15 research outputs found
64-Slice CT angiography of the abdominal aorta and abdominal arteries: comparison of the diagnostic efficacy of iobitridol 350Â mgI/ml versus iomeprol 400Â mgI/ml in a prospective, randomised, double-blind multi-centre trial
Versatile workflow for cell-type resolved transcriptional and epigenetic profiles from cryopreserved human lung
Complexity of lung microenvironment and changes in cellular composition during disease make it exceptionally hard to understand molecular mechanisms driving development of chronic lung diseases. Although recent advances in cell typeâresolved approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a versatile workflow that allows storage of lung tissue with high viability, permits thorough sample quality check before cell isolation, and befits sequencing-based profiling. We demonstrate that cryopreservation enables isolation of multiple cell types from both healthy and diseased lungs. Basal cells from cryopreserved airways retain their differentiation ability, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for omics profiling of lung cells. Moreover, we obtained high-quality single-cell RNA-sequencing data of cells from cryopreserved human lungs, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our workflow is well suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to viable human tissue
Synthesis and antiplasmodial activity of highly active reverse analogues of the antimalarial drug candidate fosmidomycin
Haplo-identical transplantation following "FLAMSA-RIC" conditioning in children with refractory acute leukaemia
Hydrothermal Activity in the Northern Guaymas Basin
Rift-related magmatism in the Guaymas Basin, Gulf of California induces hydrothermal activity within the basin sediments. Mobilized fluids migrate to the seafloor where they are emitted into the water column changing ocean chemistry and fuelling chemosynthetic ecosystems. New seismic and geochemical data from the northern rift arm of the Guaymas Basin document the variety of fluid expulsion phenomena from large-scale subsurface sediment mobilization related to contact metamorphosis to focused small-scale structures. The geochemical composition of emitted fluids depends largely on the age of the fluid escape structures with respect to the underlying intrusions. Whereas, old structures are dominated by methane emission, young vent sites are characterized by hot fluids that carry a wide range of minerals in solution. The overall high geothermal gradient within the basin (mainly between 160 and 260 °C/km) leads to a thin gas hydrate stability zone. Thus, deep hydrothermal fluid advection affects the gas hydrate system and makes it more dynamic than in colder sedimentary basins
IspC as Target for Antiinfective Drug Discovery: Synthesis, Enantiomeric Separation, and Structural Biology of Fosmidomycin Thia Isosters
Binding Modes of Reverse Fosmidomycin Analogs toward the Antimalarial Target IspC
1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodium
falciparum (<i>Pf</i>IspC, <i>Pf</i>Dxr), believed to be the rate-limiting enzyme of the nonmevalonate
pathway of isoprenoid biosynthesis (MEP pathway), is a clinically
validated antimalarial target. The enzyme is efficiently inhibited
by the natural product fosmidomycin. To gain new insights into the
structure activity relationships of reverse fosmidomycin analogs,
several reverse analogs of fosmidomycin were synthesized and biologically
evaluated. The 4-methoxyphenyl substituted derivative <b>2c</b> showed potent inhibition of <i>Pf</i>IspC as well as of P. falciparum growth and was more than one order
of magnitude more active than fosmidomycin. The binding modes of three new derivatives in complex
with <i>Pf</i>IspC, reduced nicotinamide adenine dinucleotide
phosphate, and Mg<sup>2+</sup> were determined by X-ray structure
analysis. Notably, <i>Pf</i>IspC selectively binds the <i>S</i>-enantiomers of the study compounds
IspC as Target for Antiinfective Drug Discovery: Synthesis, Enantiomeric Separation, and Structural Biology of Fosmidomycin Thia Isosters
The emergence and spread of multidrug-resistant
pathogens are widely
believed to endanger human health. New drug targets and lead compounds
exempt from cross-resistance with existing drugs are urgently needed.
We report on the synthesis and properties of âreverseâ
thia analogs of fosmidomycin, which inhibit the first committed enzyme
of a metabolic pathway that is essential for the causative agents
of tuberculosis and malaria but is absent in the human host. Notably,
IspC displays a high level of enantioselectivity for an α-substituted
fosmidomycin derivative
Mechanisms underlying the health benefits of intermittent hypoxia conditioning
Intermittent hypoxia (IH) is commonly associated with pathological conditions, particularly obstructive sleep apnoea. However, IH is also increasingly used to enhance health and performance and is emerging as a potent nonâpharmacological intervention against numerous diseases. Whether IH is detrimental or beneficial for health is largely determined by the intensity, duration, number and frequency of the hypoxic exposures and by the specific responses they engender. Adaptive responses to hypoxia protect from future hypoxic or ischaemic insults, improve cellular resilience and functions, and boost mental and physical performance. The cellular and systemic mechanisms producing these benefits are highly complex, and the failure of different components can shift longâterm adaptation to maladaptation and the development of pathologies. Rather than discussing in detail the wellâcharacterized individual responses and adaptations to IH, we here aim to summarize and integrate hypoxiaâactivated mechanisms into a holistic picture of the body's adaptive responses to hypoxia and specifically IH, and demonstrate how these mechanisms might be mobilized for their health benefits while minimizing the risks of hypoxia exposure