Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis

<p>Abstract</p> <p>Background</p> <p>Tuberous sclerosis (TSC) is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus) leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235.</p> <p>Results</p> <p>Using ENU to enhance <it>Tsc2</it>^+-kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week) and NVP-BEZ235 (45 mg/kg PO QD) had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation.</p> <p>Conclusion</p> <p>Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.</p

Application of transfer learning to predict drug-induced human in vivo gene expression changes using rat in vitro and in vivo data

The liver is the primary site for the metabolism and detoxification of many compounds, including pharmaceuticals. Consequently, it is also the primary location for many adverse reactions. As the liver is not readily accessible for sampling in humans; rodent or cell line models are often used to evaluate potential toxic effects of a novel compound or candidate drug. However, relating the results of animal and in vitro studies to relevant clinical outcomes for the human in vivo situation still proves challenging. In this study, we incorporate principles of transfer learning within a deep artificial neural network allowing us to leverage the relative abundance of rat in vitro and in vivo exposure data from the Open TG-GATEs data set to train a model to predict the expected pattern of human in vivo gene expression following an exposure given measured human in vitro gene expression. We show that domain adaptation has been successfully achieved, with the rat and human in vitro data no longer being separable in the common latent space generated by the network. The network produces physiologically plausible predictions of human in vivo gene expression pattern following an exposure to a previously unseen compound. Moreover, we show the integration of the human in vitro data in the training of the domain adaptation network significantly improves the temporal accuracy of the predicted rat in vivo gene expression pattern following an exposure to a previously unseen compound. In this way, we demonstrate the improvements in prediction accuracy that can be achieved by combining data from distinct domains.</p

Application of transfer learning to predict drug-induced human in vivo gene expression changes using rat in vitro and in vivo data

The liver is the primary site for the metabolism and detoxification of many compounds, including pharmaceuticals. Consequently, it is also the primary location for many adverse reactions. As the liver is not readily accessible for sampling in humans; rodent or cell line models are often used to evaluate potential toxic effects of a novel compound or candidate drug. However, relating the results of animal and in vitro studies to relevant clinical outcomes for the human in vivo situation still proves challenging. In this study, we incorporate principles of transfer learning within a deep artificial neural network allowing us to leverage the relative abundance of rat in vitro and in vivo exposure data from the Open TG-GATEs data set to train a model to predict the expected pattern of human in vivo gene expression following an exposure given measured human in vitro gene expression. We show that domain adaptation has been successfully achieved, with the rat and human in vitro data no longer being separable in the common latent space generated by the network. The network produces physiologically plausible predictions of human in vivo gene expression pattern following an exposure to a previously unseen compound. Moreover, we show the integration of the human in vitro data in the training of the domain adaptation network significantly improves the temporal accuracy of the predicted rat in vivo gene expression pattern following an exposure to a previously unseen compound. In this way, we demonstrate the improvements in prediction accuracy that can be achieved by combining data from distinct domains.</p

A revised scheme for the reactivity of iron (oxyhydr)oxide minerals towards dissolved sulfide

The reaction between dissolved sulfide and synthetic iron (oxyhydr)oxide minerals was studied in artificial seawater and 0.1 M NaCl at pH 7.5 and 25°C. Electron transfer between surface-complexed sulfide and solid phase Fe(III) results in the oxidation of dissolved sulfide to elemental sulfur, and the subsequent dissolution of the surface-reduced Fe. Sulfide oxidation and Fe(II) dissolution kinetics were evaluated for freshly precipitated hydrous ferric oxide (HFO), lepidocrocite, goethite, magnetite, hematite, and Al-substituted lepidocrocite. Reaction kinetics were expressed in terms of an empirical rate equation of the form: R-i = k(i)(H2S)(t=0)(0.5)A where Ri is the rate of Fe(II) dissolution (RFe) or the rate of sulfide oxidation (RS), ki is the appropriate rate constant (kFe or kS), (H2S)t=0 is the initial dissolved sulfide concentration, and A is the initial mineral surface area. The rate constants derived from the above equation suggest that the reactivity of Fe (oxyhydr)oxide minerals varies over two orders of magnitude, with increasing reactivity in the order, goethite < hematite < magnetite << lepidocrocite ≈ HFO. Competitive adsorption of major seawater solutes has little effect on reaction kinetics for the most reactive minerals, but results in rates which are reduced by 65-80% for goethite, magnetite, and hematite. This decrease in reaction rates likely arises from the blocking of surface sites for sulfide complexation by the adsorption of seawater solutes during the later, slower stages of adsorption (possibly attributable to diffusion into micropores or aggregates). The derivation of half lives for the sulfide-promoted reductive dissolution of Fe (oxyhydr)oxides in seawater, suggests that mineral reactivity can broadly be considered in terms of two mineral groups. Minerals with a lower degree of crystal order (hydrous ferric oxides and lepidocrocite) are reactive on a time-scale of minutes to hours. The more ordered minerals (goethite, magnetite, and hematite) are reactive on a time-scale of tens of days. Substitution of impurities within the mineral structure (as is likely in nature) has an effect on mineral reactivity. However, these effects are unlikely to have a significant impact on the relative reactivities of the two mineral groups

Continuous Deployment Transitions at Scale

Predictable, rapid, and data-driven feature rollout; lightning-fast; and automated fix deployment are some of the benefits most large software organizations worldwide are striving for. In the process, they are transitioning toward the use of continuous deployment practices. Continuous deployment enables companies to make hundreds or thousands of software changes to live computing infrastructure every day while maintaining service to millions of customers. Such ultra-fast changes create a new reality in software development. Over the past four years, the Continuous Deployment Summit, hosted at Facebook, Netflix, Google, and Twitter has been held. Representatives from companies like Cisco, Facebook, Google, IBM, Microsoft, Netflix, and Twitter have shared the triumphs and struggles of their transition to continuous deployment practices—each year the companies press on, getting ever faster. In this chapter, the authors share the common strategies and practices used by continuous deployment pioneers and adopted by newcomers as they transition and use continuous deployment practices at scale

Holistic approach to dissolution kinetics : linking direction-specific microscopic fluxes, local mass transport effects and global macroscopic rates from gypsum etch pit analysis

Dissolution processes at single crystal surfaces often involve the initial formation and expansion of localized, characteristic (faceted) etch-pits at defects, in an otherwise comparatively unreactive surface. Using natural gypsum single crystal as an example, a simple but powerful morphological analysis of these characteristic etch pit features is proposed that allows important questions concerning dissolution kinetics to be addressed. Significantly, quantitative mass transport associated with reactive microscale interfaces in quiescent solution (well known in the field of electrochemistry at ultramicroelectrodes) allows the relative importance of diffusion compared to surface kinetics to be assessed. Furthermore, because such mass transport rates are high, much faster surface kinetics can be determined than with existing dissolution methods. For the case of gypsum, surface processes are found to dominate the kinetics at early stages of the dissolution process (small etch pits) on the cleaved (010) surface. However, the contribution from mass transport becomes more important with time due to the increased area of the reactive zones and associated decrease in mass transport rate. Significantly, spatial heterogeneities in both surface kinetics and mass transport effects are identified, and the morphology of the characteristic etch features reveal direction-dependent dissolution kinetics that can be quantified. Effective dissolution velocities normal to the main basal (010) face are determined, along with velocities for the movement of [001] and [100] oriented steps. Inert electrolyte enhances dissolution velocities in all directions (salting in), but a striking new observation is that the effect is direction-dependent. Studies of common ion effects reveal that Ca2+ has a much greater impact in reducing dissolution rates compared to SO42−. With this approach, the new microscopic observations can be further analysed to obtain macroscopic dissolution rates, which are found to be wholly consistent with previous bulk measurements. The studies are thus important in bridging the gap between microscopic phenomena and macroscopic measurements

Geochemical and physical sources of radon variation in a subterranean estuary — implications for groundwater radon activities in submarine groundwater discharge studies

Author Posting. © Elsevier B.V., 2007. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Marine Chemistry 110 (2008): 120-127, doi:10.1016/j.marchem.2008.02.011.Submarine groundwater discharge (SGD), in form of springs and diffuse seepage, has long been recognized as a source of chemical constituents to the coastal ocean. Because groundwater is two to four orders of magnitude richer in radon than surface water, it has been used as both a qualitative and a quantitative tracer of groundwater discharge. Besides this large activity gradient, the other perceived advantage of radon stems from its classification as noble gas; that is, its chemical behavior is expected not to be influenced by salinity, redox, and diagenetic conditions present in aquatic environments. During our three-year monthly sampling of the subterranean estuary (STE) in Waquoit Bay, MA, we found highly variable radon activities (50-1600 dpm L-1) across the fresh-saline interface of the aquifer. We monitored pore water chemistry and radon activity at 8 fixed depths spanning from 2 to 5.6 m across the STE, and found seasonal fluctuations in activity at depths where elevated radon was observed. We postulate that most of pore water 222Rn is produced from particle-surface bound 226Ra, and that the accumulation of this radium is likely regulated by the presence of manganese (hydr)oxides. Layers of manganese (hydr)oxides form at the salinity transition zone (STZ), where water with high salinity, high manganese, and low redox potential mixes with fresh water. Responding to the seasonality of aquifer recharge, the location of the STZ and the layers with radium enriched manganese (hydr)oxide follows the seasonal land- or bay-ward movement of the freshwater lens. This results in seasonal changes in the depth where elevated radon activities are observed. The conclusion of our study is that the freshwater part of the STE has a radon signature that is completely different from the STZ or recirculated sea water. Therefore, the radon activity in SGD will depend on the ratio of fresh and recirculated seawater in the discharging groundwater.This work is a result of research sponsored by NSF (OCE- 0425061 to M.A.C.) and the WHOI Postdoctoral Scholar program (to H.D.)

Einführung des cloudbasierten Bibliothekssystems Alma in Berlin – ein Erfahrungsbericht

Die enge Zusammenarbeit der vier Berliner Universitätsbibliotheken [Freie Universität Berlin (FU), Humboldt-Universität zu Berlin (HU), Technische Universität Berlin (TU), Universität der Künste Berlin (UdK)] reicht weit zurück. Bereits vor der Jahrtausendwende haben die Berliner Universitätsbibliotheken (UBs) gemeinsam das Bibliothekssystem Aleph 500 ausgewählt und implementiert, danach folgten weitere Systeme – das Linking System SFX, die Digitale Bibliothek MetaLib und das Bibliotheksportal Primo. Es war daher folgerichtig und selbstverständlich, dass auch die Auswahl und Implementierung eines neuen Bibliothekssystems in enger Abstimmung und Zusammenarbeit erfolgte. Die Erfahrungen bei Vertragsverhandlungen und Implementierung von Alma sind Gegenstand des folgenden Berichtes.As regards implementing new library technology, the Berlin University libraries have been working closely together for more than 20 years. It was the case for the implementation of the legacy system Aleph 500, the linking system SFX, the digital library MetaLib and the library portal Primo, and therefore it was a matter of course to continue the close cooperation during the implementation of the new cloud-based library system, too. The experience gained during the contract negotiations and the implementation project, and lessons learned are the focus of this report.Peer Reviewe