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Background Transfusion with Plasmodium -infected blood represents a risk for malaria transmission, a rare but severe event. Several non-endemic countries implement a strategy for the screening of candidate blood donors including questionnaire for the identification of at-risk subjects and laboratory testing of blood samples, often serology-based, with temporary deferral from donation for individuals with a positive result. In Italy, the most recent legislation, issued in November 2015, introduced the use of serological tests for the detection of anti- Plasmodium antibodies. Methods In the absence of a gold standard for malaria serology, the aim of this work was to evaluate five commercial ELISA kits, and to determine their accuracy (sensitivity and specificity) in comparison to immuno-fluorescence antibody test (IFAT), and their agreement (concordance of results). Serum samples from malaria patients or from subjects with malaria history (N = 64), malaria naïve patients with other parasitic infections (N = 15), malaria naïve blood donors (N = 8) and malaria exposed candidate blood donors (N = 36) were tested. Results The specificity of all ELISA kits was 100%, while sensitivity ranged between 53 and 64% when compared to IFAT on malaria patients samples. When tested on candidate blood donors’ samples, ELISA kits showed highly variable agreement (42–94%) raising the possibility that the same individual could be included or excluded from donation depending on the test in use by the transfusion centre. Conclusions These preliminary results indicate how the lack of a gold standard for malaria serology must be taken into account in the application and future revision of current legislation. There is need of developing more sensitive serological assays. Moreover, the adoption of a unique serological test at national level is recommended, as well as the development of screening algorithms based on multiple laboratory tests, including molecular assays.

Multiple mitochondrial dysfunctions syndrome type 2 with hyperglycinemia (MMDS2) is a severe disorder of mitochondrial energy metabolism, associated with biallelic mutations in the gene encoding for BOLA3, a protein with a not yet completely understood role in iron-sulfur (Fe-S) cluster biogenesis, but essential for the maturation of mitochondrial [4Fe-4S] proteins. To better understand the role of BOLA3 in MMDS2, we have investigated the impact of the p.His96Arg (c.287A > G) point mutation, which involves a highly conserved residue, previously identified as a [2Fe-2S] cluster ligand in the BOLA3-[2Fe-2S]-GLRX5 heterocomplex, on the structural and functional properties of BOLA3 protein. The His96Arg mutation has been associated with a severe MMDS2 phenotype, characterized by defects in the activity of mitochondrial respiratory complexes and lipoic acid-dependent enzymes. Size exclusion chromatography, NMR, UV-visible, circular dichroism, and EPR spectroscopy characterization have shown that the His96Arg mutation does not impair the interaction of BOLA3 with its protein partner GLRX5, but leads to the formation of an aberrant BOLA3-[2Fe-2S]-GLRX5 heterocomplex, that is not functional anymore in the assembly of a [4Fe-4S] cluster on NFU1. These results allowed us to rationalize the severe phenotype observed in MMDS2 caused by His96Arg mutation.

Multiple mitochondrial dysfunctions syndrome type 3 (MMDS3) is a rare autosomal recessive mitochondrial leukoencephalopathy caused by biallelic pathogenic variants in the IBA57 gene. The gene protein product, IBA57, has an unknown role in iron–sulfur (Fe-S) cluster biogenesis but is required for the maturation of mitochondrial [4Fe-4S] proteins. To better understand the role of IBA57 in MMDS3, we have investigated the impact of the pathogenic p.Gly104Cys (c.310G > T) variant on the structural and functional properties of IBA57. The Gly104Cys variant has been associated with a severe MMDS3 phenotype in both compound heterozygous and homozygous states, and defects in the activity of mitochondrial respiratory complexes and lipoic acid-dependent enzymes have been demonstrated in the affected patients. Size exclusion chromatography, also coupled to multiple angle light scattering, NMR, circular dichroism, and fluorescence spectroscopy characterization has shown that the Gly104Cys variant does not impair the conversion of the homo-dimeric [2Fe-2S]–ISCA22 complex into the hetero-dimeric IBA57–[2Fe-2S]–ISCA2 but significantly affects the stability of IBA57, in both its isolated form and in complex with ISCA2, thus providing a rationale for the severe MMDS3 phenotype associated with this variant.