γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K–dependent proteins

γ-Glutamyl carboxylase (GGCX) is an integral membrane protein that catalyzes posttranslational carboxylation of a number of vitamin K–dependent (VKD) proteins involved in a wide variety of physiologic processes, including blood coagulation, vascular calcification, and bone metabolism. Naturally occurring GGCX mutations are associated with multiple distinct clinical phenotypes. However, the genotype–phenotype correlation of GGCX remains elusive. Here, we systematically examined the effect of all naturally occurring GGCX mutations on the carboxylation of 3 structure–function distinct VKD proteins in a cellular environment. GGCX mutations were transiently introduced into GGCX-deficient human embryonic kidney 293 cells stably expressing chimeric coagulation factor, matrix Gla protein (MGP), or osteocalcin as VKD reporter proteins, and then the carboxylation efficiency of these reporter proteins was evaluated. Our results show that GGCX mutations differentially affect the carboxylation of these reporter proteins and the efficiency of using vitamin K as a cofactor. Carboxylation of these reporter proteins by a C-terminal truncation mutation (R704X) implies that GGCX’s C terminus plays a critical role in the binding of osteocalcin but not in the binding of coagulation factors and MGP. This has been confirmed by probing the protein–protein interaction between GGCX and its protein substrates in live cells using bimolecular fluorescence complementation and chemical cross-linking assays. Additionally, using a minigene splicing assay, we demonstrated that several GGCX missense mutations affect GGCX’s pre–messenger RNA splicing rather than altering the corresponding amino acid residues. Results from this study interpreted the correlation of GGCX’s genotype and its clinical phenotypes and clarified why vitamin K administration rectified bleeding disorders but not nonbleeding disorders

Adiabatic Transfer of Electrons in Coupled Quantum Dots

We investigate the influence of dissipation on one- and two-qubit rotations in coupled semiconductor quantum dots, using a (pseudo) spin-boson model with adiabatically varying parameters. For weak dissipation, we solve a master equation, compare with direct perturbation theory, and derive an expression for the `fidelity loss' during a simple operation that adiabatically moves an electron between two coupled dots. We discuss the possibility of visualizing coherent quantum oscillations in electron `pump' currents, combining quantum adiabaticity and Coulomb blockade. In two-qubit spin-swap operations where the role of intermediate charge states has been discussed recently, we apply our formalism to calculate the fidelity loss due to charge tunneling between two dots.Comment: 13 pages, 8 figures, to appear in Phys. Rev.

Non Linear Current Response of a Many-Level Tunneling System: Higher Harmonics Generation

The fully nonlinear response of a many-level tunneling system to a strong alternating field of high frequency $\omega$ is studied in terms of the Schwinger-Keldysh nonequilibrium Green functions. The nonlinear time dependent tunneling current $I(t)$ is calculated exactly and its resonance structure is elucidated. In particular, it is shown that under certain reasonable conditions on the physical parameters, the Fourier component $I_{n}$ is sharply peaked at $n=\frac {\Delta E} {\hbar \omega}$, where $\Delta E$ is the spacing between two levels. This frequency multiplication results from the highly nonlinear process of $n$ photon absorption (or emission) by the tunneling system. It is also conjectured that this effect (which so far is studied mainly in the context of nonlinear optics) might be experimentally feasible.Comment: 28 pages, LaTex, 7 figures are available upon request from [email protected], submitted to Phys.Rev.

Charge Transport Through Open, Driven Two-Level Systems with Dissipation

We derive a Floquet-like formalism to calculate the stationary average current through an AC driven double quantum dot in presence of dissipation. The method allows us to take into account arbitrary coupling strengths both of a time-dependent field and a bosonic environment. We numerical evaluate a truncation scheme and compare with analytical, perturbative results such as the Tien-Gordon formula.Comment: 14 pages, 6 figures. To appear in Phys. Rev.

Ultrafast Nonlinear Optical Response of Strongly Correlated Systems: Dynamics in the Quantum Hall Effect Regime

We present a theoretical formulation of the coherent ultrafast nonlinear optical response of a strongly correlated system and discuss an example where the Coulomb correlations dominate. We separate out the correlated contributions to the third-order nonlinear polarization, and identify non-Markovian dephasing effects coming from the non-instantaneous interactions and propagation in time of the collective excitations of the many-body system. We discuss the signatures, in the time and frequency dependence of the four-wave-mixing (FWM) spectrum, of the inter-Landau level magnetoplasmon (MP) excitations of the two-dimensional electron gas (2DEG) in a perpendicular magnetic field. We predict a resonant enhancement of the lowest Landau level (LL) FWM signal, a strong non-Markovian dephasing of the next LL magnetoexciton (X), a symmetric FWM temporal profile, and strong oscillations as function of time delay, of quantum kinetic origin. We show that the correlation effects can be controlled experimentally by tuning the central frequency of the optical excitation between the two lowest LLs.Comment: 21 pages, 10 figure

Genome-wide association study of kidney function decline in individuals of European descent.

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.Kidney International advance online publication, 10 December 2014; doi:10.1038/ki.2014.361