Adaptive changes in GFR, tubular morphology, and transport in subtotal nephrectomized kidneys: modeling and analysis

Removal of renal mass stimulates anatomical and functional adaptations in the surviving nephrons, including elevations in single-nephron glomerular filtration rate (SNGFR) and tubular hypertrophy. A goal of this study is to assess the extent to which the concomitant increases in filtered load and tubular transport capacity preserve homeostasis of water and salt. To accomplish that goal, we developed computational models to simulate solute transport and metabolism along nephron populations in a uninephrectomized (UNX) rat and a 5/6-nephrectomized (5/6-NX) rat. Model simulations indicate that nephrectomy-induced SNGFR increase and tubular hypertrophy go a long way to normalize excretion, but alone are insufficient to fully maintain salt balance. We then identified increases in the protein density of Na+-K+-ATPase, Na+-K+-2Cl- cotransporter, Na+-Cl- cotransporter, and epithelial Na+ channel, such that the UNX and 5/6-NX models predict urine flow and urinary Na+ and K+ excretions that are similar to sham levels. The models predict that, in the UNX and 5/6-NX kidneys, fractional water and salt reabsorption is similar to sham along the initial nephron segments (i.e., from the proximal tubule to the distal convoluted tubule), with a need to further reduce Na+ reabsorption and increase K+ secretion primarily along the connecting tubules and collecting ducts to achieve balance. Additionally, the models predict that, given the substantially elevated filtered and thus transport load among each of the surviving nephrons, oxygen consumption per nephron segment in a UNX or 5/6-NX kidney increases substantially. But due to the reduced nephron population, whole animal renal oxygen consumption is lower. The efficiency of tubular Na+ transport in the UNX and 5/6-NX kidneys is predicted to be similar to sham.This research was supported by the Department of Veterans Affairs (to V. Vallon) and by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-56248 (to V. Vallon), R01-DK-106102 (A. T. Layton and V. Vallon), and the University of Alabama at Birmingham/ University of California San Diego O'Brien Center for Acute Kidney Injury Research NIH-P30-DK-079337 (to V. Vallon). (Department of Veterans Affairs; R01-DK-56248 - National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; R01-DK-106102 - National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; NIH-P30-DK-079337 - University of Alabama at Birmingham/ University of California San Diego O'Brien Center for Acute Kidney Injury Research)Accepted manuscrip

Renal potassium handling in rats with subtotal nephrectomy: modeling and analysis

We sought to decipher the mechanisms underlying the kidney's response to changes in K+ load and intake, under physiological and pathophysiological conditions. To accomplish that goal, we applied a published computational model of epithelial transport along rat nephrons in a sham rat, an uninephrectomized (UNX) rat, and a 5/6-nephrectomized (5/6-NX) rat that also considers adaptations in glomerular filtration rate and tubular growth. Model simulations of an acute K+ load indicate that elevated expression levels and activities of Na+/K+-ATPase, epithelial sodium channels, large-conductance Ca2+-activated K+ channels, and renal outer medullary K+ channels, together with downregulation of sodium-chloride cotransporters (NCC), increase K+ secretion along the connecting tubule, resulting in a >6-fold increase in urinary K+ excretion in sham rats, which substantially exceeds the filtered K+ load. In the UNX and 5/6-NX models, the acute K+ load is predicted to increase K+ excretion, but at significantly reduced levels compared with sham. Acute K+ load is accompanied by natriuresis in sham rats. Model simulations suggest that the lesser natriuretic effect observed in the nephrectomized groups may be explained by impaired NCC downregulation in these kidneys. At a single-nephron level, a high K+ intake raises K+ secretion along the connecting tubule and reabsorption along the collecting duct in sham, and even more in UNX and 5/6-NX. However, the increased K+ secretion per tubule fails to sufficiently compensate for the reduction in nephron number, such that nephrectomized rats have an impaired ability to excrete an acute or chronic K+ load.This research was supported by the Department of Veterans Affairs (V. Vallon), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grants R01-DK-112042 (V. Vallon) and R01-DK-106102 (A. T. Layton and V. Vallon), and University of Alabama at Birmingham-University of California San Diego O'Brien Center for Acute Kidney Injury Research (NIDDK Grant P30-DK-079337; V. Vallon). (Department of Veterans Affairs; R01-DK-112042 - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); R01-DK-106102 - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); P30-DK-079337 - University of Alabama at Birmingham-University of California San Diego O'Brien Center for Acute Kidney Injury Research (NIDDK Grant))Accepted manuscrip

Characteristics of Coulomb fission

Within an extended semiquantal theory we perform large-sized coupled-channel calculations involving 260 collective levels for Coulomb fission of 238U. Differential Coulomb fission cross sections are studied as a function of bombarding energy and impact parameter for several projectiles. In the Xe + U case, total cross sections are also given. We find a strong dependence on projectile charge number, PCF(180°)∼(Zp)6 in the region 50≤Zp≤92 for a fixed ratio E/ECoul, which might be helpful to separate Coulomb fission experimentally from sequential fission following transfer reactions. Since the cross sections are sensitive to the moment of inertia ⊖ at the saddle point, Coulomb fission can serve as a tool to investigate the dependence of ⊖ on elongation. The fragment angular distribution exhibits deviations from 1/sinθf which are pronounced at low incident energies. Our theory indicates that the recently measured Xe + U fission cross sections contain a major fraction of Coulomb-induced fission at E≤0.85 ECoul. NUCLEAR REACTIONS, FISSION Calculated Coulomb fission cross sections σ(Ep,θp) for 54Xe, 67Ho, 82Pb, 92U→92238U, fragment angular distribution, fission energy spectrum, mean spin value 〈Jf〉

Data uncertainty and the role of money as an information variable for monetary policy

This paper shows that money can play an important role as an information variable when initial output data are measured with error and subject to revision. Using an estimated model of the euro area we find that current output estimates may be substantially improved by including money growth in the information set. The gain in precision, however, depends on the magnitude of the output measurement error relative to the money demand shock. We find noticable but small improvements in output estimates, if the uncertainty due to money demand shocks corresponds to the estimated variance obtained from the money demand equation. Money plays a quantitatively more important role with regard to output estimation if we allow for a contribution of monetary analysis in reducing uncertainty due to money demand shocks. In this case, money also helps to reduce uncertainty about output forecasts JEL Classification: E31, E52, E58, E61euro area, Kalman ?lter, macroeconomic modelling, measurement error, monetary policy rules, Rational Expectations

The performance of forecast-based monetary policy rules under model uncertainty

We investigate the performance of forecast-based monetary policy rules using five macroeconomic models that reflect a wide range of views on aggregate dynamics. We identify the key characteristics of rules that are robust to model uncertainty: such rules respond to the one-year ahead inflation forecast and to the current output gap, and incorporate a substantial degree of policy inertia. In contrast, rules with longer forecast horizons are less robust and are prone to generating indeterminacy. In light of these results, we identify a robust benchmark rule that performs very well in all five models over a wide range of policy preferences JEL Classification: E31, E52, E58, E61

Shedding of host autophagic proteins from the parasitophorous vacuolar membrane of Plasmodium berghei

The hepatic stage of the malaria parasite Plasmodium is accompanied by an autophagy-mediated host response directly targeting the parasitophorous vacuolar membrane (PVM) harbouring the parasite. Removal of the PVM-associated autophagic proteins such as ubiquitin, p62, and LC3 correlates with parasite survival. Yet, it is unclear how Plasmodium avoids the deleterious effects of selective autophagy. Here we show that parasites trap host autophagic factors in the tubovesicular network (TVN), an expansion of the PVM into the host cytoplasm. In proliferating parasites, PVM-associated LC3 becomes immediately redirected into the TVN, where it accumulates distally from the parasite's replicative centre. Finally, the host factors are shed as vesicles into the host cytoplasm. This strategy may enable the parasite to balance the benefits of the enhanced host catabolic activity with the risk of being eliminated by the cell's cytosolic immune defence