Predicting potentially pathogenic effects of hRPE65 missense mutations: a computational strategy based on molecular dynamics simulations

The human retinal pigment epithelium-specific 65-kDa protein (hRPE65) plays a crucial role within the retinoid visual cycle and several mutations affecting either its expression level or its enzymatic function are associated with inherited retinal diseases such as Retinitis Pigmentosa. The gene therapy product voretigene neparvovec (Luxturna) has been recently approved for treating hereditary retinal dystrophies; however, the treatment is currently accessible only to patients presenting confirmed biallelic mutations that severely impair hRPE65 function, and many reported hRPE65 missense mutations lack sufficient evidences for proving their pathogenicity. In this context, we developed a computational approach aimed at evaluating the potential pathogenic effect of hRPE65 missense variants located on the dimerisation domain of the protein. The protocol evaluates how mutations may affect folding and conformation stability of this protein region, potentially helping clinicians to evaluate the eligibility for gene therapy of patients diagnosed with this type of hRPE65 variant of uncertain significance.     

L’apport de l’imagerie hybride TEMP/TDM dans la prise en charge du cancer différencié de la thyroïde

IntroductionSingle photon emission computed tomography combined with a low dose computed tomography (SPECT/CT), is a hybrid imaging integrating functional and anatomical data. The purpose of our study was to evaluate the contribution of the SPECT/CT over traditional planar imaging of patients with differentiated thyroid carcinoma (DTC).MethodsPost-therapy iodine 131 (¹³¹I) whole-body scan followed by cervico-thoracic SPECT/CT, were performed in 100 patients with DTC.ResultsAmong these 100 patients followed for a predominantly papillary DTC, planar imaging and SPECT/CT, were perfectly concordant in 70% of patients and discordant in the remaining 30%. The use of fusion imaging SPECT/CT compared to conventional planar imaging allowed us to correct our therapeutic approach in 27% (27/100 patients), according to the protocols of therapeutic management of our institute.ConclusionSPECT/CT is a hybrid imaging modality which provides better identification and more correct anatomic localization of the foci of radioiodine uptake with impact on therapeutic management.     

Human milk oligosaccharides: an enzymatic protection step simplifies the synthesis of 3'- and 6'-O-sialyllactose and their analogues

We describe a chemo-enzymatic synthesis of 3'- and 6'-O-sialyllactose, two trisaccharides occurring in the 'acidic fraction' of the human milk oligosaccharides and endowed with potential antiadhesive activity. The key step is the highly regioselective 6'-O-acylation of benzyllactoside, which gave access to suitably protected lactose building blocks to be used as acceptors in the sialylation reaction. Moreover, the synthesis of the carboxymethyl and sulfo analogues of the title compounds is reported.     

Sic1 is phosphorylated by CK2 on Ser201 in budding yeast cells

We have previously identified Ser201 of Sic1, a yeast cyclin-dependent kinase inhibitor, as an in vitro target of protein kinase CK2. Here we present new evidence, by using specific anti-P-Ser201 antibodies and 2-D gel electrophoresis coupled to MALDI mass spectrometry analysis, that Sic1 is phosphorylated in vivo on Ser201 shortly after its de novo synthesis, during late anaphase in glucose-grown cells. This phosphorylation is also detected in Sic1 immunopurified from G1 cells. In agreement with these data we also show that the catalytic alpha' subunit of CK2, whose function is required for cell cycle progression, is detected in Sic1 immunopurified complexes, and that phosphorylation on Ser201 is reduced after CK2 inactivation at the non-permissive temperature in a cka1delta cka2(ts) yeast strain. These data strongly support the notion that CK2 phosphorylates Sic1 in vivo.     

Identification of parasitoses in a child burial from Adak Island (Central Aleutian Islands, Alaska)

Bothriocephalid (Diphyllobothrium pacificum) and Ascarid (Ascaris lumbricoides) eggs have been identified in a sample taken in the abdominal cavity of a child skeleton found in Zeto Point (ADK-011), an archaeological site on Adak Island in the Central Aleutian Islands (Alaska).     

Description and mapping of the resistance of DBA/2 mice to TNF-induced lethal shock

In our search for genes that inhibit the inflammatory effects of TNF without diminishing its antitumor capacities we found that, compared with C57BL/6 mice, DBA/2 mice exhibit a dominant resistance to TNF-induced lethality. Tumor-bearing (C57BL/6 x DBA/2)(BXD)F(1) mice completely survived an otherwise lethal TNF/IFN-gamma-antitumor therapy with complete regression of the tumor. This was not the case for C57BL/6 mice. Genetic linkage analysis revealed that TNF resistance is linked to a major locus on distal chromosome 6 and a minor locus on chromosome 17. Compared with littermate controls, chromosome substitution mice carrying a DBA/2 chromosome 6 in a C57BL/6 background were significantly protected against TNF and TNF/IFN-gamma, albeit less so than DBA/2 mice. Definition of a critical region of 13 Mb on chromosome 6 was the highest mapping resolution obtained. Further analysis of candidate genes may provide a powerful tool to control TNF-induced pathologies in humans.