Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel

Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of K(ATP) channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second K(ATP) channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K(+) depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic K(ATP) channels and a contributory role for these subunits in the control of insulin secretion

Resonant Magnetization Tunneling in Mn12 Acetate: The Absence of Inhomogeneous Hyperfine Broadening

We present the results of a detailed study of the thermally-assisted-resonant-tunneling relaxation rate of Mn12 acetate as a function of an external, longitudinal magnetic field and find that the data can be fit extremely well to a Lorentzian function. No hint of inhomogeneous broadening is found, even though some is expected from the Mn nuclear hyperfine interaction. This inconsistency implies that the tunneling mechanism cannot be described simply in terms of a random hyperfine field.Comment: Some minor revisions, title changed, updated figures, two added notes, one added reference. RevTeX, 4 pages, 3 postscript figures. Submitted to Rapid Communication

Single and double qubit gates by manipulating degeneracy

A novel mechanism is proposed for single and double qubit state manipulations in quantum computation with four-fold degenerate energy levels. The principle is based on starting with a four fold degeneracy, lifting it stepwise adiabatically by a set of control parameters and performing the quantum gate operations on non-degenerate states. A particular realization of the proposed mechanism is suggested by using inductively coupled rf-squid loops in the macroscopic quantum tunnelling regime where the energy eigen levels are directly connected with the measurable flux states. The one qubit and two qubit controlled operations are demonstrated explicitly. The appearance of the flux states also allows precise read-in and read-out operations by the measurement of flux.Comment: 6 pages + 5 figures (separately included

The Basics of American Government

Newly revised, The Basics of American Government offers a comprehensive overview of the American political system for students taking introductory courses in American national government and combines the best aspects of both a traditional textbook and a reader. The Basics of American Government is a collaborative effort among eight current and one former faculty members in the Department of Political Science & Criminal Justice at the University of North Georgia. Most of its chapters offer a piece of original scholarship as a case study bolstering the material in the chapter. Additionally, most chapters present a civic engagement-type exercise and discussion questions that are challenging and engaging, and help foster student participation in the political system. The purpose of this book is to offer a no-frills, low-cost, yet comprehensive overview of the American political system for students taking introductory courses in American national government. A print version of this book is available for $27.99. Contact the University of North Georgia Press for details and ordering information. [email protected] | 706-864-1556https://digitalcommons.northgeorgia.edu/books/1004/thumbnail.jp

The Initial Response to the Boston Marathon Bombing

We discuss the strengths of the medical response to the Boston Marathon bombings that led to the excellent outcomes. Potential shortcomings were recognized, and lessons learned will provide a foundation for further improvements applicable to all institutions

Dynamic recruitment of microRNAs to their mRNA targets in the regenerating liver.

BACKGROUND: Validation of physiologic miRNA targets has been met with significant challenges. We employed HITS-CLIP to identify which miRNAs participate in liver regeneration, and to identify their target mRNAs. RESULTS: miRNA recruitment to the RISC is highly dynamic, changing more than five-fold for several miRNAs. miRNA recruitment to the RISC did not correlate with changes in overall miRNA expression for these dynamically recruited miRNAs, emphasizing the necessity to determine miRNA recruitment to the RISC in order to fully assess the impact of miRNA regulation. We incorporated RNA-seq quantification of total mRNA to identify expression-weighted Ago footprints, and developed a microRNA regulatory element (MRE) prediction algorithm that represents a greater than 20-fold refinement over computational methods alone. These high confidence MREs were used to generate candidate \u27competing endogenous RNA\u27 (ceRNA) networks. CONCLUSION: HITS-CLIP analysis provide novel insights into global miRNA:mRNA relationships in the regenerating liver

GUTs and Exceptional Branes in F-theory - I

Motivated by potential phenomenological applications, we develop the necessary tools for building GUT models in F-theory. This approach is quite flexible because the local geometrical properties of singularities in F-theory compactifications encode the physical content of the theory. In particular, we show how geometry determines the gauge group, matter content and Yukawa couplings of a given model. It turns out that these features are beautifully captured by a four-dimensional topologically twisted N=4 theory which has been coupled to a surface defect theory on which chiral matter can propagate. From the vantagepoint of the four-dimensional topological theory, these defects are surface operators. Specific intersection points of these defects lead to Yukawa couplings. We also find that the unfolding of the singularity in the F-theory geometry precisely matches to properties of the topological theory with a defect.Comment: v2: 121 pages, 5 figures, reference and clarification adde

Combined carbonate carbon isotopic and cellular ultrastructural studies of individual benthic foraminifera : method description

Author Posting. © American Geophysical Union, 2010. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 25 (2010): PA2211, doi:10.1029/2009PA001846.Carbon isotopes of foraminiferal tests provide a widely used proxy for past oceanographic environmental conditions. This proxy can be calibrated using live specimens, which are reliably identified with observations of cell ultrastructure. Observations of ultrastructures can also be used for studies of biological characteristics such as diet and presence of symbionts. Combining biological and isotopic studies on individual foraminifera could provide novel information, but standard isotopic methods destroy ultrastructures by desiccating specimens and observations of ultrastructure require removal of carbonate tests, preventing isotope measurements. The approach described here preserves cellular ultrastructure during isotopic analyses by keeping the foraminifera in an aqueous buffer (Phosphate Buffered Saline (PBS)). The technique was developed and standardized with 36 aliquots of NBS-19 standard of similar weight to foraminiferal tests (5 to 123 μg). Standard errors ranged from ± 0.06 to ± 0.85‰ and were caused by CO2 contaminants dissolved in the PBS. The technique was used to measure δ13C values of 96 foraminifera, 10 of which do not precipitate carbonate tests. Calcareous foraminiferal tests had corrected carbon isotope ratios of −8.5 to +3.2‰. This new technique allows comparisons of isotopic compositions of tests made by foraminifera known to be alive at the time of collection with their biological characteristics such as prey composition and presence or absence of putative symbionts. The approach may be applied to additional biomineralizing organisms such as planktonic foraminifera, pteropods, corals, and coccolithophores to elucidate certain biological controls on their paleoceanographic proxy signatures.Support was provided by NSF grants OCE‐0550396 (to J.B.M.), OCE‐0551001 (to J.M.B.), and OCE‐ 0550401 (to A.E.R.)

Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total