Enhancing the Activation and Releasing the Brakes: A Double Hit Strategy to Improve NK Cell Cytotoxicity Against Multiple Myeloma.

Natural killer (NK) cells are innate lymphocytes with a strong antitumor ability. In tumor patients, such as multiple myeloma (MM) patients, an elevated number of NK cells after stem cell transplantation (SCT) has been reported to be correlated with a higher overall survival rate. With the aim of improving NK cell use for adoptive cell therapy, we also addressed the cytotoxicity of patient-derived, cytokine-stimulated NK cells against MM cells at specific time points: at diagnosis and before and after autologous stem cell transplantation.

A point mutation in the signal peptide impairs the development of innate lymphoid cell subsets.

NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCR strain.

Natural killer cells as a therapeutic tool for infectious diseases - current status and future perspectives.

Natural Killer (NK) cells are involved in the host immune response against infections due to viral, bacterial and fungal pathogens, all of which are a significant cause of morbidity and mortality in immunocompromised patients. Since the recovery of the immune system has a major impact on the outcome of an infectious complication, there is major interest in strengthening the host response in immunocompromised patients, either by using cytokines or growth factors or by adoptive cellular therapies transfusing immune cells such as granulocytes or pathogen-specific T-cells. To date, relatively little is known about the potential of adoptively transferring NK cells in immunocompromised patients with infectious complications, although the anti-cancer property of NK cells is already being investigated in the clinical setting.

Multivalent Siderophore-DOTAM Conjugates as Theranostics for Imaging and Treatment of Bacterial Infections.

There is a strong need to better diagnose infections at deep body sites through noninvasive molecular imaging methods. Herein, we describe the synthesis and characterization of probes based on siderophore conjugates with catechol moieties and a central DOTAM scaffold. The probes can accommodate a metal ion as well as an antibiotic moiety and are therefore suited for theranostic purposes.

Sub-Femto-g Free Fall for Space-Based Gravitational Wave Observatories: LISA Pathfinder Results.

We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2±0.

Evaluation of the inflammatory potential of implant materials in a mouse model by bioluminescent imaging of intravenously injected bone marrow cells.

To evaluate the inflammatory potential of implants a bioluminescent imaging assay was developed using luciferase-expressing bone marrow cells that were injected into the blood circulation of wild-type mice. After subcutaneous implantation of titanium discs as an example for a clinically established biocompatible material, the luminosity was modest. Similarly, low luminosity signals were generated by pure magnesium implants that were used to represent metallic alloys that are presently under investigation as novel degradable implant materials.

Susceptibility of metallic magnesium implants to bacterial biofilm infections.

Magnesium alloys have promising mechanical and biological properties as biodegradable medical implant materials for temporary applications during bone healing or as vascular stents. Whereas conventional implants are prone to colonization by treatment resistant microbial biofilms in which bacteria are embedded in a protective matrix, magnesium alloys have been reported to act antibacterial in vitro. To permit a basic assessment of antibacterial properties of implant materials in vivo an economic but robust animal model was established.

Alkalization is responsible for antibacterial effects of corroding magnesium.

Magnesium alloys are presently investigated as potential medical implant materials for temporary applications. Magnesium has been reported to have antibacterial activities and could therefore be used to prevent antibiotic treatment-resistant bacterial implant infections. For characterizing the effects of magnesium on infectious bacteria, bioluminescent S.

The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies.

Background And Purpose: Recent data have indicated that α3β4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal.

Experimental Approaches: To assess the role of α3β4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools.

Note: He puff system for dust detector upgrade.

Local detection of surface dust is needed for the safe operation of next-step magnetic fusion devices such as ITER. An electrostatic dust detector, based on a grid of interlocking circuit traces biased to 50 V, has been developed to detect dust on remote surfaces and was successfully tested for the first time on the National Spherical Torus Experiment. In this note, we report a helium puff system that clears residual dust from this detector and any incident debris or fibers that might cause a permanent short circuit.

First real-time detection of surface dust in a tokamak.

The first real-time detection of surface dust inside a tokamak was made using an electrostatic dust detector. A fine grid of interlocking circuit traces was installed in the NSTX vessel and biased to 50 V. Impinging dust particles created a temporary short circuit and the resulting current pulse was recorded by counting electronics.

Control of the threonine-synthesis pathway in Escherichia coli: a theoretical and experimental approach.

A computer simulation of the threonine-synthesis pathway in Escherichia coli Tir-8 has been developed based on our previous measurements of the kinetics of the pathway enzymes under near-physiological conditions. The model successfully simulates the main features of the time courses of threonine synthesis previously observed in a cell-free extract without alteration of the experimentally determined parameters, although improved quantitative fits can be obtained with small parameter adjustments. At the concentrations of enzymes, precursors and products present in cells, the model predicts a threonine-synthesis flux close to that required to support cell growth.

Threonine synthesis from aspartate in Escherichia coli cell-free extracts: pathway dynamics.

We have developed an experimental model of the whole threonine pathway that allows us to study the production of threonine from aspartate under different conditions. The model consisted of a desalted crude extract of Escherichia coli to which we added the substrates and necessary cofactors of the pathway: aspartate, ATP and NADPH. In this experimental model we measured not only the production of threonine, but also the time dependence of all the intermediate metabolites and of the initial substrates, aspartate, ATP and NADPH.

An integrated study of threonine-pathway enzyme kinetics in Escherichia coli.

We have determined the kinetic parameters of the individual steps of the threonine pathway from aspartate in Escherichia coli under a single set of experimental conditions chosen to be physiologically relevant. Our aim was to summarize the kinetic behaviour of each enzyme in a single tractable equation that takes into account the effect of the products as competitive inhibitors of the substrates in the forward reaction and also, when appropriate (e.g.

Quantitative characterization of homo- and heteroassociations of muscle phosphofructokinase with aldolase.

Dissociation of purified phosphofructokinase accompanied with inactivation was analyzed in the absence and presence of aldolase and the data were compared with those obtained with muscle extract. The kinetics of the decrease in enzymatic activity was highly dependent on the dilution factor in both cases, but the inactivation appeared to be biphasic only with extract. The inactivation of the phosphofructokinase was impeded by addition of excess of aldolase.

Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle.

Transketolase (TK) reactions play a crucial role in tumor cell nucleic acid ribose synthesis utilizing glucose carbons, yet, current cancer treatments do not target this central pathway. Experimentally, a dramatic decrease in tumor cell proliferation after the administration of the TK inhibitor oxythiamine (OT) was observed in several in vitro and in vivo tumor models. Here, we demonstrate that pentose cycle (PC) inhibitors, OT and dehydroepiandrosterone (DHEA), efficiently regulate the cell cycle and tumor proliferation processes.

New semisynthetic vinca alkaloids: chemical, biochemical and cellular studies.

A new semisynthetic anti-tumour bis-indol compound, KAR-2 [3'-(beta-chloroethyl)-2',4'-dioxo-3,5'-spiro-oxazolidino-4-dea cetoxy-vinblastine] with lower toxicity than vinca alkaloids used in chemotherapy binds to calmodulin but, in contrast to vinblastine, does not exhibit anti-calmodulin activity. To investigate whether the modest chemical modification of bis-indol structure is responsible for the lack of anti-calmodulin potency and for the different pharmacological effects, new derivatives have been synthesized for comparative studies. The synthesis of the KAR derivatives are presented.

Comparison of control analysis data using different approaches: modelling and experiments with muscle extract.

Experimental and model studies have been performed to characterize the control properties of hexokinase and phosphofructokinase in muscle glycolysis and to examine the nature of error associated with experimental flux control coefficient determinations. Different approaches of metabolic control analysis, classical titration, co-response analysis and kinetic modelling indicated that flux control coefficients could be reliably estimated experimentally for the upper part of glycolysis. The kinetic parameters applied to construct the mathematical model were determined in muscle extract under similar conditions used for flux studies.

Control of threonine pathway in E. coli. Application to biotechnologies.

Threonine is an essential amino acid for mammals and birds and an adequate supply is necessary for growth and maintenance. Its production has become the aim of metabolic bioengineering and genetic manipulations. We propose in this paper a rational approach for increasing threonine production in an E.

[Control of the metabolic pathway of threonine in E coli. Application of biotechnology].

This paper deals with the application of the metabolic control theory, especially the measurement of control coefficients, to the threonine pathway in E. coli. The control coefficient of a step on a metabolic flux quantitatively assesses the flux response to the step variations.