Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements

Cilia are multi-functional organelles that are constructed using intraflagellar transport (IFT) of cargo to and from their tip. It is widely held that the retrograde IFT motor, dynein-2, must be controlled in order to reach the ciliary tip and then unleashed to power the return journey. However, the mechanism is unknown. Here, we systematically define the mechanochemistry of human dynein-2 motors as monomers, dimers, and multi-motor assemblies with kinesin-II. Combining these data with insights from single-particle electron microscopy, we discover that dynein-2 dimers are intrinsically autoinhibited. Inhibition is mediated by trapping dynein-2’s mechanical “linker” and “stalk” domains within a novel motor-motor interface. We find that linker-mediated inhibition enables efficient transport of dynein-2 by kinesin-II in vitro. These results suggest a conserved mechanism for autoregulation among dimeric dyneins, which is exploited as a switch for dynein-2’s recycling activity during IFT

Rural High North: A High Rate of Fatal Injury and Prehospital Death

Finnmark County is the northernmost county in Norway. For several decades, the rate of mortality after injury in this sparsely inhabited region has remained above the national average. Following documentation of this discrepancy for the period 1991–1995, improvements to the trauma system were implemented. The present study aims to assess whether trauma-related mortality rates have subsequently improved. All injury-associated fatalities in Finnmark from 1995–2004 were identified retrospectively from the National Registry of Death and reviewed. Low-energy trauma in elderly individuals and poisonings were excluded. A total of 453 cases of trauma-related death occurred during the study period, and 327 of those met the inclusion criteria. Information was retrievable for 266 cases. The majority of deaths (86%) occurred in the prehospital phase. The main causes of death were suicide (33%) and road traffic accidents (21%). Drowning and snowmobile injuries accounted for an unexpectedly high proportion (12 and 8%, respectively). The time of death did not show trimodal distribution. Compared to the previous study period, there was a significant overall decline in injury-related mortality, yet there was no change in place of death, mechanism of injury, or time from injury until death. Changes in injury-related mortality cannot be linked to improvements in the trauma system. There was no change in the epidemiological patterns of injury. The high rate of on-scene mortality indicates that any major improvement in the number of injury-related deaths lies in targeted prevention

Identification of Dipeptidyl-Peptidase (DPP)5 and DPP7 in Porphyromonas endodontalis, Distinct from Those in Porphyromonas gingivalis

Dipeptidyl peptidases (DPPs) that liberate dipeptides from the N-terminal end of oligopeptides are crucial for the growth of Porphyromonas species, anaerobic asaccharolytic gram negative rods that utilize amino acids as energy sources. Porphyromonas endodontalis is a causative agent of periapical lesions with acute symptoms and Asp/Glu-specific DPP11 has been solely characterized in this organism. In this study, we identified and characterized two P. endodontalis DPPs, DPP5 and DPP7. Cell-associated DPP activity toward Lys-Ala-4-methylcoumaryl-7- amide (MCA) was prominent in P. endodontalis ATCC 35406 as compared with the Porphyromonas gingivalis strains ATCC 33277, 16-1, HW24D1, ATCC 49417, W83, W50, and HNA99. The level of hydrolysis of Leu-Asp-MCA by DPP11, Gly- Pro-MCA by DPP4, and Met-Leu-MCA was also higher than in the P. gingivalis strains. MER236725 and MER278904 are P. endodontalis proteins belong to the S9- and S46-family peptidases, respectively. Recombinant MER236725 exhibited enzymatic properties including substrate specificity, and salt- and pH-dependence similar to P. gingivalis DPP5 belonging to the S9 family. However, the kcat/Km figure (194 mM21?sec21) for the most potent substrate (Lys-Ala-MCA) was 18.4-fold higher as compared to the P. gingivalis entity (10.5 mM21?sec21). In addition, P. endodontalis DPP5 mRNA and protein contents were increased several fold as compared with those in P. gingivalis. Recombinant MER278904 preferentially hydrolyzed Met-Leu-MCA and exhibited a substrate specificity similar to P. gingivalis DPP7 belonging to the S46 family. In accord with the deduced molecular mass of 818 amino acids, a 105-kDa band was immunologically detected, indicating that P. endodontalis DPP7 is an exceptionally large molecule in the DPP7/DPP11/S46 peptidase family. The enhancement of four DPP activities was conclusively demonstrated in P. endodontalis, and remarkable Lys-Ala-MCAhydrolysis was achieved by qualitative and quantitative potentiation of the DPP5 molecule

Imaging and Endovascular Treatment of Bleeding Pelvic Fractures: Review Article

Pelvic fractures are potentially life-threatening injuries with high mortality rates, mainly due to intractable pelvic arterial bleeding. However, concomitant injuries are frequent and may also be the cause of significant blood loss. As treatment varies depending on location and type of hemorrhage, timely imaging is of critical importance. Contrast-enhanced CT offers fast and detailed information on location and type of bleeding. Angiography with embolization for pelvic fracture hemorrhage, particularly when performed early, has shown high success rates as well as low complication rates and is currently accepted as the first method of bleeding control in pelvic fracture-related arterial hemorrhage. In the current review imaging workup, patient selection, technique, results and complications of pelvic embolization are described