BACKGROUND: A biomechanical model of the heart can be used to incorporate multiple data sources (electrocardiography, imaging, invasive hemodynamics). The purpose of this study was to use this approach in a cohort of patients with tetralogy of Fallot after complete repair (rTOF) to assess comparative influences of residual right ventricular outflow tract obstruction (RVOTO) and pulmonary regurgitation on ventricular health. METHODS: Twenty patients with rTOF who underwent percutaneous pulmonary valve replacement (PVR) and cardiovascular magnetic resonance imaging were included in this retrospective study. Biomechanical models specific to individual patient and physiology (before and after PVR) were created and used to estimate the RV myocardial contractility. The ability of models to capture post-PVR changes of right ventricular (RV) end-diastolic volume (EDV) and effective flow in the pulmonary artery (Qeff) was also compared with expected values. RESULTS: RV contractility before PVR (mean 66 ± 16 kPa, mean ± standard deviation) was increased in patients with rTOF compared with normal RV (38-48 kPa) (P < 0.05). The contractility decreased significantly in all patients after PVR (P < 0.05). Patients with predominantly RVOTO demonstrated greater reduction in contractility (median decrease 35%) after PVR than those with predominant pulmonary regurgitation (median decrease 11%). The model simulated post-PVR decreased EDV for the majority and suggested an increase of Qeff-both in line with published data. CONCLUSIONS: This study used a biomechanical model to synthesize multiple clinical inputs and give an insight into RV health. Individualized modeling allows us to predict the RV response to PVR. Initial data suggest that residual RVOTO imposes greater ventricular work than isolated pulmonary regurgitation.

• MeSH
• biologické modely * MeSH
• chirurgická náhrada chlopně metody   MeSH
• dospělí MeSH
• Fallotova tetralogie chirurgie   MeSH
• hemodynamika fyziologie   MeSH
• insuficience plicnice vrozené   diagnóza   chirurgie   MeSH
• kardiochirurgické výkony metody   MeSH
• lidé MeSH
• magnetická rezonance kinematografická MeSH
• mnohočetné abnormality * MeSH
• následné studie MeSH
• plicní chlopeň abnormality   diagnostické zobrazování   chirurgie   MeSH
• reoperace MeSH
• retrospektivní studie MeSH
• srdeční komory diagnostické zobrazování   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.

• MeSH
• akvaporin 2 * chemie   genetika   metabolismus   MeSH
• akvaporiny chemie   genetika   metabolismus   MeSH
• léková rezistence účinky léků   genetika   MeSH
• melarsoprol farmakologie   MeSH
• mutace MeSH
• pentamidin farmakologie   MeSH
• trypanocidální látky farmakologie   MeSH
• Trypanosoma brucei brucei * účinky léků   genetika   metabolismus   MeSH
• trypanozomóza africká farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

PURPOSE: The quality and precision of post-mortem MRI microscopy may vary depending on the embedding medium used. To investigate this, our study evaluated the impact of 5 widely used media on: (1) image quality, (2) contrast of high spatial resolution gradient-echo (T1 and T2* -weighted) MR images, (3) effective transverse relaxation rate (R2* ), and (4) quantitative susceptibility measurements (QSM) of post-mortem brain specimens. METHODS: Five formaldehyde-fixed brain slices were scanned using 7.0T MRI in: (1) formaldehyde solution (formalin), (2) phosphate-buffered saline (PBS), (3) deuterium oxide (D2 O), (4) perfluoropolyether (Galden), and (5) agarose gel. SNR and contrast-to-noise ratii (SNR/CNR) were calculated for cortex/white matter (WM) and basal ganglia/WM regions. In addition, median R2* and QSM values were extracted from caudate nucleus, putamen, globus pallidus, WM, and cortical regions. RESULTS: PBS, Galden, and agarose returned higher SNR/CNR compared to formalin and D2 O. Formalin fixation, and its use as embedding medium for scanning, increased tissue R2* . Imaging with agarose, D2 O, and Galden returned lower R2* values than PBS (and formalin). No major QSM offsets were observed, although spatial variance was increased (with respect to R2* behaviors) for formalin and agarose. CONCLUSIONS: Embedding media affect gradient-echo image quality, R2* , and QSM in differing ways. In this study, PBS embedding was identified as the most stable experimental setup, although by a small margin. Agarose and Galden were preferred to formalin or D2 O embedding. Formalin significantly increased R2* causing noisier data and increased QSM variance.

• MeSH
• ethery MeSH
• fluorokarbony MeSH
• formaldehyd MeSH
• fosfáty MeSH
• kontrastní látky MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie přístrojové vybavení   metody   MeSH
• mapování mozku metody   MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• odběr biologického vzorku MeSH
• oxid deuteria MeSH
• pitva přístrojové vybavení   metody   MeSH
• počítačové zpracování obrazu MeSH
• poměr signál - šum MeSH
• sefarosa chemie   MeSH
• senioři MeSH
• zalévání tkání přístrojové vybavení   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Transport of proteins across membranes is a fundamental process, achieved in every cell by the 'Sec' translocon. In prokaryotes, SecYEG associates with the motor ATPase SecA to carry out translocation for pre-protein secretion. Previously, we proposed a Brownian ratchet model for transport, whereby the free energy of ATP-turnover favours the directional diffusion of the polypeptide (Allen et al., 2016). Here, we show that ATP enhances this process by modulating secondary structure formation within the translocating protein. A combination of molecular simulation with hydrogendeuterium-exchange mass spectrometry and electron paramagnetic resonance spectroscopy reveal an asymmetry across the membrane: ATP-induced conformational changes in the cytosolic cavity promote unfolded pre-protein structure, while the exterior cavity favours its formation. This ability to exploit structure within a pre-protein is an unexplored area of protein transport, which may apply to other protein transporters, such as those of the endoplasmic reticulum and mitochondria.

• MeSH
• adenosintrifosfát chemie   metabolismus   MeSH
• adenosintrifosfatasy chemie   metabolismus   MeSH
• Escherichia coli metabolismus   MeSH
• membránové transportní proteiny chemie   metabolismus   MeSH
• molekulární modely MeSH
• proteinové prekurzory metabolismus   MeSH
• proteiny SecA chemie   metabolismus   MeSH
• proteiny z Escherichia coli chemie   metabolismus   MeSH
• sbalování proteinů * MeSH
• translokační kanály SEC chemie   metabolismus   MeSH
• transport proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH