Quinone Methide-Based Organophosphate Hydrolases Inhibitors: Trans Proximity Labelers versus Cis Labeling Activity-Based Probes

Quinone methide (QM) chemistry is widely applied including in enzyme inhibitors. Typically, enzyme-mediated bond breaking releases a phenol product that rearranges into an electrophilic QM that in turn covalently modifies protein side chains. However, the factors that govern the reactivity of QM-based inhibitors and their mode of inhibition have not been systematically explored. Foremost, enzyme inactivation might occur in cis, whereby a QM molecule inactivates the very same enzyme molecule that released it, or by trans if the released QMs diffuse away and inactivate other enzyme molecules. We examined QM-based inhibitors for enzymes exhibiting phosphoester hydrolase activity. We tested different phenolic substituents and benzylic leaving groups, thereby modulating the rates of enzymatic hydrolysis, phenolate-to-QM rearrangement, and the electrophilicity of the resulting QM. By developing assays that distinguish between cis and trans inhibition, we have identified certain combinations of leaving groups and phenyl substituents that lead to inhibition in the cis mode, while other combinations gave trans inhibition. Our results suggest that cis-acting QM-based substrates could be used as activity-based probes to identify various phospho- and phosphono-ester hydrolases, and potentially other hydrolases.     

Recognition of motion-blurred images by use of the method of moments

Image motion causes a blur that changes features of objects and therefore complicates the task of automatic recognition. In this work we develop two recognition methods for motion-blurred images. For the first method we assume that the motion function and direction during the exposure are given. We develop the relation between the blurred-image moments and the original-image moments based on the motion function only. The recognition is carried out by comparing the moments of the restored image against the moments of the image database. In the second method the motion function is not known. In this case image moments that are invariant with respect to the motion blur are identified, and only these moments are used for recognition. The advantage of the suggested methods is that no time-consuming image restoration is required prior to recognition.     

Connectivity in one-dimensional ad hoc networks: A queueing theoretical approach

In this paper we analyze connectivity issues in one-dimensional ad hoc networks. Starting with a deterministic channel model, we show how an equivalent GI|D|∞ queueing model may be used to address network connectivity. In this way, we obtain exact results for the coverage probability, the node isolation probability and the connectivity distance for various node placement statistics. We then show how a GI|G|∞ model may be used to study broadcast percolation problems in ad hoc networks with general node placement in the presence of fading channels. In particular, we obtain explicit results for the case of nodes distributed according to a Poisson distribution operating in a fading/shadowing environment. In the latter case, heavy traffic theorems are applied to derive the critical transmission power for connectivity and broadcast percolation distance in highly dense networks. The impact of signal processing schemes able to exploit the diversity provided by small-scale fading by means of multiple antennas is considered. The analysis is then extended to the case of unreliable ad hoc networks, with an in-depth discussion of asymptotic results. This work was partially supported by the EURO NGI Network of Excellence. The work of D. Miorandi was partially supported by Fond. A. Gini. This work has been done while D. Miorandi, at that time with University of Padova (Italy), was visiting the MAESTRO project at INRIA Sophia Antipolis. Daniele Miorandi received his “Laurea” (summa cum laude) and Ph.D. degrees from Univ. of Padova (Italy) in 2001 and 2005, respectively. He currently holds a post-doc position at CREATE-NET, Trento (Italy). In 2003/04 he spent 12 months of his doctoral thesis visiting the MAESTRO team at INRIA Sophia Antipolis (France). His research interests include stochastic modelling, performance evaluation and protocols design for wireless networks. Eitan Altman received the B.Sc. degree in electrical engineering (1984), the B.A. degree in physics (1984) and the Ph.D. degree in electrical engineering (1990), all from the Technion-Israel Institute, Haifa. In (1990) he further received his B.Mus. degree in music composition in Tel-Aviv university. Since 1990, he has been with INRIA (National research institute in informatics and control) in Sophia-Antipolis, France. His current research interests include performance evaluation and control of telecommunication networks and in particular congestion control, wireless communications and networking games. He is in the editorial board of several scientific journals: Stochastic Models, JEDC, COMNET, SIAM SICON and WINET. He has been the (co)chairman of the program committee of several international conferences and workshops (on game theory, networking games and mobile networks). More informaion can be found at http://www.inria.fr/mistral/personnel/Eitan.Altman/me.html     

Shear stress induced by a gas bubble pulsating in an ultrasonic field near a wall

Some of the effects that therapeutic ultrasound has in medicine and biology may be associated with steady oscillations of gas bubbles in liquid, very close to tissue surface. The bubble oscillations induce on the surface steady shear stress attributed to microstreaming. A mathematical simulation of the problem for both free and capsulated bubbles, known as contrast agents, is presented here. The simulation is based on a solution of Laplace's equation for potential flow and existing models for microstreaming. The solution for potential flow was obtained numerically using a boundary integral method. The solution provides the evolution of the bubble shape, the distribution of the velocity potential on the surface, and the shear stress along the surface. The simulation shows that significant shear stresses develop on the surface when the bubble bounces near the tissue surface. In this case, pressure amplitude of 20 kPa generates maximal steady shear stress of several kilo Pascal. Substantial shear stress on the tissue surface takes place inside a circular zone with a radius about half of the bubble radius. The predicted shear stress is greater than stress that causes hemolysis in blood and several orders of magnitude greater than the physiological stress induced on the vessel wall by the flowing blood.     

The Mott Fragmentation Model and the Vpl break-up parameter

It is shown that the Mott fragmentation model and the Hirsch formula for the shaped charge jet break-up time complete one another to yield a unified model. This model is consistant with the microscopic picture of internal flow splitting in the metal, into shear bands undergoing a strain larger than the average and the metal between them which undergoes a strain which is smaller than the average. This splitting reduces the deformation energy dissipated by the metal while elongating. It corresponds to the splitting of the stress versus strain characteristics of the metal into the isothermic and adiabatic curves as measured by Johnson and Cook. The parameter V_plwhich describes the break-up process according to the Hirsch model, is identified with the expression (dσ_m/ϱ)^1/2 where dσ_m is the difference in yield strength between the isothermic and adiabatic curves where the adiabatic characteristic becomes a maximum. The comparison with available experimental measurements of this prediction shows a very encouraging agreement. The weak dependence of V_pl on the strain rate on the one hand and the observed increase of the jet break-up time in slowly elongating jets on the other hand are also explained using energy considerations. The recent recovery of jet particles by Zernow yields supportive evidence of the proposed theory which may be extended to all semi steady metal plastic flow phenomena. The final break-up, according to this model is due to the separation between the two sides of shear bands where the slide motion went on during the whole deformation process.     

First Principles Investigation of Cold Curves of Metals

The rapid development of better high pressure experimental techniques combined with efficient and accurate density functional calculations of the structural properties of materials provide a new avenue to promote the study of materials at high pressures, which is currently based mostly on simple phenomenological modelling. The progress of experimental results into higher-pressure regimes represents a challenge to the phenomenological approaches, which can be addressed by carefully considered ab initio calculations. We present cold curves of several elements, calculated using different approximations of DFT and compare them with available experimental data. The comparison shows good agreement both in simple single phase and complex multi-phase cases. It suggests that DFT may be used to extrapolate high pressure behaviour of materials beyond the currently possible pressure range, with a robust estimate of the accuracy of the extrapolation based on various DFT implementations.     

Effect of Chemotherapy Cytarabine and Acute Myeloid Leukemia on the Development of Spermatogenesis at the Adult Age of Immature Treated Mice

Acute myeloid leukemia (AML) accounts for around 20% of diagnosed childhood leukemia. Cytarabine (CYT) is involved in the AML treatment regimen. AML and CYT showed impairment in spermatogenesis in human and rodents in adulthood. We successfully developed an AML disease model in sexually immature mice. Monocytes and granulocytes were examined in all groups: untreated control, AML alone, CYT alone and AML+CYT (in combination). There was a significant increase in the counts of monocytes and granulocytes in the AML-treated immature mice (AML) compared to the control, and AML cells were demonstrated in the blood vessels of the testes. AML alone and CYT alone impaired the development of spermatogenesis at the adult age of the AML-treated immature mice. The damage was clear in the structure/histology of their seminiferous tubules, and an increase in the apoptotic cells of the seminiferous tubules was demonstrated. Our results demonstrated a significant decrease in the meiotic/post-meiotic cells compared to the control. However, CYT alone (but not AML) significantly increased the count of spermatogonial cells (premeiotic cells) that positively stained with SALL4 and PLZF per tubule compared to the control. Furthermore, AML significantly increased the count of proliferating spermatogonial cells that positively stained with PCNA in the seminiferous tubules compared to the control, whereas CYT significantly decreased the count compared to the control. Our result showed that AML and CYT affected the microenvironment/niche of the germ cells. AML significantly decreased the levels growth factors, such as SCF, GDNF and MCSF) compared to control, whereas CYT significantly increased the levels of MCSF and GDNF compared to control. In addition, AML significantly increased the RNA expression levels of testicular IL-6 (a proinflammatory cytokine), whereas CYT significantly decreased testicular IL-6 levels compared to the control group. Furthermore, AML alone and CYT alone significantly decreased RNA expression levels of testicular IL-10 (anti-inflammatory cytokine) compared to the control group. Our results demonstrate that pediatric AML disease with or without CYT treatment impairs spermatogenesis at adult age (the impairment was more pronounced in AML+CYT) compared to control. Thus, we suggest that special care should be considered for children with AML who are treated with a CYT regimen regarding their future fertility at adult age.     

Characterization of channel hot electron injection by thesubthreshold slope of NROMTM device

Channel hot electron (CHE) injection, is widely used as main programming method in flash products. The spatial distribution could only be measured indirectly through stress-based experiments. A simple measurement technique to spatially characterize CHE injection is presented. It is shown that subthreshold slope degradation during programming of NROM^TM device provides the location and distribution of the injected electrons. It is shown that injection takes place mostly above the drain region and thus, results in subthreshold slope degradation. It is further shown, based on two-dimensional modeling, that charge distribution width is narrower than 40 nm     

Leakage of relevant information to innocent examinees in the GKT: An attempt to reduce false-positive outcomes by introducing target stimuli.

This study focused on the Guilty Knowledge Test (GKT)—a psychophysiological detection method based on a series of multiple-choice questions, each having one relevant and several neutral (control) alternatives. The study examined a new method designed to reduce false-positive outcomes due to leakage of relevant items to innocent suspects by introducing target items (i.e., items known to all examinees but unrelated to the crime) to which participants have to respond (e.g., by pressing a key) while answering the GKT questions. Informed innocent participants showed relatively larger electrodermal responses to the critical items than uninformed participants, but not as large as the responses made by guilty participants. No differences between informed and uninformed innocent participants were obtained with a respiration measure. The use of the target items tended to reduce the differences between informed and uninformed innocent participants. The results further demonstrated that electrodermal responding to the relevant items was correlated with memory of these items. (PsycINFO Database Record (c) 2010 APA, all rights reserved)