Perinatal Gene Transfer to the Liver

The liver acts as a host to many functions hence raising the possibility that any one may be compromised by a single gene defect. Inherited or de novo mutations in these genes may result in relatively mild diseases or be so devastating that death within the first weeks or months of life is inevitable. Some diseases can be managed using conventional medicines whereas others are, as yet, untreatable. In this review we consider the application of early intervention gene therapy in neonatal and fetal preclinical studies. We appraise the tools of this technology, including lentivirus, adenovirus and adeno-associated virus (AAV)-based vectors. We highlight the application of these for a range of diseases including hemophilia, urea cycle disorders such as ornithine transcarbamylase deficiency, organic acidemias, lysosomal storage diseases including mucopolysaccharidoses, glycogen storage diseases and bile metabolism. We conclude by assessing the advantages and disadvantages associated with fetal and neonatal liver gene transfer

Friction and wear behavior of glasses and ceramics

Adhesion, friction, and wear behavior of glasses and ionic solids are reviewed. These materials are shown to behave in a manner similar to other solids with respect to adhesion. Their friction characteristics are shown to be sensitive to environmental constituents and surface films. This sensitivity can be related to a reduction in adhesive bonding and the changes in surficial mechanical behavior associated with Rehbinder and Joffe effects. Both friction and wear properties of ionic crystalline solids are highly anisotropic. With metals in contact with ionic solids the fracture strength of the ionic solid and the shear strength in the metal and those properties that determine these will dictate which of the materials undergoes adhesive wear. The chemical activity of the metal plays an important role in the nature and strength of the adhesive interfacial bond that develops between the metal and a glass or ionic solid

Shear rheological properties of fresh human faeces with different moisture content

Dry sanitation requires the handling of faeces, which vary in age and degree of transformation. Rheological data are necessary to support the design of equipment to handle faeces. The rheological properties of fresh human faeces were measured using a variable-speed rotational rheometer. Samples were further tested for moisture content, total solids, volatile content, and ash content. Faecal samples were found to have a yield stress; there was a decrease in apparent viscosity with increasing shear rate. For any given shear rate, higher apparent viscosities are associated with lower moisture contents. Across a range of water contents of 58.5% to 88.7%, apparent viscosities of 27 Pa∙s to 2 014 Pa∙s were measured at a shear rate of 1 s-1. During constant shear tests, the apparent viscosity of all faeces was found to decrease asymptotically, where the minimum apparent viscosity value increased with decreasing moisture content. A structural recovery test indicates that human faeces are thixotropic in behaviour, where the viscosity permanently decreases to 0.5% of the initial value after a 20 s exposure to a shear rate of 10 s-1. A linear relationship between viscosity and temperature was found, with a recorded 30.6% decrease in viscosity for a 35.6 °C increase in temperature from 13.4°C.Keywords: Human stool, mechanical properties, water content, flow curve, viscosity, yield stres

Setting the Record Straight: Assessing the Reliability of Retrospective Accounts of Change

This is the final version of the article. Available from Wiley via the DOI in this record.Ecological degradation is accelerating, reducing our ability to detect and reverse declines. Resource user accounts have the potential to provide critical information on past change but their reliability can rarely be tested, hence they are often perceived as less valid than other forms of scientific data. We compared individual fishers' catch records, recorded 1-50 years ago, with their memories of past good, typical and poor catches for the corresponding time period. Good and poor catches were recalled with reasonable accuracy, matching variability in recorded catch with no significant change observed over time. Typical recalled catches were overestimated and became significantly more exaggerated over time, but were more comparable to mean than median recorded values. While accuracy of resource users' memory varied with the type of information recalled, our results suggest that carefully structured interview questions can produce reliable quantitative data to inform resource management, even after several decades have elapsed.All authors were supported by the Australian Research Council’s Centre for Excellence for Coral Reef Studies. Fieldwork components were supported by The University of Queensland’s New Staff Start-Up Fund (Project No. 2012000643) and the FRDC (Project No. 2013–018), on behalf of the Australian Government

Historical spatial reconstruction of a spawning-aggregation fishery

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Aggregations of individual animals that form for breeding purposes are a critical ecological processfor many species, yet these aggregations are inherently vulnerable to exploitation. Studies of the decline ofexploited populations that form breeding aggregations tend to focus on catch rate and thus often overlookreductions in geographic range. We tested the hypothesis that catch rate and site occupancy of exploited fish-spawning aggregations (FSAs) decline in synchrony over time. We used the Spanish mackerel (Scomberomoruscommerson) spawning-aggregation fishery in the Great Barrier Reef as a case study. Data were compiled fromhistorical newspaper archives, fisher knowledge, and contemporary fishery logbooks to reconstruct catchrates and exploitation trends from the inception of the fishery. Our fine-scale analysis of catch and effort dataspanned 103 years (1911–2013) and revealed a spatial expansion of fishing effort. Effort shifted offshore at arate of 9.4 nm/decade, and 2.9 newly targeted FSAs were reported/decade. Spatial expansion of effort maskedthe sequential exploitation, commercial extinction, and loss of 70% of exploited FSAs. After standardizing forimprovements in technological innovations, average catch rates declined by 90.5% from 1934 to 2011 (from119.4 to 11.41 fish/vessel/trip). Mean catch rate of Spanish mackerel and occupancy of exploited mackerelFSAs were not significantly related. Our study revealed a special kind of shifting spatial baseline in which acontraction in exploited FSAs occurred undetected. Knowledge of temporally and spatially explicit informationon FSAs can be relevant for the conservation and management of FSA species.S.B., R.T., andJ.P. were supported by the Australian Research Council(ARC) Centre of Excellence for Coral Reef Studies and the Fisheries Research and Development Corporation(project 2013-018). A.T. and S.B. were supported by funding from the Fisheries Research and Development Corporation (project 2010-007) on behalf of the Australian Government

In vitro co-culture and ex vivo organ culture assessment of primed and cryopreserved stromal cell microcapsules for intervertebral disc regeneration

Priming towards a discogenic phenotype and subsequent cryopreservation of microencapsulated bone marrow stromal cells (BMSCs) may offer an attractive therapeutic approach for disc repair. It potentially obviates the need for in vivo administration of exogenous growth factors, otherwise required to promote matrix synthesis, in addition to providing 'off-the-shelf' availability. Cryopreserved and primed BMSC microcapsules were evaluated in an in vitro surrogate co-culture model system with nucleus pulposus (NP) cells under intervertebral disc (IVD)-like culture conditions and in an ex vivo bovine organ culture disc model. BMSCs were microencapsulated in alginate microcapsules and primed for 14 d with transforming growth factor beta-3 (TGF-β3) under low oxygen conditions prior to cryopreservation. For the in vitro phase, BMSC microcapsules (unprimed or primed) were cultured for 28 d in a surrogate co-culture model system mimicking that of the IVD. For the ex vivo phase, microcapsules (unprimed or primed) were injected into the NP of bovine discs that underwent nucleotomy. In vitro results revealed that although NP cells produced significantly more matrix components in co-culture with BMSC microcapsules regardless of the differentiation state, unprimed microcapsules were inadequate at synthesising matrix as compared to primed microcapsules. However, this difference was diminished when evaluated in the ex vivo organ culture model,withboth unprimed and primed BMSC microcapsules accumulating large amounts of sulphated glycosaminoglycan (sGAG) and collagen and filling the defect cavity. Both models demonstrated that cryopreservation of BMSC microcapsules may offer a feasible strategy for predesigned delivery through cryobanking for on-demand regeneration of the IVD

The Maximal U(1)LU(1)_L Inverse Seesaw from d=5d=5 Operator and Oscillating Asymmetric Sneutrino Dark Matter

The maximal $U(1)_L$ supersymmetric inverse seesaw mechanism (M$L$SIS) provides a natural way to relate asymmetric dark matter (ADM) with neutrino physics. In this paper we point out that, M$L$SIS is a natural outcome if one dynamically realizes the inverse seesaw mechanism in the next-to minimal supersymmetric standard model (NMSSM) via the dimension-five operator $(N)^2S^2/M_*$, with $S$ the NMSSM singlet developing TeV scale VEV; it slightly violates lepton number due to the suppression by the fundamental scale $M_*$, thus preserving $U(1)_L$ maximally. The resulting sneutrino is a distinguishable ADM candidate, oscillating and favored to have weak scale mass. A fairly large annihilating cross section of such a heavy ADM is available due to the presence of singlet.Comment: journal versio

Internalisation Theory and outward direct investment by emerging market multinationals

The rise of multinational enterprises from emerging countries (EMNEs) poses an important test for theories of the multinational enterprise such as internalisation theory. It has been contended that new phenomena need new theory. This paper proposes that internalisation theory is appropriate to analyse EMNEs. This paper examines four approaches to EMNEs—international investment strategies, domestic market imperfections, international corporate networks and domestic institutions—and three case studies—Chinese outward FDI, Indian foreign acquisitions and investment in tax havens—to show the enduring relevance and predictive power of internalisation theory. This analysis encompasses many other approaches as special cases of internalisation theory. The use of internalisation theory to analyse EMNEs is to be commended, not only because of its theoretical inclusivity, but also because it has the ability to connect and to explain seemingly desperate phenomena

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 The American Society of Gene & Cell Therapy.Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.Imperial College London, the Wellcome Trust, and Brunel University