Examination of BDNF Treatment on BACE1 Activity and Acute Exercise on Brain BDNF Signaling

Perturbations in metabolism results in the accumulation of beta-amyloid peptides, which is a pathological feature of Alzheimer’s disease. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme responsible for beta-amyloid production. Obesogenic diets increase BACE1 while exercise reduces BACE1 activity, although the mechanisms are unknown. Brain-derived neurotropic factor (BDNF) is an exercise inducible neurotrophic factor, however, it is unknown if BDNF is related to the effects of exercise on BACE1. The purpose of this study was to determine the direct effect of BDNF on BACE1 activity and to examine neuronal pathways induced by exercise. C57BL/6J male mice were assigned to either a low (n = 36) or high fat diet (n = 36) for 10 weeks. To determine the direct effect of BDNF on BACE1, a subset of mice (low fat diet = 12 and high fat diet n = 12) were used for an explant experiment where the brain tissue was directly treated with BDNF (100 ng/ml) for 30 min. To examine neuronal pathways activated with exercise, mice remained sedentary (n = 12) or underwent an acute bout of treadmill running at 15 m/min with a 5% incline for 120 min (n = 12). The prefrontal cortex and hippocampus were collected 2-h post-exercise. Direct treatment with BDNF resulted in reductions in BACE1 activity in the prefrontal cortex (p < 0.05), but not the hippocampus. The high fat diet reduced BDNF content in the hippocampus; however, the acute bout of exercise increased BDNF in the prefrontal cortex (p < 0.05). These novel findings demonstrate the region specific differences in exercise induced BDNF in lean and obese mice and show that BDNF can reduce BACE1 activity, independent of other exercise-induced alterations. This work demonstrates a previously unknown link between BDNF and BACE1 regulation.Brock Library Open Access Publishing Fun

Hamiltonians for Reduced Gravity

A generalised canonical formulation of gravity is devised for foliations of spacetime with codimension $n\ge1$. The new formalism retains n-dimensional covariance and is especially suited to 2+2 decompositions of spacetime. It is also possible to use the generalised formalism to obtain boundary contributions to the 3+1 Hamiltonian.Comment: 18 pages, revtex, 3 postscript figures include

Late Miocene to early Pliocene biofacies of Wanganui and Taranaki Basins, New Zealand: Applications to paleoenvironmental and sequence stratigraphic analysis

The Matemateaonga Formation is late Miocene to early Pliocene (upper Tongaporutuan to lower Opoitian New Zealand Stages) in age. The formation comprises chiefly shellbeds, siliciclastic sandstone, and siltstone units and to a lesser extent non-marine and shallow marine conglomerate and rare paralic facies. The Matemateaonga Formation accumulated chiefly in shelf paleoenvironments during basement onlap and progradation of a late Miocene to early Pliocene continental margin wedge in the Wanganui and Taranaki Basins. The formation is strongly cyclothemic, being characterised by recurrent vertically stacked facies successions, bounded by sequence boundaries. These facies accumulated in a range of shoreface to mid-outer shelf paleoenvironments during conditions of successively oscillating sea level. This sequential repetition of facies and the biofacies they enclose are the result of sixth-order glacio-eustatic cyclicity. Macrofaunal associations have been identified from statistical analysis of macrofossil occurrences collected from multiple sequences. Each association is restricted to particular lithofacies and stratal positions and shows a consistent order and/or position within the sequences. This pattern of temporal paleoecologic change appears to be the result of lateral, facies-related shifting of broad biofacies belts, or habitat-tracking, in response to fluctuations of relative sea level, sediment flux, and other associated paleoenvironmental variables. The associations also show strong similarity in terms of their generic composition to biofacies identified in younger sedimentary strata and the modern marine benthic environment in New Zealand

Reduction of pro-tumorigenic activity of human prostate cancer-associated fibroblasts using Dlk1 or SCUBE1

SUMMARY Human prostatic cancer-associated fibroblasts (CAFs) can elicit malignant changes in initiated but non-tumorigenic human prostate epithelium, demonstrating that they possess pro-tumorigenic properties. We set out to reduce the pro-tumorigenic activity of patient CAFs using the Dlk1 and SCUBE1 molecules that we had previously identified in prostate development. Our hypothesis was that mesenchymally expressed molecules might reduce CAF pro-tumorigenic activity, either directly or indirectly. We isolated primary prostatic CAFs and characterised their expression of CAF markers, expression of Notch2, Dlk1 and SCUBE1 transcripts, and confirmed their ability to stimulate BPH1 epithelial cell proliferation. Next, we expressed Dlk1 or SCUBE1 in CAFs and determined their effects upon tumorigenesis in vivo following recombination with BPH1 epithelia and xenografting in SCID mice. Tumour size was reduced by about 75% and BPH1 proliferation was reduced by about 50% after expression of Dlk1 or SCUBE1 in CAFs, and there was also a reduction in invasion of BPH1 epithelia into the host kidney. Inhibition of Notch signalling, using inhibitor XIX, led to a reduction in BPH1 cell proliferation in CAF-BPH1 co-cultures, whereas inhibition of Dlk1 in NIH3T3-conditioned media led to an increase in BPH1 growth. Our results suggest that pro-tumorigenic CAF activity can be reduced by the expression of developmental pathways

Characterization of Alzheimer's disease‐like neuropathology in Duchenne's muscular dystrophy using the DBA/2J mdx mouse model

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by a mutation in the dystrophin gene. In addition to muscle pathology, some patients with DMD will exhibit cognitive impairments with severity being linked to age and type of genetic mutation. Likewise, some studies have shown that mdx mice display impairments in spatial memory compared with wild-type (WT) controls, while others have not observed any such effect. Most studies have utilized the traditional C57BL/10 (C57) mdx mouse, which exhibits a mild disease phenotype. Recently, the DBA/2J (D2) mdx mouse has emerged as a more severe and perhaps clinically relevant DMD model; however, studies examining cognitive function in these mice are limited. Thus, in this study we examined cognitive function in age-matched C57 and D2 mdx mice along with their respective WT controls. Our findings show that 8- to 12-week-old C57 mdx mice did not display any differences in exploration time when challenged with a novel object recognition test. Conversely, age-matched D2 mdx mice spent less time exploring objects in total as a well as less time exploring the novel object, suggestive of impaired recognition memory. Biochemical analyses of the D2 mdx brain revealed higher soluble amyloid precursor protein b(APPb) and APP in the prefrontal cortex of mdx mice compared with WT, and lower soluble APPa in the hippocampus, suggestive of a shift towards amyloidogenesis and a similar pathogenesis to Alzheimer’s disease. Furthermore, our study demonstrates the utility of the D2 mdx model in studying cognitive impairment.Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canad

The use of whole genome sequencing in the investigation of a nosocomial influenza virus outbreak

Traditional epidemiological investigation of nosocomial transmission of influenza involves the identification of patients who have the same influenza virus type and who have overlapped in time and place. This method may miss-identify transmission where it has not occurred or miss transmission when it has. We applied influenza virus whole genome sequencing (WGS) to an outbreak of influenza A in a haematology/oncology ward and identified two separate introductions; one which resulted in 5 additional infections and 79 bed-days lost. Results from WGS are becoming rapidly available and may supplement traditional infection control procedures in the investigation and management of nosocomial outbreaks

Can the Universe Create Itself?

The question of first-cause has troubled philosophers and cosmologists alike. Now that it is apparent that our universe began in a Big Bang explosion, the question of what happened before the Big Bang arises. Inflation seems like a very promising answer, but as Borde and Vilenkin have shown, the inflationary state preceding the Big Bang must have had a beginning also. Ultimately, the difficult question seems to be how to make something out of nothing. This paper explores the idea that this is the wrong question --- that that is not how the Universe got here. Instead, we explore the idea of whether there is anything in the laws of physics that would prevent the Universe from creating itself. Because spacetimes can be curved and multiply connected, general relativity allows for the possibility of closed timelike curves (CTCs). Thus, tracing backwards in time through the original inflationary state we may eventually encounter a region of CTCs giving no first-cause. This region of CTCs, may well be over by now (being bounded toward the future by a Cauchy horizon). We illustrate that such models --- with CTCs --- are not necessarily inconsistent by demonstrating self-consistent vacuums for Misner space and a multiply connected de Sitter space in which the renormalized energy-momentum tensor does not diverge as one approaches the Cauchy horizon and solves Einstein's equations. We show such a Universe can be classically stable and self-consistent if and only if the potentials are retarded, giving a natural explanation of the arrow of time. Some specific scenarios (out of many possible ones) for this type of model are described. For example: an inflationary universe gives rise to baby universes, one of which turns out to be itself. Interestingly, the laws of physics may allow the Universe to be its own mother.Comment: 48 pages, 8 figure

POT1 mutations predispose to familial melanoma

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.D.J.A., C.D.R.-E., Z.D., J.Z.L., J.C.T., M.P. and T.M.K. were supported by Cancer Research UK and the Wellcome Trust (WT098051). C.D.R.-E. was also supported by the Consejo Nacional de Ciencia y Tecnología of Mexico. K.A.P. and A.M.D. were supported by Cancer Research UK (grants C1287/A9540 and C8197/A10123) and by the Isaac Newton Trust. N.K.H. was supported by a fellowship from the National Health and Medical Research Council of Australia (NHMRC). L.G.A. was supported by an Australia and New Zealand Banking Group Limited Trustees PhD scholarship. A.L.P. is supported by Cure Cancer Australia. The work was funded in part by the NHMRC and Cancer Council Queensland. The work of N.A.G. was in part supported by the Dutch Cancer Society (UL 2012-5489). M.H., J.A.N.-B. and D.T.B. were supported by Cancer Research UK (programme awards C588/A4994 and C588/A10589 and the Genomics Initiative). C.L.-O., A.J.R. and V.Q. are funded by the Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (ISCIII), the Red Temática de Investigación del Cáncer (RTICC) del ISCIII and the Consolider-Ingenio RNAREG Consortium. C.L.-O. is an investigator with the Botín Foundation.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.294

Ventilation of the abyssal Southern Ocean during the late Neogene: A new perspective from the subantarctic Pacific

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94630/1/palo1532.pd