Unraveling the Big Sleep:Molecular Aspects of Stem Cell Dormancy and Hibernation

Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Given that both conditions represent cell survival strategies, we here compare the molecular aspects of cellular quiescence, particularly of well-studied hematopoietic stem cells, and torpor at the cellular level. Critical processes of dormancy are reviewed, including the suppression of the cell cycle, changes in metabolic characteristics, and cellular mechanisms of dealing with damage. Key factors shared by hematopoietic stem cell quiescence and torpor include a reversible activation of factors inhibiting the cell cycle, a shift in metabolism from glucose to fatty acid oxidation, downregulation of mitochondrial activity, key changes in hypoxia-inducible factor one alpha (HIF-1α), mTOR, reversible protein phosphorylation and autophagy, and increased radiation resistance. This similarity is remarkable in view of the difference in cell populations, as stem cell quiescence regards proliferating cells, while torpor mainly involves terminally differentiated cells. A future perspective is provided how to advance our understanding of the crucial pathways that allow stem cells and hibernating animals to engage in their 'great slumbers.'</p

WASP-4 Is Accelerating toward the Earth

The orbital period of the hot Jupiter WASP-4b appears to be decreasing at a rate of −8.64 ± 1.26 ms yr⁻¹, based on transit-timing measurements spanning 12 yr. Proposed explanations for the period change include tidal orbital decay, apsidal precession, and acceleration of the system along the line of sight. To investigate further, we performed new radial-velocity measurements and speckle imaging of WASP-4. The radial-velocity data show that the system is accelerating toward the Sun at a rate of −0.0422 ± 0.0028 m s⁻¹ day⁻¹. The associated Doppler effect should cause the apparent period to shrink at a rate of −5.94 ± 0.39 ms yr⁻¹, comparable to the observed rate. Thus, the observed change in the transit period is mostly or entirely produced by the line-of-sight acceleration of the system. This acceleration is probably caused by a wide-orbiting companion of mass 10–300 M_(Jup) and orbital distance 10–100 au, based on the magnitude of the radial-velocity trend and the nondetection of any companion in the speckle images. We expect that the orbital periods of one out of three hot Jupiters will change at rates similar to WASP-4b, based on the hot-Jupiter companion statistics of Knutson et al. Continued radial-velocity monitoring of hot Jupiters is therefore essential to distinguish the effects of tidal orbital decay or apsidal precession from line-of-sight acceleration

Appropriate use criteria for echocardiography in the Netherlands

Introduction Appropriate use criteria (AUC) for echocardiography based on clinical scenarios were previously published by an American Task Force. We determined whether members of the Dutch Working Group on Echocardiography (WGE) would rate these scenarios in a similar way. Methods All 32 members of the WGE were invited to judge clinical scenarios independently using a blanked version of the previously published American version of AUC for echocardiography. During a face-to-face meeting, consensus about the final rating was reached by open discussion for each indication. For reasons of simplicity, the scores were reduced from a 9-point scale to a 3-point scale (indicating an appropriate, uncertain or inappropriate echo indication, respectively). Results Nine cardiologist members of the WGE reported their judgment on the echo cases (n = 153). Seventy-one indications were rated as appropriate, 35 were rated as uncertain, and 47 were rated as inappropriate. In 5% of the cases the rating was opposite to that in the original (appropriate compared with inappropriate and vice versa), whereas in 20% judgements differed by 1 level of appropriateness. After the consensus meeting, the appropriateness of 7 (5%) cases was judged differently compared with the original paper. Conclusions Echocardiography was rated appropriate when it is applied for an initial diagnosis, a change in clinical status or a change in patient management. However, in about 5% of the listed clinical scenarios, members of the Dutch WGE rated the AUC for echocardiography differently as compared with their American counterparts. Further research is warranted to analyse this decreased external validity

Co‐location of the Downdip End of Seismic Coupling and the Continental Shelf Break

International audienceAlong subduction margins, the morphology of the near shore domain records the combined action of erosion from ocean waves and permanent tectonic deformation from the convergence of plates. We observe that at subduction margins around the globe, the edge of continental shelves tends to be located above the downdip end of seismic coupling on the megathrust. Coastlines lie farther landward at variable distances. This observation stems from a compilation of well-resolved coseismic and interseismic coupling data sets. The permanent interseismic uplift component of the total tectonic deformation can explain the localization of the shelf break. It contributes a short wave-length gradient in vertical deformation on top of the structural and isostatic deformation of the margin. This places a hinge line between seaward subsidence and landward uplift above the downdip end of high coupling. Landward of the hinge line, rocks are uplifted in the domain of wave-base erosion and a shelf is maintained by the competition of rock uplift and wave erosion. Wave erosion then sets the coastline back from the tectonically meaningful shelf break. We combine a wave erosion model with an elastic deformation model to illustrate how the downdip end of high coupling pins the location of the shelf break. In areas where the shelf is wide, onshore geodetic constraints on seismic coupling are limited and could be advantageously complemented by considering the location of the shelf break. Subduction margin morphology integrates hundreds of seismic cycles and could inform the persistence of seismic coupling patterns through time

Zeniplatin in patients with advanced ovarian cancer, a phase II study with a third generation platinum complex

25 patients with residual or recurrent ovarian cancer were treated with the new platinum complex zeniplatin (CL 286,558) and 23 patients were evaluable for response. Responses were achieved in 4 patients, 1 complete and 3 partial remissions (16%). 7 patients had stable disease and 12 patients had tumour progression. At a median follow-up of 12 months, the median progression-free survival in responding patients was 11 months and overall survival 81%. The median overall survival of progressive patients amounted to 9 months, indicating the advanced stage of disease in most patients. Renal function was monitored by isotope clearance studies. There was no significant change in effective renal plasma flow (ERPF) or glomerular filtration rate (GFR) in 10 patients who completed six cycles of treatment. 1 patient with a marginal creatinine clearance at baseline suffered from sudden and severe renal failure during the first cycle. Zeniplatin may be active in relapsing, platinum-pretreated patients, and has no direct effects on renal function as measured by isotope clearance. Despite these findings, occasional nephrotoxicity may occur in patients with compromised kidney function, even with prophylactic hydration, and thus limit the application of this new analogue