Steady state and (bi-) stability evaluation of simple protease signalling networks

Signal transduction networks are complex, as are their mathematical models. Gaining a deeper understanding requires a system analysis. Important aspects are the number, location and stability of steady states. In particular, bistability has been recognised as an important feature to achieve molecular switching. This paper compares different model structures and analysis methods particularly useful for bistability analysis. The biological applications include proteolytic cascades as, for example, encountered in the apoptotic signalling pathway or in the blood clotting system. We compare three model structures containing zero-order, inhibitor and cooperative ultrasensitive reactions, all known to achieve bistability. The combination of phase plane and bifurcation analysis provides an illustrative and comprehensive understanding of how bistability can be achieved and indicates how robust this behaviour is. Experimentally, some so-called “inactive” components were shown to have a residual activity. This has been mostly ignored in mathematical models. Our analysis reveals that bistability is only mildly affected in the case of zero-order or inhibitor ultrasensitivity. However, the case where bistability is achieved by cooperative ultrasensitivity is severely affected by this perturbation

Dark states of single NV centers in diamond unraveled by single shot NMR

The nitrogen-vacancy (NV) center in diamond is supposed to be a building block for quantum computing and nanometer scale metrology at ambient conditions. Therefore, precise knowledge of its quantum states is crucial. Here, we experimentally show that under usual operating conditions the NV exists in an equilibrium of two charge states (70% in the expected negative (NV-) and 30% in the neutral one (NV0)). Projective quantum non-demolition measurement of the nitrogen nuclear spin enables the detection even of the additional, optically inactive state. The nuclear spin can be coherently driven also in NV0 (T1 ~ 90 ms and T2 ~ 6 micro-s).Comment: 4 pages, 3 figure

Photo induced ionization dynamics of the nitrogen vacancy defect in diamond investigated by single shot charge state detection

The nitrogen-vacancy centre (NV) has drawn much attention for over a decade, yet detailed knowledge of the photophysics needs to be established. Under typical conditions, the NV can have two stable charge states, negative (NV-) or neutral (NV0), with photo induced interconversion of these two states. Here, we present detailed studies of the ionization dynamics of single NV centres in bulk diamond at room temperature during illumination in dependence of the excitation wavelength and power. We apply a recent method which allows us to directly measure the charge state of a single NV centre, and observe its temporal evolution. Results of this work are the steady state NV- population, which was found to be always < 75% for 450 to 610 nm excitation wavelength, the relative absorption cross-section of NV- for 540 to 610 nm, and the energy of the NV- ground state of 2.6 eV below the conduction band. These results will help to further understand the photo-physics of the NV centre.Comment: 9 pages, 7 figure

A comparison of 111In-DOTATOC and 111In-DOTATATE: biodistribution and dosimetry in the same patients with metastatic neuroendocrine tumours

[Yttrium-90-DOTA-Tyr3]-octreotide (DOTATOC) and [177Lu-DOTA-Tyr3-Thr8]-octreotide (DOTATATE) are used for peptide receptor-mediated radionuclide therapy (PRMRT) in neuroendocrine tumours. No human data comparing these two compounds are available so far. We used 111In as a surrogate for 90Y and 177Lu and examined whether one of the 111In-labelled peptides had a more favourable biodistribution in patients with neuroendocrine tumours. Special emphasis was given to kidney uptake and tumour-to-kidney ratio since kidney toxicity is usually the dose-limiting factor. Five patients with metastatic neuroendocrine tumours were injected with 222MBq 111In-DOTATOC and 111In-DOTATATE within 2 weeks. Up to 48h after injection, whole-body scans were performed and blood and urine samples were collected. The mean absorbed dose was calculated for tumours, kidney, liver, spleen and bone marrow. In all cases 111In-DOTATATE showed a higher uptake (%IA) in kidney and liver. The amount of 111In-DOTATOC excreted into the urine was significantly higher than for 111In-DOTATATE. The mean absorbed dose to the red marrow was nearly identical. 111In-DOTATOC showed a higher tumour-to-kidney absorbed dose ratio in seven of nine evaluated tumours. The variability of the tumour-to-kidney ratio was high and the significance level in favour of 111In-DOTATOC was P=0.065. In five patients the pharmacokinetics of 111In-DOTATOC and 111In-DOTATATE was found to be comparable. The two peptides appear to be nearly equivalent for PRMRT in neuroendocrine tumours, with minor advantages for 111In/90Y-DOTATOC; on this basis, we shall continue to use 90Y-DOTATOC for PRMRT in patients with metastatic neuroendocrine tumour

Delocalized single-photon Dicke states and the Leggett- Garg inequality in solid state systems

We show how to realize a single-photon Dicke state in a large one-dimensional array of two- level systems, and discuss how to test its quantum properties. Realization of single-photon Dicke states relies on the cooperative nature of the interaction between a field reservoir and an array of two-level-emitters. The resulting dynamics of the delocalized state can display Rabi-like oscillations when the number of two-level emitters exceeds several hundred. In this case the large array of emitters is essentially behaving like a mirror-less cavity. We outline how this might be realized using a multiple-quantum-well structure and discuss how the quantum nature of these oscillations could be tested with the Leggett-Garg inequality and its extensions.Comment: 29 pages, 5 figures, journal pape

Peptide receptor radiotherapy: a new option for the management of aggressive fibromatosis on behalf of the Italian Sarcoma Group

The management of aggressive fibromatosis (AF) is problematic, and few options are available to patients unsuitable for surgery and resistant to external-beam radiation therapy (EBRT). We report on two patients with fast-growing recurrences of AF resistant to EBRT who obtained protracted clinical benefits with 90Y-DOTATOC. 90Y-DOTATOC should be further investigated in this setting

FREE ORAL COMMUNICATIONS 2: ALCOHOL AND LIVER—CLINICAL RESEARCHO2.1RAPID DECLINE OF LIVER STIFFNESS WITH ALCOHOL WITHDRAWAL IN HEAVY DRINKERS

Background and aims. Measurement of liver stiffness using real-time elastography appears as a promising tool to evaluate the severity of chronic liver diseases. Previous studies in patients with alcoholic liver disease have suggested that fibrosis was the only histological parameter to influence liver stiffness. To challenge this hypothesis, we have prospectively tested the short-term impact of alcohol withdrawal on liver stiffness value. Methods. All patients hospitalized for alcohol withdrawal in our Liver Unit between September 2008 and December 2010 had a liver stiffness determination (using a FibroScan® device) at entry (D0) and 7 days after alcohol withdrawal (D7). Stiffness values were compared using non-parametric test for paired-values. We compared (i) the 10 measures performed at D0 and at D7 for each patient; (ii) the variation of the median result of all patients (using Wilcoxon test in both cases). Results. A total of 138 patients were included in the study [median alcohol consumption: 150g/day (range: 40-400); hepatitis C: n=22 (15.9%); cirrhosis: n=29 (21.0%)]. From D0 to D7, the liver stiffness decreased significantly in 61 patients (44.2%) and increased significantly in 18 (13.0%). Considering all patients, median liver stiffness value decreased from 7.25 to kPa (P<0.001). The stage of fibrosis indicated by liver stiffness changed in 47 patients between D0 and D7 (decrease in 33 and increase in 14). Conclusion. Liver stiffness decreases significantly in nearly half of alcoholic patients after only 7 days of abstinence. This result strongly suggests that non-fibrotic lesions (such as inflammatory ones) may influence liver stiffness. From a practical point of view, it also shows that variation in alcohol consumption must be taken into account for the interpretation of liver stiffness valu

Lutetium-labelled peptides for therapy of neuroendocrine tumours

Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with 177Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with 177Lu-[DOTA0,Tyr3]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with 177Lu-DOTATATE as well as the limited side effects with additional cycles of 177Lu-DOTATATE suggest that more cycles of 177Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of 90Y-[DOTA0,Tyr3]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with 177Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with 177Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours