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排序方式: 共有258条查询结果,搜索用时 31 毫秒
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Wong Jasin Kallish Natasha Crown Deborah Capraro Pamela Trierweiler Robert Wafford Q. Eileen Tiema-Benson Laurine Hassan Shahzeb Engel Edeth Tamayo Christina Heinemann Allen W. 《Journal of occupational rehabilitation》2021,31(3):474-490
Journal of Occupational Rehabilitation - Purpose We aimed to identify job accommodations that help persons with physical disabilities maintain or return to work and explore the barriers and... 相似文献
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Morsli Madjid Vincent Jean-Jacques Milliere Laurine Colson Philippe Drancourt Michel 《European journal of clinical microbiology & infectious diseases》2021,40(9):2037-2039
European Journal of Clinical Microbiology & Infectious Diseases - The prognosis of central nervous system infections caused by enteroviruses partially depends on the viral genotype, which is... 相似文献
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Noudjoud Attaf Sabrina Baaklini Laurine Binet Pierre Milpied 《European journal of immunology》2021,51(11):2555-2567
Upon antigen exposure, activated B cells in antigen-draining lymphoid organs form microanatomical structures, called germinal centers (GCs), where affinity maturation occurs. Within the GC microenvironment, GC B cells undergo proliferation and B cell receptor (BCR) genes somatic hypermutation in the dark zone (DZ), and affinity-based selection in the light zone (LZ). In the current paradigm of GC dynamics, high-affinity LZ B cells may be selected by cognate T- follicular helper cells to either differentiate into plasma cells or memory B cells, or re-enter the DZ and initiate a new round of proliferation and BCR diversification, before migrating back to the LZ. Given the diversity of cell states and potential cell fates that GC B cells may adopt, the two-state DZ-LZ paradigm has been challenged by studies that explored GC B-cell heterogeneity with a variety of single-cell technologies. Here, we review studies and single-cell technologies which have allowed to refine the working model of GC B-cell cellular and molecular heterogeneity during affinity maturation. This review also covers the use of single-cell quantitative data for mathematical modeling of GC reactions, and the application of single-cell genomics to the study of GC-derived malignancies. 相似文献
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Pietro Mesirca Isabelle Bidaud Fran?ois Briec Stéphane Evain Angelo G. Torrente Khai Le Quang Anne-Laure Leoni Matthias Baudot Laurine Marger Antony Chung You Chong Jo?l Nargeot Joerg Striessnig Kevin Wickman Flavien Charpentier Matteo E. Mangoni 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(7):E932-E941
Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies “sick sinus” syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Cav1.3 Ca2+ channels (Cav1.3−/−) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K+ channel (IKACh) could rescue SSS and heart block in Cav1.3−/− mice. We found that genetic inactivation of IKACh abolished SSS symptoms in Cav1.3−/− mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of IKACh either in Cav1.3−/− mice or following selective inhibition of Cav1.3-mediated L-type Ca2+ (ICa,L) current in vivo. Ablation of IKACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from IKACh suppression achieved by gene therapy or selective pharmacological inhibition.Pacemaker activity of the sinoatrial node (SAN) controls heart rate under physiological conditions. Abnormal generation of SAN automaticity underlies “sick sinus” syndrome (SSS), a pathological condition manifested when heart rate is not sufficient to meet the physiological requirements of the organism (1). Typical hallmarks of SSS include SAN bradycardia, chronotropic incompetence, SAN arrest, and/or exit block (1–3). SSS carries incapacitating symptoms, such as fatigue and syncope (1–3). A significant percentage of patients with SSS present also with tachycardia-bradycardia syndrome (3). SSS can also be associated with atrioventricular (AV) conduction block (heart block) (1–3). Although aging is a known intrinsic cause of SSS (4), this disease appears also in the absence of any associated cardiac pathology and displays a genetic legacy (1, 2). Heart disease or drug intake can induce acquired SSS (2). Symptomatic SSS requires the implantation of an electronic pacemaker. SSS accounts for about half of all pacemaker implantations in the United States (5, 6). The incidence of SSS has been forecasted to increase during the next 50 y, particularly in the elder population (7). Furthermore, it has been estimated that at least half of SSS patients will need to be electronically paced (7). Although pacemakers are continuously ameliorated, they remain costly and require lifelong follow-up. Moreover, the implantation of an electronic pacemaker remains difficult in pediatric patients (8). Development of alternative and complementary pharmacological or molecular therapies for SSS management could improve quality of life and limit the need for implantation of electronic pacemakers.Recently, the genetic bases of some inherited forms of SSS have been elucidated (recently reviewed in 1, 9) with the discovery of mutations in genes encoding for ion channels involved in cardiac automaticity (4, 9, 10). Notably, loss of function of L-type Cav1.3 Ca2+ channels is central in some inherited forms of SSS. For instance, loss of function in Cav1.3-mediated L-type Ca2+ (ICa,L) current causes the sinoatrial node dysfunction and deafness syndrome (SANDD) (10). Affected individuals with SANDD present with profound deafness, bradycardia, and dysfunction of AV conduction (10). Mutation in ankyrin-B causes SSS by reduced membrane targeting of Cav1.3 channels (11). The relevance of Cav1.3 channels to SSS is demonstrated also by work on the pathophysiology of congenital heart block, where down-regulation of Cav1.3 channels by maternal Abs causes heart block in infants (12). Additionally, recent data show that chronic iron overload induces acquired SSS via a reduction in Cav1.3-mediated ICa,L (13).In mice and humans, Cav1.3 channels are expressed in the SAN, atria, and the AV node but are absent in adult ventricular tissue (14, 15). Cav1.3-mediated ICa,L plays a major role in the generation of the diastolic depolarization in SAN and AV myocytes, thereby constituting important determinants of heart rate and AV conduction velocity (14, 16). The heart rate of mice lacking Cav1.3 channels (Cav1.3−/− mice) fairly recapitulates the hallmarks of SSS and associated symptoms, including bradycardia and tachycardia-bradycardia syndrome (17, 18). In addition, severe AV dysfunction is recorded in Cav1.3−/− mice to variable degrees. Typically, these mice show first- and second-degree AV block (16, 17, 19). Complete AV block with dissociated atrial and ventricular rhythms can also be observed in these animals. The phenotype of Cav1.3−/− mice thus constitutes a unique model for developing new therapeutic strategies against SSS (10).The muscarinic-gated K+ channel (IKACh) is involved in the negative chronotropic effect of the parasympathetic nervous system on heart rate (20, 21). Two subunits of the G-protein activated inwardly rectifying K+ channels (GIRK1 and GIRK4) of the GIRK/Kir3 subfamily assemble as heterotetramers to form cardiac IKACh channels (22). Indeed, both Girk1−/− and Girk4−/− mice lack cardiac IKACh (20, 21, 23). We recently showed that silencing of the hyperpolarization-activated current “funny” (If) channel in mice induces a complex arrhythmic profile that can be rescued by concurrent genetic ablation of Girk4 (24). In this study, we tested the effects of genetic ablation and pharmacological inhibition of IKACh on the Cav1.3−/− mouse model of SSS. We found that Girk4 ablation or pharmacological inhibition of IKACh rescues SSS and AV dysfunction in Cav1.3−/−. Thus, our study shows that IKACh targeting may be pursued as a therapeutic strategy for treatment of SSS and heart block. 相似文献