Operability and Results of Retro and On-Going Commission Tools Applied to an Existing Building

Several tools in the scope of Annex 40 (PECI Model Commissioning Plan and Guide specification, Emma-CTA, IPMVP) have been used to realise the retro and the on-going commissioning of an existing building. The aim of the work was to evaluate operability, consumed time, results of these tools used by HVAC operation technicians. Analysis of making use of the different tools in a common framework is proposed, giving feedback information to creative authors

Targeting Tumour-Initiating Cells with TRAIL Based Combination Therapy Ensures Complete and Lasting Eradication of Multiple Myeloma Tumours In Vivo

Multiple myeloma (MM) remains an incurable disease despite improvements to available treatments and efforts to identify new drug targets. Consequently new approaches are urgently required. We have investigated the potential of native tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with doxorubicin, to induce apoptotic cell death in phenotypically distinct populations of myeloma cells in vitro and in vivo. The cytotoxic potential of TRAIL alone, and in combination with DOX, was assessed in vitro in purified CD138+ and CD138− cells from the MM cell lines and samples from patients with MM. Mouse xenografts obtained by implanting CD138− MM cells were used to assess the efficacy of TRAIL, alone and in combination with DOX, in vivo. CD138− cells were shown to be more resistant to the cytotoxic activity of TRAIL than CD138+ cells and have reduced expression of TRAIL death receptors. This resistance results in preferential killing of CD 138+ cells during exposure of MM culture to TRAIL. Furthermore, prolonged exposure results in the appearance of TRAIL-resistant CD138− cells. However, when TRAIL is combined with doxorubicin, this results in complete eradication of MM cells in vivo. Most importantly, this treatment successfully eliminates CD138− cells implicated in tumour initiation and growth maintenance. These findings may explain the failure of current therapies and offer a promising new approach in the quest to cure MM and disseminated cancers

mTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F-Actin polymerization, structural modifications, and consumption

Actin is highly enriched at dendritic spines, and actin remodeling plays an essential role in structural plasticity. The mammalian target of rapamycin complex 2 (mTORC2) is a regulator of actin polymerization. Here, we report that alcohol consumption increases F-actin content in the dorsomedial striatum (DMS) of mice, thereby altering dendritic spine morphology in a mechanism that requires mTORC2. Specifically, we found that excessive alcohol consumption increases mTORC2 activity in the DMS, and that knockdown of Rictor, an essential component of mTORC2 signaling, reduces actin polymerization, and attenuates the alcohol-dependent alterations in spine head size and the number of mushroom spines. Finally, we show that knockdown of Rictor in the DMS reduces alcohol consumption, whereas intra-DMS infusion of the mTORC2 activator, A-443654, increases alcohol intake. Together, these results suggest that mTORC2 in the DMS facilitates the formation of F-actin, which in turn induces changes in spine structure to promote and/or maintain excessive alcohol intake. © 2018 American College of Neuropsychopharmacolog

The first alcohol drink triggers mTORC1-dependent synaptic plasticity in nucleus accumbens dopamine D1 receptor neurons

Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1 + neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORCl is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORCl in NAc shell Dl + neurons and increased synaptic expression of the AMPAR subunit GluAl and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1 + neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. © 2016 the authors

Jejunal atresia and persistent mullerian duct syndrome

International audienc

High frequencies of leukemia stem cells in poor-outcome childhood precursor-B acute lymphoblastic leukemias.

In order to develop a xenograft model to determine the efficacy of new therapies against primary human precursor-B acute lymphoblastic leukemia (ALL) stem cells (LSCs), we used the highly immunodeficient non-obese diabetic (NOD).Cg-Prkdc(scid)IL2rg(tmlWjl)/SzJ (NOD-severe combined immune deficient (scid) IL2rg(-/-)) mouse strain. Intravenous transplantation of 2 of 2 ALL cell lines and 9 of 14 primary ALL cases generated leukemia-like proliferations in recipient mice by 1-7 months after transplant. Leukemias were retransplantable, and the immunophenotypes, gene rearrangements and expression profiles were identical or similar to those of the original primary samples. NOD-scid mice transplanted with the same primary samples developed similar leukemias with only a slightly longer latency than did NOD-scid-IL2Rg(-/-) mice. In this highly sensitive NOD-scid-IL2Rg(-/-)-based assay, 1-100 unsorted primary human ALL cells from five of five tested patients, four of whom eventually experienced leukemia relapse, generated leukemias in recipient mice. This very high frequency of LSCs suggests that a hierarchical LSC model is not valuable for poor-outcome ALL