Cloning and Functional Characterization of Dog OCT1 and OCT2: Another Step in Exploring Species Differences in Organic Cation Transporters

OCT1 and OCT2 are polyspecific membrane transporters that are involved in hepatic and renal drug clearance in humans and mice. In this study, we cloned dog OCT1 and OCT2 and compared their function to the human and mouse orthologs. We used liver and kidney RNA to clone dog OCT1 and OCT2. The cloned and the publicly available RNA-Seq sequences differed from the annotated exon-intron structure of OCT1 in the dog genome CanFam3.1. An additional exon between exons 2 and 3 was identified and confirmed by sequencing in six additional dog breeds. Next, dog OCT1 and OCT2 were stably overexpressed in HEK293 cells and the transport kinetics of five drugs were analyzed. We observed strong differences in the transport kinetics between dog and human orthologs. Dog OCT1 transported fenoterol with 12.9-fold higher capacity but 14.3-fold lower affinity (higher K_M) than human OCT1. Human OCT1 transported ipratropium with 5.2-fold higher capacity but 8.4-fold lower affinity than dog OCT1. Compared to human OCT2, dog OCT2 showed 10-fold lower transport of fenoterol and butylscopolamine. In conclusion, the functional characterization of dog OCT1 and OCT2 reported here may have implications when using dogs as pre-clinical models as well as for drug therapy in dogs.     

Effects of Long-Term Temozolomide Treatment on Glioblastoma and Astrocytoma WHO Grade 4 Stem-like Cells

Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse.     

Influence of glycerol on the mechanical reversibility and thermal damage susceptibility of collagenous tissues

Clinical procedures wherein supraphysiologic temperatures must be achieved in deep layers of tissue via light are often compromised by optical scattering and absorption. Optical clearing of tissue superficial to the target improves the efficacy of such procedures. Glycerol is an attractive chemical agent for achieving dramatic reductions in tissue turbidity, but its net effects on healthy tissue are not fully understood. In this paper, we investigate possible alterations of biaxial mechanical properties in a model collagenous tissue, bovine epicardium, induced by glycerol. Furthermore, we examine the effects of glycerol on the biaxial thermomechanical properties of epicardium constrained at near-physiologic length. It is seen that mechanical changes induced by glycerol are fully reversed upon rehydration in normal saline. Moreover, glycerol protects cleared tissue by increasing its thermal stability and minimizing thermal alterations of mechanical properties.     

Bio‐inspired Highly Scattering Networks via Polymer Phase Separation

A common strategy to optimize whiteness in living organisms consists in using 3D random networks with dense and polydisperse scattering elements constituted by relatively low refractive index materials. Inspired by these natural architectures, a fast and scalable method to produce highly scattering porous polymer films via phase separation is developed. By varying the molecular weight of the polymer, the morphology of the porous films is modified, and therefore their scattering properties are tuned. The achieved transport mean free paths are in the micrometer range, improving the scattering strength of analogous low refractive index systems, e.g., standard white paper, by an order of magnitude. The produced porous films show a broadband reflectivity of ≈75% while only 4 µm thick. In addition, the films are flexible and can be readily index‐matched with water (i.e., they become transparent when wet), allowing for various applications such as coatings with tunable transmittance and responsive paints.     

Removal of spurious coherence in MEG source-space coherence analysis

Source-space coherence analysis has become a popular method to estimate functional connectivity based on MEG/EEG. Source-space analysis involves solving the inverse problem, estimating the time courses of specific brain regions, and then examining the coherence between activities at different brain regions. However, source-space coherence analysis can be confounded by spurious coherence caused due to the leakage properties of the inverse algorithm employed. Such spurious coherence is typically manifested as an artifactual large peak around the seed voxel, called seed blur, in the resulting coherence images. This seed blur often obscures important details of brain interactions. This paper proposes the use of the imaginary part of the coherence to remove the spurious coherence caused by the leakage of an imaging algorithm. We present a theoretical analysis that explains how the use of imaginary part can remove this spurious coherence. We then present results from both computer simulations and experiments using resting-state MEG data which demonstrate the validity of our analysis.     

Methods for Compression of Feedback in Adaptive Multi-carrier 4G Schemes

In this paper, several algorithms for compressing the feedback of channel quality information are presented and analyzed. These algorithms are developed for a proposed adaptive modulation scheme for future multi-carrier 4G mobile systems. These strategies compress the feedback data and, used together with opportunistic scheduling, drastically reduce the feedback data rate. Thus the adaptive modulation schemes become more suitable and efficient to be implemented in future mobile systems, increasing data throughput and overall system performance.

Evaluation of registration methods on thoracic CT: the EMPIRE10 challenge

EMPIRE10 (Evaluation of Methods for Pulmonary Image REgistration 2010) is a public platform for fair and meaningful comparison of registration algorithms which are applied to a database of intrapatient thoracic CT image pairs. Evaluation of nonrigid registration techniques is a nontrivial task. This is compounded by the fact that researchers typically test only on their own data, which varies widely. For this reason, reliable assessment and comparison of different registration algorithms has been virtually impossible in the past. In this work we present the results of the launch phase of EMPIRE10, which comprised the comprehensive evaluation and comparison of 20 individual algorithms from leading academic and industrial research groups. All algorithms are applied to the same set of 30 thoracic CT pairs. Algorithm settings and parameters are chosen by researchers expert in the configuration of their own method and the evaluation is independent, using the same criteria for all participants. All results are published on the EMPIRE10 website (http://empire10.isi.uu.nl). The challenge remains ongoing and open to new participants. Full results from 24 algorithms have been published at the time of writing. This paper details the organization of the challenge, the data and evaluation methods and the outcome of the initial launch with 20 algorithms. The gain in knowledge and future work are discussed.     

Investigation of the Growth of Intermetallic Compounds Between Cu Pillars and Solder Caps

In flip chip applications, Cu pillars with solder caps are regarded as next-generation electronic interconnection technology, because of high input/output density. However, because of diffusion and reaction of Sn and Cu during the high-temperature reflow process, intermetallic compounds (IMC) are formed, and grow, at the interface between the cap and the pillar. Understanding the growth behavior of interfacial IMC is critical in the design of solder interconnections, because excessive growth of IMC can reduce the reliability of connections. In this study, the growth of IMC during thermal cycling, an accelerated method of testing the service environment of electronic devices, was studied by use of focused ion beam–scanning electron microscopy. Under alternating high and low-temperature extremes, growth of Cu₆Sn₅ (η-phase) and Cu₃Sn (ε-phase) IMC was imaged and measured as a function of the number of cycles. The total IMC layer grew significantly thicker but became more uniform during thermal cycling. The Cu₃Sn layer was initially thinner than the Cu₆Sn₅ layer but outgrew the Cu₆Sn₅ layer after 1000 cycles. It was found that, with limited Cu and Sn diffusion, consumption of Cu₆Sn₅ for growth of the Cu₃Sn layer can result in a thinner Cu₆Sn₅ layer after thermal cycling.     

Active antenna array lumped ring configuration

Coupled active antenna oscillator arrays are used for power-combining at microwave and millimeter-wave frequencies. It is known that the relative phase determined by the element separation distance ultimately determines the array operational mode and, hence, far-field radiation characteristics. Separately, it is known that coupled oscillator modal stability is achieved by coupling oscillators through lumped capacitive elements. In this paper, an arrangement whereby lumped capacitive elements (placed across the oscillator loads) and radiative coupling are employed concurrently is investigated. The arrangement takes the form of a ring of coupled oscillators used to excite a 2×2 antenna array. The effect that these couplings have on array behavior are evaluated using time-domain analysis and analytically derived equations. Experimental results for far-field radiation patterns are discussed in relation to coupled oscillator dynamical behavior. These suggest that the theoretical predictions are valid, offering a robust design tool for studies of larger power-combining arrays