Structural and molecular basis of the assembly of the TRPP2/PKD1 complex

Mutations in PKD1 and TRPP2 account for nearly all cases of autosomal dominant polycystic kidney disease (ADPKD). These 2 proteins form a receptor/ion channel complex on the cell surface. Using a combination of biochemistry, crystallography, and a single-molecule method to determine the subunit composition of proteins in the plasma membrane of live cells, we find that this complex contains 3 TRPP2 and 1 PKD1. A newly identified coiled-coil domain in the C terminus of TRPP2 is critical for the formation of this complex. This coiled-coil domain forms a homotrimer, in both solution and crystal structure, and binds to a single coiled-coil domain in the C terminus of PKD1. Mutations that disrupt the TRPP2 coiled-coil domain trimer abolish the assembly of both the full-length TRPP2 trimer and the TRPP2/PKD1 complex and diminish the surface expression of both proteins. These results have significant implications for the assembly, regulation, and function of the TRPP2/PKD1 complex and the pathogenic mechanism of some ADPKD-producing mutations

Single Nucleotide Polymorphism (SNP) Detection and Genotype Calling from Massively Parallel Sequencing (MPS) Data

Massively parallel sequencing (MPS), since its debut in 2005, has transformed the field of genomic studies. These new sequencing technologies have resulted in the successful identification of causal variants for several rare Mendelian disorders. They have also begun to deliver on their promise to explain some of the missing heritability from genome-wide association studies (GWAS) of complex traits. We anticipate a rapidly growing number of MPS-based studies for a diverse range of applications in the near future. One crucial and nearly inevitable step is to detect SNPs and call genotypes at the detected polymorphic sites from the sequencing data. Here, we review statistical methods that have been proposed in the past five years for this purpose. In addition, we discuss emerging issues and future directions related to SNP detection and genotype calling from MPS data

Wigner Crystals Phases in Bilayer Quantum Hall Systems

(This is a substantially shortened version of the original abstract:) The Wigner crystal phase diagram of the bilayer systems have been studied using variational methods. Five crystal phases are obtained. As the layer spacing increases, the system will undergo a sequence of phase transitions. A common feature of most bilayer Wigner crystals is that they have mixed (pseudo-spin) ferromagnetic and antiferromagnetic order.Comment: 19 figures. Figures will be provided upon request. Submitted in PRB in Nov 94

Quantum Correlated Interstitials and the Hall Resistivity of the Magnetically Induced Wigner Crystal

We study a trial wavefunction for an interstitial in a Wigner crystal. We find that the electron correlations, ignored in a conventional Hartree-Fock treatment, dramatically lower the interstitial energy, especially at fillings close to an incompressible liquid state. The correlation between the interstitial electron and the lattice electrons at $\nu <1/m$ is introduced by constructing a trial wave- function which bears a Jastrow factor of a Laughlin state at $\nu=1/m$. For fillings close to but just below $\nu=1/m$, we find that a perfect Wigner crystal becomes unstable against formation of such interstitials. It is argued that conduction due to correlated interstitials in the presence of weak disorder leads to the {\it classical} Hall resistivity, as seen experimentally.Comment: 10 pages, RevTe

Intra-articular delivery of AAV vectors encoding PD-L1 attenuates joint inflammation and tissue damage in a mouse model of rheumatoid arthritis

Objective: Rheumatoid arthritis (RA) is the most common form of autoimmune inflammatory arthritis. Intra-articular gene delivery to block proinflammatory cytokines has been studied in pre-clinical models and human clinical trials. It has been demonstrated that the level of programmed death-ligand 1 (PD-L1) is associated with rheumatoid arthritis (RA). This study examined the therapeutic role of PD-L1 by intra-articular delivery via adeno-associated virus (AAV) vectors in the mouse collagen-induced arthritis (CIA) model. Methods: Mice were intra-articularly injected with AAV5 vectors encoding human PD-L1 on day 0 and immunized with bovine type II collagen to induce CIA simultaneously. On day 49 post AAV administration, joints were collected for histo-pathological and cytokine analysis. Additionally, the systemic impacts of intra-articular injection of AAV5/PD-L1 vectors were also studied. To study the therapeutic effect of PD-L1, AAV5/PD-L1 vectors were administered into the joints of RA mice on day 21. Results: After administration of AAV5/PD-L1 vectors, strong PD-L1 expression was detected in AAV transduced joints. Joints treated with PD-L1 at the time of arthritis induction exhibited significantly less swelling and improved histopathological scores when compared to untreated joints. Additionally, the infiltration of T cells and macrophages was decreased in joints of CIA mice that received AAV5/PD-L1 vectors (P<0.05). The levels of pro-inflammatory cytokines, including IL-1, IL-6, IL-17 and TNFα, were lower in AAV5/PD-L1 treated than untreated joints (P<0.05). Furthermore, the administration of AAV5/PD-L1 vectors into the joints of CIA mice did not impact serum cytokine levels and the antibody titers to type II collagen. Biodistribution of AAV vectors after intra-articular injection showed undetectable AAV genomes in other tissues except for a low level in the liver. Similar to the results of AAV5/PD-L1 vector administration on day 0, decreased joint swelling and lower histopathological damage were observed in joints treated with AAV5/PD-L1 vectors on day 21. Conclusion: The results from this study demonstrate that local AAV mediated PD-L1 gene delivery into the joints is able to prevent the development and block the progression of arthritis in CIA mice without impacting systemic immune responses. This study provides a novel strategy to effectively treat inflammatory joint diseases using local AAV gene therapy by interference with immune checkpoint pathways

Evolution of the Southwest Australian Rifted Continental Margin During Breakup of East Gondwana: Results from IODP Expedition 369

International Ocean Discovery Program Expedition 369 drilled four sites on the southwestern Australian continental margin, in the deep water Mentelle Basin (MB) and on the neighboring Naturaliste Plateau (NP). The drillsites are located on continental crust that continued rifting after seafloor spreading began further north on the Perth Abyssal Plain (PAP) between magnetochrons M11r and M11n (133‐132 Ma), ending when spreading began west of the NP between chrons M5n and M3n (126‐124 Ma). Drilling recovered the first in‐situ samples of basalt flows overlying the breakup unconformity on the NP, establishing a magnetostratigraphically constrained eruption age of >131‐133 Ma and confirming a minimal late Valanginian age for the breakup unconformity (coeval with the onset of PAP seafloor spreading). Petrogenetic modeling indicates the basalts were generated by 25% melting at 1.5 GPa and a potential temperature of 1380‐1410 °C, consistent with proximity of the Kerguelen plume during breakup. Benthic foraminiferal fossils indicate that the NP remained at upper bathyal or shallower depths during the last 6 Myr of rifting and for 3‐5 Myr after breakup between India and Australia. The limited subsidence is attributed to heat from the nearby Kerguelen plume and PAP spreading ridge. The margin subsided to middle bathyal depths by Albian time and to lower bathyal (NP) or greater (MB) depths by late Paleogene time. Periods of rapid sedimentation accompanied a westward jump of the PAP spreading ridge (108 Ma), rifting on the southern margin (100‐84 Ma), and opening of the southern seaway between Australia and Antarctica (60‐47 Ma)

Sliding conduction by the quasi one-dimensional charge-ordered state in Sr14−x_{14-x}Cax_xCu24_{24}O41_{41}

Nonlinear conduction (NLC) of the two-leg spin ladder, Sr$_{14-x}$Ca$_x$Cu$_{24}$O$_{41}$, was investigated for the $x$=0, 1 and 12 materials . Although insulating materials ($x$=0 and 1) exibited the NLC both in the ladder- and rung directions, the NLC in the ladder direction of the $x$=0-material was found to be very special. We considered this to be due to the sliding motion of the charge ordered state, which was responsible for the resonance at microwave frequencies. We discussed possible candidates for the charge ordered state responsible for the NLC, including Wigner crystal in quasi one dimension (4$k_F$-CDW).Comment: 5 figure