The ER resident chaperone molecule GRP78 has been shown to translocate to the cell surface where it associates with Cripto and signals cell growth, playing a still partially understood role in tumorigenesis. Consequently, a better understanding of GRP78 topology and structure at the surface of cancer cells represents an important step in the development of a new class of therapeutics. Here, we used a set of programs for creation of a complex containing GRP78 and Cripto proteins. We elucidated possible interactions of GRP78, Cripto, and their complex with the membrane. Using molecular dynamics simulations, we demonstrated that Cripto binding to GRP78 completely changes the dynamics of its behavior on the membrane, not allowing GRP78 to disconnect from it, thus enabling GRP78 tumorigenic functions.
A 40-year-old woman developed erythematous, raised and pruritic, migratory lesions on a daily basis affecting her whole body for the past 3 months; the appearance of the rash was consistent with urticaria. There was associated angioedema affecting her lips and face. Her medical history was significant for MS, diagnosed 9 years before, manifesting clinically with mobility, speech, and cognitive impairment. Initial treatment was with β-interferon and glatiramer acetate; however, disease relapse prompted switching to alemtuzumab, with 2 standard courses given 12 months apart (60 and 36 mg, respectively, the last dose given 12 months before the onset of rash), and achieved remission with a new baseline Expanded Disability Status Scale of 2.
Familial forms of the severe immunoregulatory disease Haemophagocytic Lymphohistiocytosis (HLH) arise from bi-allelic mutations in the PRF1, UNC13D, STXBP2 and STX11 genes. Early and accurate diagnosis of the disease is important to determine the most appropriate treatment option, including potentially curative stem cell transplantation. The diagnosis of familial HLH (FHL) is traditionally based on finding bi-allelic mutations in patients with HLH symptoms and reduced natural killer (NK) cell cytotoxicity. However, patients often have a low NK cell count or receive immunosuppressive therapies that may render the NK cytotoxicity assay unreliable. Furthermore, to fully understand the nature of a disease it is critical to directly assess the effect of mutations on cellular function; this will help to avoid instances where carriers of innocuous mutations may be recommended for invasive procedures including transplantation. To overcome this diagnostic problem, we have developed a rapid and robust method that takes advantage of the functional equivalence of the human and mouse orthologues of PRF1, UNC13D, STX11 and STXBP2 proteins. By knocking out endogenous mouse genes in CD8+ T cells and simultaneously replacing them with their mutated human orthologues, we can accurately assess the effect of mutations on cell function. The wide dynamic range of this novel system allowed us to understand the basis of otherwise cryptic cases of FHL/HLH and, in some instances, to demonstrate that previously reported mutations are unlikely to cause FHL. This novel approach provides valuable new information to enable more accurate diagnosis and treatment of HLH/FHL patients who inherit mutations of undetermined pathogenicity.
Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychol Med 2012; 42: 647-56. 5 Lord C, Rutter M, Le Couteur A. The autism diagnostic observation schedule generic: a standard measure of social and communication deficits associated with the spectrum of autism.
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