The fate of bone marrow-derived cells carrying a polycystic kidney disease mutation in the genetically normal kidney

Polycystic Kidney Disease (PKD) is a genetic condition in which dedifferentiated and highly proliferative epithelial cells form renal cysts and is frequently treated by renal transplantation. Studies have reported that bone marrow-derived cells give rise to renal epithelial cells, particularly following renal injury as often occurs during transplantation. This raises the possibility that bone marrow-derived cells from a PKD-afflicted recipient could populate a transplanted kidney and express a disease phenotype. However, for reasons that are not clear the reoccurrence of PKD has not been reported in a genetically normal renal graft. We used a mouse model to examine whether PKD mutant bone marrow-derived cells are capable of expressing a disease phenotype in the kidney

Carbon lock-in through capital stock inertia associated with weak near-term climate policies

Stringent long-term climate targets necessitate a limit on cumulative emissions in this century for which sufficient policy signals are lacking. Using nine energy-economy models, we explore how policies pursued during the next two decades impact long-term transformation pathways towards stringent long-term climate targets. Less stringent near-term policies (i.e., those with larger emissions) consume more of the long-term cumulative emissions budget in the 2010–2030 period, which increases the likelihood of overshooting the budget and the urgency of reducing GHG emissions after 2030. Furthermore, the larger near-term GHG emissions associated with less stringent policies are generated primarily by additional coal-based electricity generation. Therefore, to be successful in meeting the long-term target despite near-term emissions reductions that are weaker than those implied by cost-optimal mitigation pathways, models must prematurely retire significant coal capacity while rapidly ramping up low-carbon technologies between 2030 and 2050 and remove large quantities of CO2 from the atmosphere in the latter half of the century. While increased energy efficiency lowers mitigation costs considerably, even with weak near-term policies, it does not substantially reduce the short-term reliance on coal electricity. However, increased energy efficiency does allow the energy system more flexibility in mitigating emissions and, thus, facilitates the post-2030 transition

Carbon lock-in through capital stock inertia associated with weak near-term climate policies

Stringent long-term climate targets necessitate a limit on cumulative emissions in this century for which sufficient policy signals are lacking. Using nine energy-economy models, we explore how policies pursued during the next two decades impact long-term transformation pathways towards stringent long-term climate targets. Less stringent near-term policies (i.e., those with larger emissions) consume more of the long-term cumulative emissions budget in the 2010-2030 period, which increases the likelihood of overshooting the budget and the urgency of reducing GHG emissions after 2030. Furthermore, the larger near-term GHG emissions associated with less stringent policies are generated primarily by additional coal-based electricity generation. Therefore, to be successful in meeting the long-term target despite near-term emissions reductions that are weaker than those implied by cost-optimal mitigation pathways, models must prematurely retire significant coal capacity while rapidly ramping up low-carbon technologies between 2030 and 2050 and remove large quantities of CO2 from the atmosphere in the latter half of the century. While increased energy efficiency lowers mitigation costs considerably, even with weak near-term policies, it does not substantially reduce the short-term reliance on coal electricity. However, increased energy efficiency does allow the energy system more flexibility in mitigating emissions and, thus, facilitates the post-2030 transition

Abelian Yang-Mills theory on Real tori and Theta divisors of Klein surfaces

The purpose of this paper is to compute determinant index bundles of certain families of Real Dirac type operators on Klein surfaces as elements in the corresponding Grothendieck group of Real line bundles in the sense of Atiyah. On a Klein surface these determinant index bundles have a natural holomorphic description as theta line bundles. In particular we compute the first Stiefel-Whitney classes of the corresponding fixed point bundles on the real part of the Picard torus. The computation of these classes is important, because they control to a large extent the orientability of certain moduli spaces in Real gauge theory and Real algebraic geometry.Comment: LaTeX, 44 pages, to appear in Comm. Math. Phy

Complex Patterns of Metabolic and Ca²⁺ Entrainment in Pancreatic Islets by Oscillatory Glucose

Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca(2+) in pancreatic islets. Periodic variations in glucose can entrain islet Ca(2+) and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca(2+), NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca(2+) influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas

Complex Patterns of Metabolic and Ca²⁺ Entrainment in Pancreatic Islets by Oscillatory Glucose

Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca(2+) in pancreatic islets. Periodic variations in glucose can entrain islet Ca(2+) and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca(2+), NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca(2+) influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas

Locked into Copenhagen pledges - Implications of short-term emission targets for the cost and feasibility of long-term climate goals

This paper provides an overview of the AMPERE modeling comparison project with focus on the implications of near-term policies for the costs and attainability of long-term climate objectives. Nine modeling teams participated in the project to explore the consequences of global emissions following the proposed policy stringency of the national pledges from the Copenhagen Accord and Cancun Agreements to 2030. Specific features compared to earlier assessments are the explicit consideration of near-term 2030 emission targets as well as the systematic sensitivity analysis for the availability and potential of mitigation technologies. Our estimates show that a 2030 mitigation effort comparable to the pledges would result in a further "lock-in" of the energy system into fossil fuels and thus impede the required energy transformation to reach low greenhouse-gas stabilization levels (450 ppm CO2e). Major implications include significant increases in mitigation costs, increased risk that low stabilization targets become unattainable, and reduced chances of staying below the proposed temperature change target of 2 degrees C in case of overshoot. With respect to technologies, we find that following the pledge pathways to 2030 would narrow policy choices, and increases the risks that some currently optional technologies, such as carbon capture and storage (CCS) or the large-scale deployment of bioenergy, will become "a must" by 2030

Observations of APAN during TexAQS 2000

Measurements of peroxycarboxylic nitric anhydrides (PANs) made in Houston, Texas during TexAQS (Texas Air Quality Study) 2000 showed a relatively abundant PAN compound that had not been identified in previous studies in North America [cf. Williams et al., 2000]. This compound was hypothesized to be peroxyacrylic nitric anhydride { CH2=CHC(O)OONO2, APAN} based on the work of Tanimoto and Akimoto, [2001]. APAN was synthesized and characterized on one of the two GC systems used to make those measurements, subsequent to the TexAQS 2000 field study, confirming that APAN was observed during TexAQS 2000, both on the ground and in airborne measurements. Mixing ratios of APAN were estimated from the response of the system to PAN and PPN and ranged up to 502 pptv, which was 30% of PAN. High APAN values were associated with the precursor species 1,3-butadiene and acrolein, which had local petrochemical sources. The presence of APAN at these unprecedented levels demonstrates the impact of these reactive VOC species, and may have associated health effects

Stops making sense: translational trade-offs and stop codon reassignment

Background Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature. Results In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences. Conclusions We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants