The deregulated microRNAome contributes to the cellular response to aneuploidy.

BACKGROUND: Aneuploidy, or abnormal chromosome numbers, severely alters cell physiology and is widespread in cancers and other pathologies. Using model cell lines engineered to carry one or more extra chromosomes, it has been demonstrated that aneuploidy per se impairs proliferation, leads to proteotoxic as well as replication stress and triggers conserved transcriptome and proteome changes. RESULTS: In this study, we analysed for the first time miRNAs and demonstrate that their expression is altered in response to chromosome gain. The miRNA deregulation is independent of the identity of the extra chromosome and specific to individual cell lines. By cross-omics analysis we demonstrate that although the deregulated miRNAs differ among individual aneuploid cell lines, their known targets are predominantly associated with cell development, growth and proliferation, pathways known to be inhibited in response to chromosome gain. Indeed, we show that up to 72% of these targets are downregulated and the associated miRNAs are overexpressed in aneuploid cells, suggesting that the miRNA changes contribute to the global transcription changes triggered by aneuploidy. We identified hsa-miR-10a-5p to be overexpressed in majority of aneuploid cells. Hsa-miR-10a-5p enhances translation of a subset of mRNAs that contain so called 5'TOP motif and we show that its upregulation in aneuploids provides resistance to starvation-induced shut down of ribosomal protein translation. CONCLUSIONS: Our work suggests that the changes of the microRNAome contribute on one hand to the adverse effects of aneuploidy on cell physiology, and on the other hand to the adaptation to aneuploidy by supporting translation under adverse conditions.

Radiographic cup position following posterior and lateral approach to total hip arthroplasty. An explorative randomized controlled trial.

The two most common surgical approaches to total hip arthroplasty are the posterior approach and lateral approach. The surgical approach may influence cup positioning and restoration of the offset, which may affect the biomechanical properties of the hip joint. The primary aim was to compare cup position between posterior approach and lateral approach. Secondary aims were to compare femoral offset, abductor moment arm and leg length discrepancy between the two approaches. Eighty patients with primary hip osteoarthritis were included in a randomized controlled trial and assigned to total hip arthroplasty using posterior approach or lateral approach. Postoperative radiographs from 38 patients in each group were included in this study for measurement of cup anteversion and inclination. Femoral offset, cup offset, total offset, abductor moment arm and leg length discrepancy were measured on preoperative and postoperative radiographs in 28 patients in each group. We found that mean anteversion was 5° larger in the posterior approach group (95% CI, -8.1 to -1.4; p = 0.006), while mean inclination was 5° less steep (95% CI, 2.7 to 7.2; p<0.001) compared with the lateral approach group. The posterior approach group had a larger mean femoral offset of 4.3mm (95% CI, -7.4 to -1.3, p = 0.006), mean total offset of 6.3mm (95% CI, -9.6 to -3; p<0.001) and mean abductor moment arm of 4.8mm (95% CI, -7.6 to -1.9; p = 0.001) compared with the lateral approach group. We found a larger cup anteversion but less steep cup inclination in the posterior approach group compared with the lateral approach group. Femoral offset and abductor moment arm were restored after total hip arthroplasty using lateral approach but significantly increased when using posterior approach.

Coi1 is a novel assembly factor of the yeast complex III-complex IV supercomplex.

The yeast bc1 complex (complex III) and cytochrome oxidase (complex IV) are mosaics of core subunits encoded by the mitochondrial genome and additional nuclear-encoded proteins imported from the cytosol. Both complexes build in the mitochondrial inner membrane various supramolecular assemblies. The formation of the individual complexes and their supercomplexes depends on the activity of dedicated assembly factors. We identified a so far uncharacterized mitochondrial protein (open reading frame YDR381C-A) as an important assembly factor for complex III, complex IV, and their supercomplexes. Therefore, we named this protein Cox interacting (Coi) 1. Deletion of COI1 results in decreased respiratory growth, reduced membrane potential, and hampered respiration, as well as slow fermentative growth at low temperature. In addition, coi1Δ cells harbour reduced steady-state levels of subunits of complexes III and IV as well as of the assembled complexes and supercomplexes. Interaction of Coi1 with respiratory chain subunits seems transient, as it appears to be a stoichiometric subunit neither of complex III nor of complex IV. Collectively, this work identifies a novel protein that plays a role in the assembly of the mitochondrial respiratory chain.

Sickle cell anemia: conclusions from a forensic case report of a young African woman who died after anesthesia.

A 20-year old African woman underwent anesthesia for interruption of an unwanted pregnancy. As a consequence of the anesthesia, she went into coma because of an as yet unknown and untested homozygotic state of sickle cell anemia. Her vital functions were maintained for more than 1 year by intensive medicine, but she died finally in multiorgan failure and aspiration pneumonia. Because of the complications under anesthesia and the missing preanesthetic test for hemoglobinopathy, autopsy was conducted in the forensic medicine department and not in the department of pathology. The sickle cell disease was diagnosed by electrophoresis of the blood, by molecular detection of mutation in the hemoglobin gene, as well as by postmortem light and electron microscopy. Sickle cells were found in capillaries of brain, liver, lung, bone marrow, and spleen. Electrophoretic analysis revealed 80.2% HbS in addition to 3.2% HbA2 and 16.6% HbF, whereas no HbA0 could be detected in blood, confirming the homozygosity of sickle cell anemia. Because of sickle cell crisis, occluded blood vessels, and severe brain cortex necrosis, the patient died in spite of reanimation and intensive medicine. This case demonstrates that it is still important to realize the possibility of this disease and diagnostic obstacles even in regions where its manifestation is not endemic, as in Northern and Central Europe.