Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway.

A systematic evaluation of the influence of sex on transduction by recombinant adeno-associated viral vector (rAAV) indicated that transgene expression after liver-targeted delivery of vector particles was between 5- to 13-fold higher in male mice compared with female mice, irrespective of the proviral promoter or cDNA and mouse strain. Molecular analysis revealed that the rAAV genome was stably retained in male liver at levels that were 7-fold higher than those observed in females. Further, the sex difference in transduction was observed with AAV-2- and AAV-5-based vectors, which use distinct receptor complexes for infection. In concordance with the differences in AAV transduction, gel shift analysis with nuclear extracts derived from the liver of mice and humans revealed substantially higher binding of host nuclear protein to the rep-binding site (RBS) of AAV inverted terminal repeat (ITR) in males compared with females. Transduction efficiency and binding of nuclear protein to RBS was dramatically reduced in male mice by castration. In contrast, although oophorectomy did not significantly influence rAAV transduction, administration of 5alpha dihydrotestosterone, prior to gene transfer, increased stable hepatocyte gene transfer in females to levels observed in male mice, implying that androgens significantly influence hepatocyte gene transfer. Interestingly, sex did not have a significant effect on AAV gene transfer into nonhepatic tissue, indicating that there are distinct tissue- and sex-specific differences in the mechanisms responsible for efficient transduction with this vector. These results have significant implications for gene therapy of autosomal and acquired disorders affecting the liver

Type Iax Supernovae

Type Iax supernovae (SN Iax), also called SN 2002cx-like supernovae, are the largest class of peculiar white dwarf (thermonuclear) supernovae, with over fifty members known. SN Iax have lower ejecta velocity and lower luminosities, and these parameters span a much wider range, than normal type Ia supernovae (SN Ia). SN Iax are spectroscopically similar to some SN Ia near maximum light, but are unique among all supernovae in their late-time spectra, which never become fully nebular. SN Iax overwhelmingly occur in late-type host galaxies, implying a relatively young population. The SN Iax 2012Z is the only white dwarf supernova for which a pre-explosion progenitor system has been detected. A variety of models have been proposed, but one leading scenario has emerged: a type Iax supernova may be a pure-deflagration explosion of a carbon-oxygen (or hybrid carbon-oxygen-neon) white dwarf, triggered by helium accretion to the Chandrasekhar mass, that does not necessarily fully disrupt the star.Comment: Author version of a chapter in the 'Handbook of Supernovae', edited by A. Alsabti and P. Murdin, Springer. 31 pages, 6 figure

Toward Automatic Model Comparison: An Adaptive Sequential Monte Carlo Approach

Model comparison for the purposes of selection, averaging, and validation is a problem found throughout statistics. Within the Bayesian paradigm, these problems all require the calculation of the posterior probabilities of models within a particular class. Substantial progress has been made in recent years, but difficulties remain in the implementation of existing schemes. This article presents adaptive sequential Monte Carlo (SMC) sampling strategies to characterize the posterior distribution of a collection of models, as well as the parameters of those models. Both a simple product estimator and a combination of SMC and a path sampling estimator are considered and existing theoretical results are extended to include the path sampling variant. A novel approach to the automatic specification of distributions within SMC algorithms is presented and shown to outperform the state of the art in this area. The performance of the proposed strategies is demonstrated via an extensive empirical study. Comparisons with state-of-the-art algorithms show that the proposed algorithms are always competitive, and often substantially superior to alternative techniques, at equal computational cost and considerably less application-specific implementation effort. Supplementary materials for this article are available online.AJ was supported by EPSRC grant EP/I017984/1; JA by EPSRC grant EP/K021672/1 and the EPSRC/HEFCE CRiSM grant

Effect of Relative Density on Settlements above Tunnels in Sands

This paper presents centrifuge experiment data related to the problem of tunnelling-induced ground displacement in sand. The paper focuses on the examination of the effect that relative density has on greenfield soil displacements above tunnels in sandy ground. Data from a series of plane strain centrifuge tests on tunnels in silica sand are presented. The relative density of the sand ranged from 50% to 90% in the tests. The soil displacement data were obtained using an imaged-based deformation measurement technique and examined to determine features of greenfield settlement, both surface and subsurface. The effect that relative density has on the settlement trough shape is demonstrated and discussed

Quantum Computing with Very Noisy Devices

In theory, quantum computers can efficiently simulate quantum physics, factor large numbers and estimate integrals, thus solving otherwise intractable computational problems. In practice, quantum computers must operate with noisy devices called ``gates'' that tend to destroy the fragile quantum states needed for computation. The goal of fault-tolerant quantum computing is to compute accurately even when gates have a high probability of error each time they are used. Here we give evidence that accurate quantum computing is possible with error probabilities above 3% per gate, which is significantly higher than what was previously thought possible. However, the resources required for computing at such high error probabilities are excessive. Fortunately, they decrease rapidly with decreasing error probabilities. If we had quantum resources comparable to the considerable resources available in today's digital computers, we could implement non-trivial quantum computations at error probabilities as high as 1% per gate.Comment: 47 page

Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques

The feasibility, safety, and efficacy of liver-directed gene transfer was evaluated in 5 male macaques (aged 2.5 to 6.5 years) by using a recombinant adeno-associated viral (rAAV) vector (rAAV-2 CAGG-hFIX) that had previously mediated persistent therapeutic expression of human factor IX (hFIX; 6%-10% of physiologic levels) in murine models. A dose of 4 × 1012 vector genomes (vgs)/kg of body weight was administered through the hepatic artery or portal vein. Persistence of the rAAV vgs as circular monomers and dimers and high-molecular-weight concatamers was documented in liver tissue by Southern blot analysis for periods of up to 1 year. Vector particles were present in plasma, urine, or saliva for several days after infusion (as shown by polymerase chain reaction analysis), and the vgs were detected in spleen tissue at low copy numbers. An enzyme-linked immunosorption assay capable of detecting between 1% and 25% of normal levels of hFIX in rhesus plasma was developed by using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two macaques having 3 and 40 rAAV genome equivalents/cell, respectively, in liver tissue had 4% and 8% of normal physiologic plasma levels of hFIX, respectively. A level of hFIX that was 3% of normal levels was transiently detected in one other macaque, which had a genome copy number of 25 before abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman-primate model will be useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B. © 2002 by The American Society of Hematology

Inactivation of hypoxia inducible factor (HIF) 1 alpha induces obesity-associated metabolic disorders through brown adipose tissue dysfunction

published_or_final_versionThe 14th Medical Research Conference, Hong Kong, 10 January 2009. In Hong Kong Medical Journal, 2009, v. 15, suppl. 1, p. 40, article no. 6

T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells

Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells. © 2013 Li et al

Deleterious Mutations in the TPO Gene Associated with Familial Thyroid Follicular Cell Carcinoma in Dutch German Longhaired Pointers

Familial thyroid cancer originating from follicular cells accounts for 5–15% of all the thyroid carcinoma cases in humans. Previously, we described thyroid follicular cell carcinomas in a large number of the Dutch German longhaired pointers (GLPs) with a likely autosomal recessive inheritance pattern. Here, we investigated the genetic causes of the disease using a combined approach of genome-wide association study and runs of homozygosity (ROH) analysis based on 170k SNP array genotype data and whole-genome sequences. A region 0–5 Mb on chromosome 17 was identified to be associated with the disease. Whole-genome sequencing revealed many mutations fitting the recessive inheritance pattern in this region including two deleterious mutations in the TPO gene, chr17:800788G>A (686F>V) and chr17:805276C>T (845T>M). These two SNP were subsequently genotyped in 186 GLPs (59 affected and 127 unaffected) and confirmed to be highly associated with the disease. The recessive genotypes had higher relative risks of 16.94 and 16.64 compared to homozygous genotypes for the reference alleles, respectively. This study provides novel insight into the genetic causes leading to the familial thyroid follicular cell carcinoma, and we were able to develop a genetic test to screen susceptible dogs.</p

Electronic stress tensor analysis of hydrogenated palladium clusters

We study the chemical bonds of small palladium clusters Pd_n (n=2-9) saturated by hydrogen atoms using electronic stress tensor. Our calculation includes bond orders which are recently proposed based on the stress tensor. It is shown that our bond orders can classify the different types of chemical bonds in those clusters. In particular, we discuss Pd-H bonds associated with the H atoms with high coordination numbers and the difference of H-H bonds in the different Pd clusters from viewpoint of the electronic stress tensor. The notion of "pseudo-spindle structure" is proposed as the region between two atoms where the largest eigenvalue of the electronic stress tensor is negative and corresponding eigenvectors forming a pattern which connects them.Comment: 22 pages, 13 figures, published online, Theoretical Chemistry Account