it performs as a selectin ligand and yielded unexpected insights that extend its scope from supporting leukocyte rolling in inflammatory settings to homeostasis including stem cell homing to the thymus and mature T-cell homing to secondary lymphoid organs. PSGL-1 has been found to bind homeostatic chemokines CCL19 and CCL21 and to support the chemotactic response to these chemokines. Surprisingly, the O-glycan modifications of PSGL-1 that support rolling mediated by selectins in inflammatory conditions interfere with PSGL-1 binding to homeostatic chemokines and thereby limit responsiveness to the chemotactic cues used in steady state T-cell traffic. The multi-level influence of PSGL-1 on cell traffic in both inflammatory and steady state settings is therefore substantially determined by the orchestrated addition of O-glycans. However, central as specific O-glycosylation is to PSGL-1 function, in vivo regulation of PSGL-1 glycosylation in T cells remains poorly understood. It is our purpose herein to review what is known, and not known, of PSGL-1 glycosylation and to update understanding of PSGL-1 functional scope.     

T-lymphocyte production, function, and death in children who recovered from opsoclonus-myoclonus syndrome

Reduced CD4⁺ lymphocytes have been recently found in peripheral blood of children with active opsoclonus-myoclonus syndrome. The authors identified 2 children who recovered from this syndrome, one of whom showed reduced CD4⁺ lymphocytes 2 years after the disease onset. Except for a decrease of “naive” CD45RA⁺ CD4⁺ population and a mild restriction of T-cell heterogeneity in this patient, probably related to the immune response to viral infections, no alterations of T-cell homeostasis and function were found in either child. Therefore, the decrease of CD4⁺ cells may persist after clinical recovery, but the causes of this abnormality cannot be ascribed to intrinsic T-cell defects.     

Sleep and its homeostatic regulation in mice lacking the adenosine A1 receptor

Sleep deprivation (SD) increases extracellular adenosine levels in the basal forebrain, and pharmacological manipulations that increase extracellular adenosine in the same area promote sleep. As pharmacological evidence indicates that the effect is mediated through adenosine A1 receptors (A1R), we expected A1R knockout (KO) mice to have reduced rebound sleep after SD. Male homozygous A1R KO mice, wild-type (WT) mice, and heterozygotes (HET) from a mixed 129/C57BL background were implanted during anesthesia with electrodes for electroencephalography (EEG) and electromyography (EMG). After 1 week of recovery, they were allowed to adapt to recording leads for 2 weeks. EEG and EMG were recorded continuously. All genotypes had a pronounced diurnal sleep/wake rhythm after 2 weeks of adaptation. We then analyzed 24 h of baseline recording, 6 h of SD starting at light onset, and 42 h of recovery recording. Neither rapid eye movement sleep (REM sleep) nor non-REM sleep (NREMS) amounts differed significantly between the groups. SD for 6 h induced a strong NREMS rebound in all three groups. NREMS time and accumulated EEG delta power were equal in WT, HET and KO. Systemic administration of the selective A1R antagonist 8-cyclopentyltheophylline (8-CPT) inhibited sleep for 30 min in WT, whereas saline and 8-CPT both inhibited sleep in KO. We conclude that constitutional lack of adenosine A1R does not prevent the homeostatic regulation of sleep.     

Inter-individual Differences in the Dynamics of Sleep Homeostasis

Study Objectives:

The two-process model posits that sleep is regulated by 2 independent processes, a circadian Process C and a homeostatic Process S. EEG slow-wave activity (SWA) is a marker of NREM sleep intensity and is used as an indicator of sleep homeostasis. So far, parameters of the two-process model have been derived mainly from average data. Our aim was to quantify inter-individual differences.

Design:

Polysomnographic recordings (analysis of existing data).

Setting:

Sound attenuated sleep laboratory.

Patients or Participants:

Eight healthy young males.

Interventions:

40-h sustained wakefulness.

Measurements and Results:

Process S was modeled by a saturating exponential function during wakefulness and an exponential decline during sleep. Empirical mean SWA (derivation C3A2) per NREM sleep episode at episode midpoint were used for parameter estimation. Parameters were estimated simultaneously by minimizing the mean square error between data and simulations of Process S. This approach was satisfactory for average data and most individual data. We further improved our methodological approach by limiting the time constants to a physiologically meaningful range. This allowed a satisfactory fit also for the one individual whose parameters were beyond a physiological range. The time constants of the buildup of Process S ranged from 14.1 h to 26.4 h and those of the decline from 1.2 h to 2.9 h with similar inter-individual variability of the buildup and decline of Process S.

Conclusions:

We established a robust method for parameter estimation of Process S on an individual basis.

Citation:

Rusterholz T; Dürr R; Achermann P. Inter-individual differences in the dynamics of sleep homeostasis. SLEEP 2010;33(4):491-498.     

The effects of sleep deprivation in humans: topographical electroencephalogram changes in non‐rapid eye movement (NREM) sleep versus REM sleep

Studies on homeostatic aspects of sleep regulation have been focussed upon non‐rapid eye movement (NREM) sleep, and direct comparisons with regional changes in rapid eye movement (REM) sleep are sparse. To this end, evaluation of electroencephalogram (EEG) changes in recovery sleep after extended waking is the classical approach for increasing homeostatic need. Here, we studied a large sample of 40 healthy subjects, considering a full‐scalp EEG topography during baseline (BSL) and recovery sleep following 40 h of wakefulness (REC). In NREM sleep, the statistical maps of REC versus BSL differences revealed significant fronto‐central increases of power from 0.5 to 11 Hz and decreases from 13 to 15 Hz. In REM sleep, REC versus BSL differences pointed to significant fronto‐central increases in the 0.5–7 Hz and decreases in the 8–11 Hz bands. Moreover, the 12–15 Hz band showed a fronto‐parietal increase and that at 22–24 Hz exhibited a fronto‐central decrease. Hence, the 1–7 Hz range showed significant increases in both NREM sleep and REM sleep, with similar topography. The parallel change of NREM sleep and REM sleep EEG power is related, as confirmed by a correlational analysis, indicating that the increase in frequency of 2–7 Hz possibly subtends a state‐aspecific homeostatic response. On the contrary, sleep deprivation has opposite effects on alpha and sigma activity in both states. In particular, this analysis points to the presence of state‐specific homeostatic mechanisms for NREM sleep, limited to <2 Hz frequencies. In conclusion, REM sleep and NREM sleep seem to share some homeostatic mechanisms in response to sleep deprivation, as indicated mainly by the similar direction and topography of changes in low‐frequency activity.