Fast Translation Research Articles

Nanoscale polymeric penetration enhancers in topical drug delivery

Although recent advances in polymeric nanomaterials hold promise to develop effective transdermal delivery systems, the lack of fundamental understanding of polymer–skin interactions has hindered their fast translation. In this review, we provide a comprehensive overview, focusing on the chemistry aspects of the polymeric nanomaterials, such as surface modification, hydrophilic–hydrophobic grafting, and conjugation with biodegradable polymers or links. These chemical modifications to the nanomaterials have been reported to significantly affect their interactions with skin and delivery of drugs across the skin layers. This review highlights recently developed polymeric systems based on polyester nanoparticles, polymeric micelles, dendrimers, and chitosan, which opens a new avenue through which transdermal drug delivery with high efficiency and low toxicity can be potentially achieved.

An Analysis of Vortices Embedded within a Quasi-Linear Convective System Using X-Band Polarimetric Radar

Abstract On 2 April 2010, a developing quasi-linear convective system (QLCS) moved rapidly northeastward through central Oklahoma spawning at least three intense, mesoscale vortices. At least two of these vortices caused damage rated as category 0 to 1 on the enhanced Fujita scale (EF0–EF1) in and near the town of Rush Springs. Two radar networks—the National Weather Service Weather Surveillance Radar-1988 Doppler network (WSR-88D) and the Engineering Research Center for Collaborative Adaptive Sensing of the Atmosphere (CASA) radar network—collected high spatial and temporal resolution data of the event. This study is an in-depth polarimetric analysis of mesovortices within a QLCS. In this case study, the storm development and evolution of the QLCS mesovortices are examined. Significant findings include the following: 1) The damage in Rush Springs was caused by a combination of the fast translation speed and the embedded circulations associated with QLCS vortices. The vortices’ relative winds nearly negated the storm motion to the left of the vortex, but doubled the ground-relative wind to the right of the vortex. 2) A significant differential reflectivity (ZDR) arc developed along the forward flank of the first vortex. The ZDR arc propagated northeastward along the QLCS with the development of each new vortex. 3) A minimum in the copolar correlation coefficient (ρhv) in the center of the strongest vortex was observed, indicating the likely existence of a polarimetric tornado debris signature (TDS). A secondary ρhv minimum also was found just to the right of the vortex center, possibly associated with lofted debris from straight-line winds.

SU-E-T-613: Improving Dose-Shaping and OAR-Sparing Using Robust Statistical Methods.

To achieve a better balance between tumor coverage and organ-at-risk (OAR) sparing by applying robust statistical methods to IMRT inverse optimization. We propose a novel approach to shape dose dropoff from the PTV by minimizing the L1 norm of the difference between the obtained and aimed dose value and the total variation of the dose distribution on the PTV and OAR regions. Minimizing the L1 norm results in operand values that are mostly small but potentially large on a sparse set. Applying this structure to both dose discrepancy and dose gradient, our method achieves: 1) sparsely-distributed, high-dose gradients; 2) structure dose-homogeneity; and 3) connectivity in the distribution of high-gradient voxels on the PTV's surface. Dose-volume histograms (DVHs) and visual observations of dose maps were compared among two plans optimized for the same dynamic IMRT prostate case: 1) the clinical plan (plan_c); and 2) a plan optimized using the TV energy, L-1 norm, and an over-dose quadratic (plan_r). Importance factors for the objective function of planr were chosen empirically. The beam geometry was obtained from the clinical plan, and the solution was optimized with linear programming. Plan_r improved dose conformity, increased overall bladder-sparing, and globally increased rectum-sparing relative to plan_c. These results suggest that robust formulations may be used to improve dose-shaping and OAR-sparing. The numerical stability and implementation simplicity of our method permits fast translation to the clinic.

Nanobodies Targeting Mouse/Human VCAM1 for the Nuclear Imaging of Atherosclerotic Lesions

A noninvasive tool allowing the detection of vulnerable atherosclerotic plaques is highly needed. By combining nanomolar affinities and fast blood clearance, nanobodies represent potential radiotracers for cardiovascular molecular imaging. Vascular cell adhesion molecule-1 (VCAM1) constitutes a relevant target for molecular imaging of atherosclerotic lesions. We aimed to generate, radiolabel, and evaluate anti-VCAM1 nanobodies for noninvasive detection of atherosclerotic lesions. Ten anti-VCAM1 nanobodies were generated, radiolabeled with technetium-99m, and screened in vitro on mouse and human recombinant VCAM1 proteins and endothelial cells and in vivo in apolipoprotein E-deficient (ApoE(-/-)) mice. A nontargeting control nanobody was used in all experiments to demonstrate specificity. All nanobodies displayed nanomolar affinities for murine VCAM1. Flow cytometry analyses using human human umbilical vein endothelial cells indicated murine and human VCAM1 cross-reactivity for 6 of 10 nanobodies. The lead compound cAbVCAM1-5 was cross-reactive for human VCAM1 and exhibited high lesion-to-control (4.95±0.85), lesion-to-heart (8.30±1.11), and lesion-to-blood ratios (4.32±0.48) (P<0.05 versus control C57Bl/6J mice). Aortic arch atherosclerotic lesions of ApoE(-/-) mice were successfully identified by single-photon emission computed tomography imaging. (99m)Tc-cAbVCAM1-5 binding specificity was demonstrated by in vivo competition experiments. Autoradiography and immunohistochemistry further confirmed cAbVCAM1-5 uptake in VCAM1-positive lesions. The (99m)Tc-labeled, anti-VCAM1 nanobody cAbVCAM1-5 allowed noninvasive detection of VCAM1 expression and displayed mouse and human cross-reactivity. Therefore, this study demonstrates the potential of nanobodies as a new class of radiotracers for cardiovascular applications. The nanobody technology might evolve into an important research tool for targeted imaging of atherosclerotic lesions and has the potential for fast clinical translation.

Typhoon‐induced phytoplankton blooms and primary productivity increase in the western North Pacific subtropical ocean

Using multiple satellite observations and series of numerical experiments, this work systematically studied phytoplankton blooms induced by tropical cyclones in the western North Pacific subtropical ocean (WNPSO) because WNPSO is among the world oceans where most number of intense tropical cyclones are found. All eleven typhoon cases passing the study domain in 2003 were examined in detail. It was observed that only two typhoons (18%) were able to induce phytoplankton blooms (chlorophyll‐a concentration increased from ≦0.1 mg m−3 to 0.4–0.8 mg m−3) and strong sea surface temperature cooling of −2.5 to −6°C. The other nine typhoons, including the most intense tropical cyclone on Earth in 2003 (i.e., supertyphoon Maemi), were not able to induce phytoplankton blooms and the associated sea surface temperature cooling was weak (0 to −1.5°C). Using series of numerical experiments, it was found that the presence of warm ocean eddy can effectively isolate the cold, nutrient‐rich water to be entrained to the surface ocean. Under this situation, even category 5 typhoon Maemi at its peak intensity of 150 kts could not induce phytoplankton bloom in the WNPSO. The weak responses of the other eight typhoons were due to insufficient wind intensity and transit time (caused by relatively small storm size and fast translation speed) in this deep nutricline/mixed layer ocean. As a result, the total annual primary production increase induced by typhoons in the WNPSO was estimated to be ∼3.27 × 1012 g C (0.00327 Pg), equivalent to 0.15% of the global annual anthropogenic CO2 uptake. This suggests that though WNPSO has the highest number and intensity of tropical cyclones among the world oceans, tropical cyclones in the WNPSO have little contribution to enhance biological carbon fixation in the context of global carbon‐climate system.

Discovery of Lung Cancer Biomarkers by Profiling the Plasma Proteome with Monoclonal Antibody Libraries

A challenge in the treatment of lung cancer is the lack of early diagnostics. Here, we describe the application of monoclonal antibody proteomics for discovery of a panel of biomarkers for early detection (stage I) of non-small cell lung cancer (NSCLC). We produced large monoclonal antibody libraries directed against the natural form of protein antigens present in the plasma of NSCLC patients. Plasma biomarkers associated with the presence of lung cancer were detected via high throughput ELISA. Differential profiling of plasma proteomes of four clinical cohorts, totaling 301 patients with lung cancer and 235 healthy controls, identified 13 lung cancer-associated (p < 0.05) monoclonal antibodies. The monoclonal antibodies recognize five different cognate proteins identified using immunoprecipitation followed by mass spectrometry. Four of the five antigens were present in non-small cell lung cancer cells in situ. The approach is capable of generating independent antibodies against different epitopes of the same proteins, allowing fast translation to multiplexed sandwich assays. Based on these results, we have verified in two independent clinical collections a panel of five biomarkers for classifying patient disease status with a diagnostics performance of 77% sensitivity and 87% specificity. Combining CYFRA, an established cancer marker, with the panel resulted in a performance of 83% sensitivity at 95% specificity for stage I NSCLC.

Genes optimized by evolution for accurate and fast translation encode in Archaea and Bacteria a broad and characteristic spectrum of protein functions

BackgroundIn many microbial genomes, a strong preference for a small number of codons can be observed in genes whose products are needed by the cell in large quantities. This codon usage bias (CUB) improves translational accuracy and speed and is one of several factors optimizing cell growth. Whereas CUB and the overrepresentation of individual proteins have been studied in detail, it is still unclear which high-level metabolic categories are subject to translational optimization in different habitats.ResultsIn a systematic study of 388 microbial species, we have identified for each genome a specific subset of genes characterized by a marked CUB, which we named the effectome. As expected, gene products related to protein synthesis are abundant in both archaeal and bacterial effectomes. In addition, enzymes contributing to energy production and gene products involved in protein folding and stabilization are overrepresented. The comparison of genomes from eleven habitats shows that the environment has only a minor effect on the composition of the effectomes. As a paradigmatic example, we detailed the effectome content of 37 bacterial genomes that are most likely exposed to strongest selective pressure towards translational optimization. These effectomes accommodate a broad range of protein functions like enzymes related to glycolysis/gluconeogenesis and the TCA cycle, ATP synthases, aminoacyl-tRNA synthetases, chaperones, proteases that degrade misfolded proteins, protectants against oxidative damage, as well as cold shock and outer membrane proteins.ConclusionsWe made clear that effectomes consist of specific subsets of the proteome being involved in several cellular functions. As expected, some functions are related to cell growth and affect speed and quality of protein synthesis. Additionally, the effectomes contain enzymes of central metabolic pathways and cellular functions sustaining microbial life under stress situations. These findings indicate that cell growth is an important but not the only factor modulating translational accuracy and speed by means of CUB.

Application of dynamic diffractive optics for enhanced femtosecond laser based cell transfection

We demonstrate the advantages of a dynamic diffractive optical element, namely a spatial light modulator (SLM) for the controlled and enhanced optoinjection and phototransfection of mammalian cells with a femtosecond light source. The SLM provides full control over the lateral and axial positioning of the beam with sub-micron precision. Fast beam translation enables time-sequenced irradiation, which is shown to enhance the optoinjection efficiency and alleviate the problem of exact beam positioning on the cell membrane. We show that irradiation in three axial positions doubles the number of viably optoinjected cells when compared with a single dose. The presented system also enables untargeted raster scan irradiation which provides a higher throughput transfection of adherent cells at the rate of 1 cell per second. Additionally, fluorescent imaging is used to demonstrate cell selective two-step gene therapy.

Translational control of Sp1 against ischemia via a hydrogen peroxide‐activated IRES pathway

The protein level of the transcription factor Sp1 (specific protein 1) is known to increase during hypoxia and oxidative stress. However, the exact mechanism underlying the increase of Sp1 and the physiological consequence thereafter remains to be fully clarified. We found in this study that, in rat primary cortical neurons, the oxygen‐glucose deprivation (OGD) causes an increase of H2O2 as well as Sp1 in the early phase of the treatment without, however, causing any change in either the level of mRNA or the stability of Sp1. We discovered hereby for the first time that there is a longer 5’‐UTR in the Sp1 mRNA that contains an IRES which is well‐known to render a fast and efficient translation of existing mRNAs. Importantly, by using the polysomal fragmentation and bicistronic luciferase assays, we found that H2O2 activates the IRES‐dependent translation. Accordingly, H2O2 or tempol, a superoxide dismutase‐mimetic agent, causes an increase of Sp1 in OGD‐treated neurons. The shRNA against Sp1 exacerbates the OGD‐induced apoptosis in primary neurons. In rat models of stroke, while the Sp1 level is increased in the cortex, blocking the Sp1 binding to DNA by mithramycin or pre‐silencing Sp1 with shRNAs leads to enhanced apoptosis and cortical injuries. Those results demonstrate that neurons can use H2O2 as a signaling molecule to activate the IRES‐dependent translation of Sp1 mRNA to increase Sp1 that defends against neuronal damage. Thus, appropriately maneuvering the H2O2 level or increasing Sp1 by targeting the IRES‐dependent translational pathway might represent efficient and novel avenue in combating neurodegenerative diseases.

Multiscale density estimation with errors in variables

We present an adaptive method for density estimation when the observations X = ( X 1 , … , X n ) are contaminated by additive errors Y = X + Z . The error distribution is not specified by the model but is estimated using repeated measurements ( Y i ) i = 1 , 2 , 3 of X . In this setting, we propose a wavelet method for density estimation which adapts both to the degree of ill posedness of the problem (smoothness of the error distribution) and to the regularity of the target density. Our method is implemented in the Fourier domain via a square-root transformation of the empirical characteristic function and yields fast translation invariant non-linear wavelet approximations with data-driven choices of fine tuning parameters. When the variable X is observed without errors our method provides a natural implementation of direct density estimation in the Meyer wavelet basis. We illustrate the adaptiveness properties of our estimator with a range of finite sample examples drawn from population with smooth and less smooth density functions.

Selection for minimization of translational frameshifting errors as a factor in the evolution of codon usage

In a wide range of genomes, it was observed that the usage of synonymous codons is biased toward specific codons and codon patterns. Factors that are implicated in the selection for codon usage include facilitation of fast and accurate translation. There are two types of translational errors: missense errors and processivity errors. There is considerable evidence in support of the hypothesis that codon usage is optimized to minimize missense errors. In contrast, little is known about the relationship between codon usage and frameshifting errors, an important form of processivity errors, which appear to occur at frequencies comparable to the frequencies of missense errors. Based on the recently proposed pause-and-slip model of frameshifting, we developed Frameshifting Robustness Score (FRS). We used this measure to test if the pattern of codon usage indicates optimization against frameshifting errors. We found that the FRS values of protein-coding sequences from four analyzed genomes (the bacteria Bacillus subtilis and Escherichia coli, and the yeasts Saccharomyces cerevisiae and Schizosaccharomyce pombe) were typically higher than expected by chance. Other properties of FRS patterns observed in B. subtilis, S. cerevisiae and S. pombe, such as the tendency of FRS to increase from the 5′- to 3′-end of protein-coding sequences, were also consistent with the hypothesis of optimization against frameshifting errors in translation. For E. coli, the results of different tests were less consistent, suggestive of a much weaker optimization, if any. Collectively, the results fit the concept of selection against mistranslation-induced protein misfolding being one of the factors shaping the evolution of both coding and non-coding sequences.

A Tyramine-Gated Chloride Channel Coordinates Distinct Motor Programs of a Caenorhabditis elegans Escape Response

A key feature of escape responses is the fast translation of sensory information into a coordinated motor output. In C. elegans, anterior touch initiates a backward escape response in which lateral head movements are suppressed. Here, we show that tyramine inhibits head movements and forward locomotion through the activation of a tyramine-gated chloride channel, LGC-55. lgc-55 mutant animals have defects in reversal behavior and fail to suppress head oscillations in response to anterior touch. lgc-55 is expressed in neurons and muscle cells that receive direct synaptic inputs from tyraminergic motor neurons. Therefore, tyramine can act as a classical inhibitory neurotransmitter. Activation of LGC-55 by tyramine coordinates the output of two distinct motor programs, locomotion and head movements that are critical for a C. elegans escape response.

The challenge of multisite epidemiologic studies in diverse populations: design and implementation of a 22-site study of tuberculosis in foreign-born people.

We designed a population-based study of the epidemiology of tuberculosis among foreign-born people in the U.S. and Canada. Challenges included standardizing recruitment and data entry at 22 sites, enrolling individuals who did not speak English and may be undocumented, and obtaining clearance from 36 institutional review boards (IRBs). We used stratified sampling to recruit patients through the Tuberculosis Epidemiologic Studies Consortium, a research consortium funded by the Centers for Disease Control and Prevention. Because recruitment sites were overseen by more than 30 local IRBs, we developed a simple process to designate a central IRB. We translated instruments into 10 main languages, arranged for fast translation of consent "short forms" into other languages, used one telephone interpretation service at all sites, and provided extensive interviewer training including mock interviews with simulated patients. We interviewed 1,696 participants in 19 states and provinces. Participants from 99 countries were interviewed in 40 languages. Twenty-three percent did not speak English at all; 64% needed an interpreter. More than 20% of participants reported they were undocumented. Participants' age, gender, and birthplaces were broadly similar to the target populations. One-third of local IRBs used the central IRB. Special confidentiality protections, substantial resources for translation and interpretation, and a centralized IRB made possible the recruitment of a representative sample of foreign-born people. The approaches may be applicable to studies of other diseases in multinational populations in the U.S. and Canada.

Runtime monitoring on multicores via OASES

Runtime monitoring support serves as a foundation for the important tasks of providing security, performing debugging, and improving performance of applications. Often runtime monitoring requires the maintenance of information associated with each of the application's original memory location, which is held in corresponding shadow memory locations. Unfortunately, existing robust shadow memory implementations are inefficient. In this paper, we present OASES: OS and Architectural Support for Efficient Shadow memory implementation for multicores that is also robust. A combination of operating system support (in the form of coupled allocation of memory pages used by the application and associated shadow memory pages) and architectural support (in the form of ISA support and exposed cache events) is proposed. Our page allocation policy enables fast translation of original addresses into corresponding shadow memory addresses; thus allowing implicit addressing of shadow memory. By exposing the cache events to the software, we ensure in software that the shadow memory instructions execute atomically with their corresponding original memory instructions. Our experiments show that the overheads of runtime monitoring tasks are significantly reduced in comparison to previous software implementations.

Anticipatory I/O Management for Clustered Flash Translation Layer in NAND Flash Memory

Recently, NAND flash memory has emerged as a next generation storage device because it has several advantages, such as low power consumption, shock resistance, and so on. However, it is necessary to use a flash translation layer (FTL) to intermediate between NAND flash memory and conventional file systems because of the unique hardware characteristics of flash memory. This paper proposes a new clustered FTL (CFTL) that uses clustered hash tables and a two-level software cache technique. The CFTL can anticipate consecutive addresses from the host because the clustered hash table uses the locality of reference in a large address space. It also adaptively switches logical addresses to physical addresses in the flash memory by using block mapping, page mapping, and a two-level software cache technique. Furthermore, anticipatory I/O management using continuity counters and a prefetch scheme enables fast address translation. Experimental results show that the proposed address translation mechanism for CFTL provides better performance in address translation and memory space usage than the well-known NAND FTL (NFTL) and adaptive FTL (AFTL).

Chinese to English automatic patent machine translation at SIPO

As a move to meet the global demand for Chinese patent information, a Chinese to English automatic patent MT service was launched by the State Intellectual Property Office (SIPO) of China, providing free of charge on-the-fly machine translation for claims and specifications of Chinese patents. The service adopts a hybrid-strategy method implemented by a semantically improved MT engine, and is integrated with the previously available English search tools for the English databases of human translation results of Chinese patent abstracts and bibliographic data. With a fast translation speed and acceptable readability, the service is expected to offer an assimilation tool for non-Chinese users. Future proposals for improving translation quality are summarized.

Imaging of Integrins as Biomarkers for Tumor Angiogenesis

The integrin family plays important roles during tumor angiogenesis, the formation of new blood vessels from pre-existing vasculature. Traditional structural and functional imaging techniques are not sufficient for early lesion detection, patient stratification, or monitoring the therapeutic efficacy against cancer. Molecular imaging, the visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems, can fulfill these goals. In this review article, we will summarize the current state-of-the-art of imaging integrin (alpha(2)beta(1), alpha(3)beta(1), alpha(4)beta(1), alpha(v)beta(3), and alpha(v)beta(6)) expression using either single molecular imaging modality (magnetic resonance imaging, ultrasound, optical, single photon emission computed tomography, and positron emission tomography) or a combination of different modalities. For clinical translation, radionuclide-based imaging will have broad potential applications in cancer patients and the currently available clinical data (exclusively on integrin alpha(v)beta(3) so far) will be discussed in detail. The design, optimization, and characterization of imaging agents targeting integrins will be presented and areas needing extensive future research effort will be discussed. In the new era of personalized medicine, fast clinical translation and incorporation of integrin imaging into anti-cancer clinical trials will be critical for the maximum benefit of cancer patients.

The Ups and Downs of Translation-Dependent Plasticity

Neuroscientists have been looking for good examples linking neuronal activity to gene expression/regulation involved in synaptic plasticity and the formation of long-term memories. New findings from Park et al. and Waung et al. in this issue of Neuron show that fast dendritic translation of the immediate-early gene Arc/Arg3.1 is involved in hippocampal mGluR-LTD, a protein synthesis-dependent form of plasticity.

Fast multipole accelerated boundary element method (FMBEM) for solution of 3D scattering problems

Wideband FMBEM codes are challenging to implement since there are problems at both very low and high frequencies. Substantially different schemes for function representation and translation are efficient for low and high frequency ranges. We present a method which is suitable for solution both high and low frequency problems since it implements a switch between different representations and uses fast translation methods appropriate to each representation. For a high frequency problem the switch between representations may occur at some intermediate levels of hierarchical space subdivision of the FMM. We also present an FMM-based preconditioner used in the flexible GMRES iterative solver for scattering problems and discuss example problems computed in range 0.001&amp;lt;kD&amp;lt;200, where k is the wave number and D is the size of the computational domain. The theoretical and experimental computational complexity of our algorithm is approximately O((kD)3) at large kD with relatively small asymptotic constant and the algorithm allows to solve problems with up to million nodes used for surface discretization in the range tested on a conventional personal computer.

High performance set associative translation lookaside buffers for low power microprocessors

A fast low power four-way set-associative translation lookaside buffer (TLB) is proposed. The proposed TLB allows single clock phase accesses at clock frequencies above 1 GHz. Comparisons to a conventional fully associative CAM tagged TLB, which is the type most commonly used in embedded processors, with the same number of entries on a 65 nm low standby power process show that the proposed design has 28% lower delay and up to 50% lower energy delay product. Unlike previous set-associative TLBs, which replicate the TLB to support multiple page sizes, multiple page sizes are supported on a way-by-way basis. Alternative conventional CAM tagged and set-associative TLBs are investigated with regard to access latency, power dissipation and hit rates.