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Journal of Thrombosis and Thrombolysis - Hydroxychloroquine (HCQ) is an antimalarial agent with pleiotropic effects and now represents a cornerstone in the management of patients with autoimmune...  相似文献   
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Notch signaling is involved in numerous cell fate decisions in invertebrates and vertebrates. The Notch receptor is a type I transmembrane (TM) protein that undergoes two proteolytic steps after ligand binding, first by an ADAM (a distintegrin and metalloprotease) in the extracellular region, followed by gamma-secretase-mediated cleavage inside the TM domain. We demonstrate here that the murine ligand Delta1 (Dll1) undergoes the same sequence of cleavages, in an apparently signal-independent manner. Identification of the ADAM-mediated shedding site localized 10 aa N-terminal to the TM domain has enabled us to generate a noncleavable mutant. Kuzbanian/ADAM10 is involved in this processing event, but other proteases can probably substitute for it. We then show that Dll1 is part of a high-molecular-weight complex containing presenilin1 and undergoes further cleavage by a gamma-secretase-like activity, therefore releasing the intracellular domain that localizes in part to the nucleus. Using the shedding-resistant mutant, we demonstrate that this gamma-secretase cleavage depends on prior ectodomain shedding. Therefore Dll1 is a substrate for regulated intramembrane proteolysis, and its intracellular region possibly fulfills a specific function in the nucleus.  相似文献   
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ObjectiveIt has been suggested that overweight is negatively associated with cognitive functions. The aim of this study was to investigate whether a reduction in body weight by dietary interventions could improve episodic memory performance and alter associated functional brain responses in overweight and obese women.Methods20 overweight postmenopausal women were randomized to either a modified paleolithic diet or a standard diet adhering to the Nordic Nutrition Recommendations for 6 months. We used functional magnetic resonance imaging to examine brain function during an episodic memory task as well as anthropometric and biochemical data before and after the interventions.ResultsEpisodic memory performance improved significantly (p = 0.010) after the dietary interventions. Concomitantly, brain activity increased in the anterior part of the right hippocampus during memory encoding, without differences between diets. This was associated with decreased levels of plasma free fatty acids (FFA). Brain activity increased in pre-frontal cortex and superior/middle temporal gyri. The magnitude of increase correlated with waist circumference reduction. During episodic retrieval, brain activity decreased in inferior and middle frontal gyri, and increased in middle/superior temporal gyri.ConclusionsDiet-induced weight loss, associated with decreased levels of plasma FFA, improves episodic memory linked to increased hippocampal activity.Key Words: Functional magnetic resonance imaging, Episodic memory, Obesity, Diet interventions, Hippocampus  相似文献   
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Mandibulofacial dysostosis, Guion‐Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss‐of‐function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.  相似文献   
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