Angiogenesis and chronic kidney disease

The number of patients requiring renal replacement therapy due to end-stage renal disease (ESRD) is increasing worldwide. The prevalence of chronic kidney disease (CKD), and the importance of CKD as a risk factor in development of ESRD and in complicating cardiovascular disease (CVD) have been confirmed. In recent years, the involvement of angiogenesis-related factors in the progression of CKD has been studied, and the potential therapeutic effects on CKD of modulating these factors have been identified. Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, in maintenance of the glomerular capillary structure and filtration barrier, and in the renal repair process after injury. VEGF-A is also involved in the development of early diabetic nephropathy, demonstrated by the therapeutic effects of anti-VEGF-A antibody. Angiopoietin (Ang)-1 induces the maturation of newly formed blood vessels, and the therapeutic effects of Ang-1 in diabetic nephropathy have been described. In experimental models of diabetic nephropathy, the therapeutic effects of angiogenesis inhibitors, including angiostatin, endostatin and tumstatin peptides, the isocoumarin NM-3, and vasohibin-1, have been reported

Single-molecule kinetics of pore assembly by the membrane attack complex

The membrane attack complex (MAC) is a hetero-oligomeric protein assembly that kills pathogens by perforating their cell envelopes. The MAC is formed by sequential assembly of soluble complement proteins C5b, C6, C7, C8 and C9, but little is known about the rate-limiting steps in this process. Here, we use rapid atomic force microscopy (AFM) imaging to show that MAC proteins oligomerize within the membrane, unlike structurally homologous bacterial pore-forming toxins. C5b-7 interacts with the lipid bilayer prior to recruiting C8. We discover that incorporation of the first C9 is the kinetic bottleneck of MAC formation, after which rapid C9 oligomerization completes the pore. This defines the kinetic basis for MAC assembly and provides insight into how human cells are protected from bystander damage by the cell surface receptor CD59, which is offered a maximum temporal window to halt the assembly at the point of C9 insertion

Resolving the fragmentation of high line-mass filaments with ALMA: the integral shaped filament in Orion A

We study the fragmentation of the nearest high line-mass filament, the integral shaped filament (ISF, line-mass ~400 M⊙ pc-1) in the Orion A molecular cloud. We have observed a 1.6 pc long section of the ISF with the Atacama Large Millimetre/submillimeter Array (ALMA) at 3 mm continuum emission, at a resolution of ~3″ (1200 AU). We identify from the region 43 dense cores with masses about a solar mass. 60% of the ALMA cores are protostellar and 40% are starless. The nearest neighbour separations of the cores do not show a preferred fragmentation scale; the frequency of short separations increases down to 1200 AU. We apply a two-point correlation analysis on the dense core separations and show that the ALMA cores are significantly grouped at separations below ~17 000 AU and strongly grouped below ~6000 AU. The protostellar and starless cores are grouped differently: only the starless cores group strongly below ~6000 AU. In addition, the spatial distribution of the cores indicates periodic grouping of the cores into groups of ~30 000 AU in size, separated by ~50 000 AU. The groups coincide with dust column density peaks detected by Herschel. These results show hierarchical, two-mode fragmentation in which the maternal filament periodically fragments into groups of dense cores. Critically, our results indicate that the fragmentation models for lower line-mass filaments (~16 M⊙ pc-1) fail to capture the observed properties of the ISF. We also find that the protostars identified with Spitzer and Herschel in the ISF are grouped at separations below ~17 000 AU. In contrast, young stars with disks do not show significant grouping. This suggests that the grouping of dense cores is partially retained over the protostar lifetime, but not over the lifetime of stars with disks. This is in agreement with a scenario where protostars are ejected from the maternal filament by the slingshot mechanism, a model recently proposed for the ISF. The separation distributions of the dense cores and protostars may also provide an evolutionary tracer of filament fragmentation