Hsp70 in mitochondrial biogenesis

The family of hsp70 (70 kilodalton heat shock protein) molecular chaperones plays an essential and diverse role in cellular physiology, Hsp70 proteins appear to elicit their effects by interacting with polypeptides that present domains which exhibit non-native conformations at distinct stages during their life in the cell. In this paper we review work pertaining to the functions of hsp70 proteins in chaperoning mitochondrial protein biogenesis. Hsp70 proteins function in protein synthesis, protein translocation across mitochondrial membranes, protein folding and finally the delivery of misfolded proteins to proteolytic enzymes in the mitochondrial matrix

Serum-free process development:improving the yield and consistency of human mesenchymal stromal cell production

Background aims: The cost-effective production of human mesenchymal stromal cells (hMSCs) for off-the-shelf and patient specific therapies will require an increasing focus on improving product yield and driving manufacturing consistency. Methods: Bone marrow-derived hMSCs (BM-hMSCs) from two donors were expanded for 36 days in monolayer with medium supplemented with either fetal bovine serum (FBS) or PRIME-XV serum-free medium (SFM). Cells were assessed throughout culture for proliferation, mean cell diameter, colony-forming potential, osteogenic potential, gene expression and metabolites. Results: Expansion of BM-hMSCs in PRIME-XV SFM resulted in a significantly higher growth rate (P 2 = 0.8705) across all conditions. PRIME-XV SFM has also shown increased consistency in BM-hMSC characteristics such as per cell metabolite utilization, in vitro colony-forming potential and osteogenic potential despite the higher number of population doublings. Conclusions: We have increased the yield and consistency of BM-hMSC expansion between donors, demonstrating a level of control over the product, which has the potential to increase the cost-effectiveness and reduce the risk in these manufacturing processes

Scalability and process transfer of mesenchymal stromal cell production from monolayer to microcarrier culture using human platelet lysate

Background aims: The selection of medium and associated reagents for human mesenchymal stromal cell (hMSC) culture forms an integral part of manufacturing process development and must be suitable for multiple process scales and expansion technologies. Methods: In this work, we have expanded BM-hMSCs in fetal bovine serum (FBS)- and human platelet lysate (HPL)-containing media in both a monolayer and a suspension-based microcarrier process. Results: The introduction of HPL into the monolayer process increased the BM-hMSC growth rate at the first experimental passage by 0.049 day and 0.127/day for the two BM-hMSC donors compared with the FBS-based monolayer process. This increase in growth rate in HPL-containing medium was associated with an increase in the inter-donor consistency, with an inter-donor range of 0.406 cumulative population doublings after 18 days compared with 2.013 in FBS-containing medium. Identity and quality characteristics of the BM-hMSCs are also comparable between conditions in terms of colony-forming potential, osteogenic potential and expression of key genes during monolayer and post-harvest from microcarrier expansion. BM-hMSCs cultured on microcarriers in HPL-containing medium demonstrated a reduction in the initial lag phase for both BM-hMSC donors and an increased BM-hMSC yield after 6 days of culture to 1.20 ± 0.17 × 105 and 1.02 ± 0.005 × 105 cells/mL compared with 0.79 ± 0.05 × 105 and 0.36 ± 0.04 × 105 cells/mL in FBS-containing medium. Conclusions: This study has demonstrated that HPL, compared with FBS-containing medium, delivers increased growth and comparability across two BM-hMSC donors between monolayer and microcarrier culture, which will have key implications for process transfer during scale-up

The solution to the Tullock rent-seeking game when R > 2: mixed-strategy equilibria and mean dissipation rates

In Tullock's rent-seeking model, the probability a player wins the game depends on expenditures raised to the power R. We show that a symmetric mixed-strategy Nash equilibrium exists when R>2, and that overdissipation of rents does not arise in any Nash equilibrium. We derive a tight lower bound on the level of rent dissipation that arises in a symmetric equilibrium when the strategy space is discrete, and show that full rent dissipation occurs when the strategy space is continuous. Our results are shown to be consistent with recent experimental evidence on the dissipation of rents. An earlier version of this paper circulated under the title, No, Virginia, There is No Overdissipation of Rents. We are grateful to Dave Furth and Frans van Winden for stimulating conversations, and for comments provided by workshop participants from the CORE-ULB-KUL IUAP project, Purdue University, Pennsylvania State University, Rijksuniversiteit Limburg, and Washington State University. We also thank Max van de Sande Bakhuyzen and Ben Heijdra for useful discussions, and Geert Gielens for computational assistance. An earlier version of the paper was presented at the ESEM 1992 in Brussels and the Mid-West Mathematical Economics Conference in Pittsburgh. All three authors would like to thank CentER for its hospitality during the formative stages of the paper. The second author has also benefited from the financial support of the Katholieke Universitieit Leuven and the Jay N. Ross Young Faculty Scholar Award at Purdue University. The third author benefitted from visiting IGIER where part of the paper was written. The third author also benefitted from grant IUAP 26 of the Belgian Government

Rapid and highly variable warming of lake surface waters around the globe

In this first worldwide synthesis of in situ and satellite-derived lake data, we find that lake summer surface water temperatures rose rapidly (global mean = 0.34°C decade−1) between 1985 and 2009. Our analyses show that surface water warming rates are dependent on combinations of climate and local characteristics, rather than just lake location, leading to the counterintuitive result that regional consistency in lake warming is the exception, rather than the rule. The most rapidly warming lakes are widely geographically distributed, and their warming is associated with interactions among different climatic factors—from seasonally ice-covered lakes in areas where temperature and solar radiation are increasing while cloud cover is diminishing (0.72°C decade−1) to ice-free lakes experiencing increases in air temperature and solar radiation (0.53°C decade−1). The pervasive and rapid warming observed here signals the urgent need to incorporate climate impacts into vulnerability assessments and adaptation efforts for lakes.Peer reviewe

The New Look pMSSM with Neutralino and Gravitino LSPs

The pMSSM provides a broad perspective on SUSY phenomenology. In this paper we generate two new, very large, sets of pMSSM models with sparticle masses extending up to 4 TeV, where the lightest supersymmetric particle (LSP) is either a neutralino or gravitino. The existence of a gravitino LSP necessitates a detailed study of its cosmological effects and we find that Big Bang Nucleosynthesis places strong constraints on this scenario. Both sets are subjected to a global set of theoretical, observational and experimental constraints resulting in a sample of \sim 225k viable models for each LSP type. The characteristics of these two model sets are briefly compared. We confront the neutralino LSP model set with searches for SUSY at the 7 TeV LHC using both the missing (MET) and non-missing ET ATLAS analyses. In the MET case, we employ Monte Carlo estimates of the ratios of the SM backgrounds at 7 and 8 TeV to rescale the 7 TeV data-driven ATLAS backgrounds to 8 TeV. This allows us to determine the pMSSM parameter space coverage for this collision energy. We find that an integrated luminosity of \sim 5-20 fb^{-1} at 8 TeV would yield a substantial increase in this coverage compared to that at 7 TeV and can probe roughly half of the model set. If the pMSSM is not discovered during the 8 TeV run, then our model set will be essentially void of gluinos and lightest first and second generation squarks that are \lesssim 700-800 GeV, which is much less than the analogous mSUGRA bound. Finally, we demonstrate that non-MET SUSY searches continue to play an important role in exploring the pMSSM parameter space. These two pMSSM model sets can be used as the basis for investigations for years to come.Comment: 54 pages, 22 figures; typos fixed, references adde

The Sudbury Neutrino Observatory

The Sudbury Neutrino Observatory is a second generation water Cherenkov detector designed to determine whether the currently observed solar neutrino deficit is a result of neutrino oscillations. The detector is unique in its use of D2O as a detection medium, permitting it to make a solar model-independent test of the neutrino oscillation hypothesis by comparison of the charged- and neutral-current interaction rates. In this paper the physical properties, construction, and preliminary operation of the Sudbury Neutrino Observatory are described. Data and predicted operating parameters are provided whenever possible.Comment: 58 pages, 12 figures, submitted to Nucl. Inst. Meth. Uses elsart and epsf style files. For additional information about SNO see http://www.sno.phy.queensu.ca . This version has some new reference

Early carboniferous brachiopod faunas from the Baoshan block, west Yunnan, southwest China

38 brachiopod species in 27 genera and subgenera are described from the Yudong Formation in the Shidian-Baoshan area, west Yunnan, southwest China. New taxa include two new subgenera: Unispirifer (Septimispirifer) and Brachythyrina (Longathyrina), and seven new species: Eomarginifera yunnanensis, Marginatia cylindrica, Unispirifer (Unispirifer) xiangshanensis, Unispirifer (Septimispirifer) wafangjieensis, Brachythyrina (Brachythyrina) transversa, Brachythyrina (Longathyrina) baoshanensis, and Girtyella wafangjieensis. Based on the described material and constraints from associated coral and conodont faunas, the age of the brachiopod fauna from the Yudon Formation is considered late Tournaisian (Early Carboniferous), with a possibility extending into earlyViseacutean.<br /

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 16 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1- 0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute.This is the author accepted manuscript. The final version is available from BMJ Group at http://dx.doi.org/10.1136/jmedgenet-2015-103529

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)