NAD(P)H quinone oxidoreductase (NQO1): an enzyme which needs just enough mobility, in just the right places

NAD(P)H quinone oxidoreductase 1 (NQO1) catalyses the two electron reduction of quinones and a wide range of other organic compounds. Its physiological role is believed to be partly the reduction of free radical load in cells and the detoxification of xenobiotics. It also has non-enzymatic functions stabilising a number of cellular regulators including p53. Functionally, NQO1 is a homodimer with two active sites formed from residues from both polypeptide chains. Catalysis proceeds via a substituted enzyme mechanism involving a tightly bound FAD cofactor. Dicoumarol and some structurally related compounds act as competitive inhibitors of NQO1. There is some evidence for negative cooperativity in quinine oxidoreductases which is most likely to be mediated at least in part by alterations to the mobility of the protein. Human NQO1 is implicated in cancer. It is often over-expressed in cancer cells and as such is considered as a possible drug target. Interestingly, a common polymorphic form of human NQO1, p.P187S, is associated with an increased risk of several forms of cancer. This variant has much lower activity than the wild-type, primarily due to its substantially reduced affinity for FAD which results from lower stability. This lower stability results from inappropriate mobility of key parts of the protein. Thus, NQO1 relies on correct mobility for normal function, but inappropriate mobility results in dysfunction and may cause disease.This work was supported by the Junta de Andalucía [grant number P11-CTS-07187 (to A.L.P.)]

Imaging features of retroperitoneal extra-adrenal paragangliomas in 10 dogs

Retroperitoneal paragangliomas are rare tumors of the neuroendocrine system. Only a few canine case reports are available with rare descriptions of their imaging features. The objectives of this multi-center, retrospective case series study were to describe the diagnostic imaging features of confirmed retroperitoneal paragangliomas and specify their location. Medical records and imaging studies of 10 affected dogs with cytological or histopathologic results concordant with retroperitoneal paragangliomas were evaluated. Dogs had a median age of 9 years. Four of them had clinical signs and laboratory reports compatible with excessive production of catecholamines. Six ultrasound, four CT, four radiographic, and one MRI studies were included. The paragangliomas did not have a specific location along the aorta. They were of various sizes (median 33 mm, range: 9–85 mm of length). Masses had heterogeneous parenchyma in six of 10 dogs, regardless of the imaging modality. Strong contrast enhancement was found in all CT studies. Encircling of at least one vessel was detected in six of 10 masses, clear invasion of a vessel was identified in one of 10 masses. In five of 10 cases, the masses were initially misconstrued as lymph nodes by the on-site radiologist. Retroperitoneal paragangliomas appear along the abdominal aorta, often presenting heterogeneous parenchyma, possibly affecting the local vasculature, and displaying strong contrast enhancement on CT. Clinical signs can be secondary to mass effects or excessive catecholamine production. Underdiagnosis and misdiagnosis of this tumor are suspected as they can be silent, of small size, or confused with other structures

Spatially Controlled Generation and Probing of Random Telegraph Noise in Metal Nanocrystal Embedded HfO2Using Defect Nanospectroscopy

Random telegraph noise (RTN) is often considered a nuisance or, more critically, a key reliability challenge for miniaturized semiconductor devices. However, this picture is gradually changing as recent works have shown emerging applications based on the inherent randomness of the RTN signals in state-of-The-Art technologies, including true random number generator and IoT hardware security. Suitable material platforms and device architectures are now actively explored to bring these technologies from an embryonic stage to practical application. A key challenge is to devise material systems, which can be reliably used for the deterministic creation of localized defects to be used for RTN generation. Toward this goal, we have investigated RTN in Au nanocrystal (Au-NC) embedded HfO2stacks at the nanoscale by combining conduction atomic force microscopy defect spectroscopy and a statistical factorial hidden Markov model analysis. With a voltage applied across the stack, there is an enhanced asymmetric electric field surrounding the Au-NC. This in turn leads to the preferential generation of atomic defects in the HfO2near the Au-NC when voltage is applied to the stack to induce dielectric breakdown. Since RTN arises from various electrostatic interactions between closely spaced atomic defects, the Au-NC HfO2material system exhibits an intrinsic ability to generate RTN signals. Our results also highlight that the spatial confinement of multiple defects and the resulting electrostatic interactions between the defects provides a dynamic environment leading to many complex RTN patterns in addition to the presence of the standard two-level RTN signals. The insights obtained at the nanoscale are useful to optimize metal nanocrystal embedded high-κ stacks and circuits for on-demand generation of RTN for emerging random number applications

Fatal Void Size Comparisons in Via-Below and Via-Above Cu Dual-Damascene Interconnects

The median-times-to-failure (t₅₀’s) for straight dual-damascene via-terminated copper interconnect structures, tested under the same conditions, depend on whether the vias connect down to underlaying leads (metal 2, M2, or via-below structures) or connect up to overlaying leads (metal 1, M1, or via-above structures). Experimental results for a variety of line lengths, widths, and numbers of vias show higher t₅₀’s for M2 structures than for analogous M1 structures. It has been shown that despite this asymmetry in lifetimes, the electromigration drift velocity is the same for these two types of structures, suggesting that fatal void volumes are different in these two cases. A numerical simulation tool based on the Korhonen model has been developed and used to simulate the conditions for void growth and correlate fatal void sizes with lifetimes. These simulations suggest that the average fatal void size for M2 structures is more than twice the size of that of M1 structures. This result supports an earlier suggestion that preferential nucleation at the Cu/Si₃N₄ interface in both M1 and M2 structures leads to different fatal void sizes, because larger voids are required to span the line thickness in M2 structures while smaller voids at the base of vias can cause failures in M1 structures. However, it is also found that the fatal void sizes corresponding to the shortest-times-to-failure (STTF’s) are similar for M1 and M2, suggesting that the voids that lead to the shortest lifetimes occur at or in the vias in both cases, where a void need only span the via to cause failure. Correlation of lifetimes and critical void volumes provides a useful tool for distinguishing failure mechanisms.Singapore-MIT Alliance (SMA

Generating Time-Varying Road Network Data Using Sparse Trajectories

While research on time-varying graphs has attracted recent attention, the research community has limited or no access to real datasets to develop effective algorithms and systems. Using noisy and sparse GPS traces from vehicles, we develop a time-varying road network data set where edge weights differ over time. We present our methodology and share this dataset, along with a graph manipulation tool. We estimate the traffic conditions using the sparse GPS data available by characterizing the sparsity issues and assessing the properties of travel sequence data frequency domain. We develop interpolation methods to complete the sparse data into a complete graph dataset with realistic time-varying edge values. We evaluate the performance of time-varying and static shortest path solutions over the generated dynamic road network. The shortest paths using the dynamic graph produce very different results than the static version. We provide an independent Java API and a graph database to analyze and manipulate the generated time-varying graph data easily, not requiring any knowledge about the inners of the graph database system. We expect our solution to support researchers to pursue problems of time-varying graphs in terms of theoretical, algorithmic, and systems aspects. The data and Java API are available at: http://elif.eser.bilkent.edu.tr/roadnetwork. © 2016 IEEE

Length Effects on the Reliability of Dual-Damascene Cu Interconnects

The effects of interconnect length on the reliability of dual-damascene Cu metallization have been investigated. As in Al-based interconnects, the lifetimes of Cu lines increase with decreasing length. However, unlike Al-based interconnects, no critical length exists, below which all Cu lines are âimmortal’. Furthermore, we found multi-modal failure statistics for long lines, suggesting multiple failure mechanisms. Some long Cu interconnect segments have very large lifetimes, whereas in Al segments, lifetimes decrease continuously with increasing line length. It is postulated that the large lifetimes observed in long Cu lines result from liner rupture at the bottom of the vias, which allows continuous flow of Cu between the two bond pads. As a consequence, the average lifetimes of short lines and long lines can be higher than those of lines with intermediate lengths.Singapore-MIT Alliance (SMA

Investigation of the Fundamental Reliability Unit for Cu Dual-Damascene Metallization

An investigation has been carried out to determine the fundamental reliability unit of copper dual-damascene metallization. Electromigration experiments have been carried out on straight via-to-via interconnects in the lower metal (M1) and the upper metal (M2), and in a simple interconnect tree structure consisting of straight via-to-via line with an extra via in the middle of the line (a "dotted-I"). Multiple failure mechanisms have been observed during electromigration testing of via-to-via Cu interconnects. The failure times of the M2 test structures are significantly longer than that of identical M1 structures. It is proposed that this asymmetry is the result of a difference in the location of void formation and growth, which is believed to be related to the ease of electromigration-induced void nucleation and growth at the Cu/Si₃N₄ interface. However, voids were also detected in the vias instead of in the Cu lines for some cases of early failure of the test lines. These early failures are suspected to be related to the integrity and reliability of the Cu via. Different magnitudes and directions of electrical current were applied independently in two segments of the interconnect tree structure. As with Al-based interconnects, the reliability of a segment in this tree strongly depends on the stress conditions of the connected segment. Beyond this, there are important differences in the results obtained under similar test conditions for Al-based and Cu-based interconnect trees. These differences are thought to be associated with variations in the architectural schemes of the two metallizations. The absence of a conducting electromigration-resistant overlayer in Cu technology allows smaller voids to cause failure in Cu compared to Al. Moreover, the Si₃N₄ overlayer that serves as an interlevel diffusion barrier provides sites for easy nucleation of voids and also provides a high diffusivity path for electromigration. The results reported here suggest that while segments are not the fundamental reliability unit for circuit-level reliability assessments for Al or Cu, vias, rather than trees, might be the appropriate fundamental units for the assessment of Cu reliability.Singapore-MIT Alliance (SMA

Hollow silicon microneedle fabrication using advanced plasma etch technologies for applications in transdermal drug delivery

A novel production process flow is presented here for the manufacture of hollow silicon microneedles using deep reactive-ion etching (DRIE) technology. The patent-pending three-step process flow has been developed to produce multiple arrays of sharp-tipped, hollow microneedles, which facilitate easy insertion and controlled fluid injection into excised skin samples. A bevelled tip and vertical sidewalls for the microneedle have been achieved with good uniformity, despite >45% open etch area. Processing steps and etch challenges are discussed, and preliminary skin testing results are presented, showing effective needle insertion and delivery of fluorescent dye into ex vivo skin from human breast tissue