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Han, H.

Publications and source records attributed to Han, H..

At least 109 records · Page 6Linked to original sources

SSR1 is a vital regulator in plant mitochondrial iron-sulfur biosynthesis

The Arabidopsis SHORT AND SWOLLEN ROOT1 (SSR1) gene encodes a mitochondrial TPR domain-containing protein and was previously reported to function in maintaining mitochondria function. In a screen for suppressors of the short-root phenotype of the loss-of-function mutant ssr1-2, two mutations, sus1 and sus2 (suppressor of ssr1-2), were isolated. sus1 and sus2 result from G87D and T55M single amino acid substitution in HSCA2 (At5g09590) and ISU1 (At4g22220), both of which are core components in iron-sulfur cluster biosynthesis pathway in mitochondria (ISC). We here demonstrated that SSR1 displayed a strong chaperone-like activity and was able to enhance the binding of HSCA2 to ISU1, an essential step for the normal operation of ISC machinery. Accordingly, the enzymatic activities of several iron-sulfur proteins, the mitochondrial membrane potential and ATP content are reduced in ssr1-2. Interestingly, SSR1 appears to exist only in plant lineages, possibly conferring adaptive advantages on plant ISC machinery to environment.

plant biology↗

Immunoengineered Nanobead System for the Isolation and Detection of Circulating Tumor Cells

Highly efficient capture and detection of circulating tumor cells (CTCs) remain elusive mainly because of their extremely low concentration in the peripheral blood of patients. Herein, we present an approach for the simultaneous capturing, isolation, and detection of CTCs using an immuno-fluorescent magnetic nanobead system (iFMNS) coated with a monoclonal anti-EpCAM antibody. The developed antibody nanobead system allows magnetic isolation and fluorescent-based quantification of CTCs. The expression of EpCAM on the surface of captured CTCs could be directly visualized without additional immune-fluorescent labeling. Our approach is shown to result in a 70 - 95% capture efficiency of CTCs, and 95% of the captured cells remain viable. Using our approach, the isolated cells could be directly used for culture, reverse transcription-polymerase chain reaction (RT-PCR), and immunocytochemistry (ICC) identification. We applied iFMNS for testing CTCs in peripheral blood samples from a lung cancer patient, which suggested that this approach would be a promising tool for CTCs enrichment and detection in one step.

bioengineering↗

AINTEGUMENTA and AINTEGUMENTA-LIKE6 directly regulate floral homeotic and growth genes in young flowers

Arabidopsis flower primordia give rise to floral organ primordia in stereotypical positions within four concentric whorls. Floral organ primordia in each whorl undergo distinct developmental programs to become one of four organ types (sepals, petals, stamens, and carpels). The Arabidopsis transcription factors AINTEGUMENTA (ANT) and AINTEGUMENTA-LIKE6 (AIL6) play critical and partially overlapping roles during floral organogenesis. They are required for correct positioning of floral organ initiation, contribute to the specification of floral organ identity, and regulate the growth and morphogenesis of developing floral organs. To gain insight into the molecular means by which ANT and AIL6 contribute to floral organogenesis, we identified the genome-wide binding sites of both ANT and AIL6 in stage 3 flower primordia, the developmental stage at which sepal primordia become visible and class B and C floral homeotic genes are first expressed. AIL6 binds to a subset of ANT sites, suggesting that AIL6 regulates some but not all of the same target genes as ANT. ANT and AIL6 binding sites are associated with genes involved in many biological processes related to meristem and flower organ development. Comparison of genes associated with both ANT and AIL6 ChIP-Seq peaks and those differentially expressed after perturbation of ANT or AIL6 activity identified likely direct targets of ANT and AIL6 regulation. These include the floral homeotic genes APETALA3 (AP3) and AGAMOUS (AG) and four growth regulatory genes: BIG BROTHER (BB), ROTUNDIFOLIA3 (ROT3), ANGUSTIFOLIA3/GRF INTERACTING FACTOR (AN3/GIF1), and XYLOGLUCAN ENDOTRANSGLUCOLSYLASE/HYDROLASE9 (XTH9). One Sentence SummaryThe transcription factors ANT and AIL6 directly regulate genes involved in different aspects of flower development including genes that specify floral organ identity and those that regulate growth.

plant biology↗

Fusobacterium nucleatum facilitates cetuximab resistance in colorectal cancer via the PI3K/AKT and JAK/STAT3 pathways

Infectious pathogens contribute to about 20% of the total tumor burden. Fusobacterium nucleatum (Fn) has been associated with the initiation, progression, and therapy resistance in colorectal cancer (CRC). The over-abundance of Fn has been observed in patients with right-sided CRC than in those with left-sided CRC. While the KRAS/NRAS/BRAF wild-type status of the CRC conferred better response to cetuximab in patients with left-sided CRC than with right-sided CRC. However, treatment failure remains the leading cause of tumor relapse and poor clinical outcome in patients with CRC. Here, we have studied the association of Fn to cetuximab resistance. Our functional studies indicate that Fn facilitates resistance of CRC to cetuximab in vitro and in vivo. Moreover, Fn was found to target the PI3K/AKT and JAK/STAT3 pathways, which altered the response to cetuximab therapy. Therefore, assessing the levels and targeting Fn and the associated signaling pathways may allow modulating the treatment regimen and improve prognoses of CRC patients.

cancer biology↗

A method to adjust a prior distribution in Bayesian second-level fMRI analysis

Previous research has shown the potential value of Bayesian methods in fMRI (functional magnetic resonance imaging) analysis. For instance, the results from Bayes factor-applied second-level fMRI analysis showed a higher hit rate compared with frequentist second-level fMRI analysis, suggesting greater sensitivity. Although the method reported more positives as a result of the higher sensitivity, it was able to maintain a reasonable level of selectivity in term of the false positive rate. Moreover, employment of the multiple comparison correction method to update the default prior distribution significantly improved the performance of Bayesian second-level fMRI analysis. However, previous studies have utilized the default prior distribution and did not consider the nature of each individual study. Thus, in the present study, a method to adjust the Cauchy prior distribution based on a priori information, which can be acquired from the results of relevant previous studies, was proposed and tested. A Cauchy prior distribution was adjusted based on the contrast, noise strength, and proportion of true positives that were estimated from a meta-analysis of relevant previous studies. In the present study, both the simulated images and real contrast images from two previous studies were used to evaluate the performance of the proposed method. The results showed that the employment of the prior adjustment method resulted in improved performance of Bayesian second-level fMRI analysis.

neuroscience↗

Three-dimensional ATUM-SEM reconstruction and analysis of hepatic endoplasmic reticulum-organelle interactions

The endoplasmic reticulum (ER) is a contiguous and complicated membrane network in eukaryotic cells, and membrane contact sites (MCSs) between the ER and other organelles perform vital cellular functions, including lipid homeostasis, metabolite exchange, calcium level regulation, and organelle division. Here, we establish a whole pipeline to reconstruct all ER, mitochondria, lipid droplets, lysosomes, peroxisomes, and nuclei by automated tape-collecting ultramicrotome scanning electron microscopy (ATUM-SEM) and deep-learning techniques, which generates an unprecedented 3D model for mapping liver samples. Furthermore, the morphology of various organelles is systematically analyzed. We found that the ER presents with predominantly flat cisternae and is knitted tightly all throughout the intracellular space and around other organelles. In addition, the ER has a smaller volume-to-membrane surface area ratio than other organelles, which suggests that the ER could be more suited for functions that require a large membrane surface area. Moreover, the MCSs between the ER and other organelles are explored. Our data indicate that ER-mitochondrial contacts are particularly abundant, especially for branched mitochondria. In addition, ER contacts with lipid droplets, lysosomes, and peroxisomes are also plentiful. In summary, we design an efficient method for obtaining a 3D reconstruction of biological structures at a nanometer resolution. Our study also provides the first 3D reconstruction of various organelles in liver samples together with important information fundamental for biochemical and functional studies in the liver.

cell biology↗

Prostate Epithelial Genes Define Docetaxel-Sensitive Prostate Cancer Molecular Subtype

BACKGROUND & OBJECTIVESAnalysis of the transcriptomic landscape of prostate adenocarcinoma shows multidimensional gene expression variability. Understanding cancer transcriptome complexity can provide biological insight and therapeutic guidance. To avoid potential confounding factors, such as stromal contamination and stress-related material degradation, we utilized a set of genes expressed by prostate epithelial cells from single-cell transcriptome data of the human prostate gland. MATERIALS & METHODSAnalyzing publicly available bulk and single-cell RNA sequencing data, we defined 1,629 genes expressed by prostate epithelial cells. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival. RESULTSTCGA-PRAD tumors were separated into four subtypes: A (30.0%), B (26.0%), C (14.7%), D (4.2%), and mixed (25.0%). Subtype A was characterized by low frequency of ETS-family fusions and high expression of KLK3, which encodes prostate-specific antigen (PSA). Subtype B showed the highest expression of ACP3, encoding PAP (prostatic acid phosphatase). Subtypes C and D were commonly associated with advanced T/N stages, high Gleason grades, and p53 or PIK3CA mutations. In silico drug-sensitivity screening suggested that subtype B is likely sensitive to docetaxel and paclitaxel. Serum PSA/PAP ratio was predictive of a radiographic response to docetaxel in metastatic castration-resistant prostate cancer patients. CONCLUSIONWe propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents. Molecular subtypes and biomarkers must be validated in a prospective cohort study.

cancer biology↗

BayesFactorFMRI: Implementing Bayesian second-level fMRI analysis with multiple comparison correction and Bayesian meta-analysis of fMRI images with multiprocessing

BayesFactorFMRI is a tool developed with R and Python to allow neuroimaging researchers to conduct Bayesian second-level analysis and Bayesian meta-analysis of fMRI image data with multiprocessing. This tool expedites computationally intensive Bayesian fMRI analysis through multiprocessing. Its GUI allows researchers who are not experts in computer programming to feasibly perform Bayesian fMRI analysis. BayesFactorFMRI is available via Zenodo and GitHub for download. It would be widely reused by neuroimaging researchers who intend to analyse their fMRI data with Bayesian analysis with better sensitivity compared with classical analysis while improving performance by distributing analysis tasks into multiple processors.

neuroscience↗

Eurycomanone regulates lipid metabolism by activating the cAMP/PKA pathway

Eurycoma longifolia Jack (ELJ) contains mainly alkaloids, and quassinoids, which are the main active ingredients. Eurycomanone (EN), one of the most common quassinoids, is said to have beneficial effects on lipid and glucose metabolism. In this study, we investigated the effects of EN on lipolysis by establishing a high-fat animal model in vivo and evaluated its efficacy as a lipolytic and anti-fatty liver agent. Oil red O staining showed morphological changes of 3T3-L1 preadipocytes after EN treatment and confirmed the inhibitory effects of EN on adipocyte differentiation. The mechanism of EN promotes lipolysis in 3T3-L1 cells was analyzed by immunofluorescence, Western blotting, quantitative real-time PCR and siRNA transfection. In C57BL/6J mice fed a high-fat diet, intragastric administration of EN (5 mg/kg and 10 mg/kg) for two weeks, decreased fat droplet mass and size, and reduced fat accumulation in the liver. Furthermore, EN activated PKA and promoted the PKA/hormone sensitive lipase lipolysis signaling pathway, thereby increasing the release of glycerol and free fatty acids from adipocytes. Our findings indicate the potential of EN as a promising alternative pharmacologic agent for the prevention of obesity.

pharmacology and toxicology↗

Metabolic labeling of RNA using multiple ribonucleoside analogs enables simultaneous evaluation of transcription and degradation rates

Gene expression is one of the factors determining cellular conditions, and its level is determined by the balance between transcription and RNA degradation. However, it has been not well elucidated how transcription and degradation are related to each other. To elucidate the relationship of them, methods enabling simultaneous measurement of transcription and degradation are required. Here, we report the development of "Dyrec-seq" to evaluate transcription and RNA degradation rates simultaneously, by using 4-thiouridine and 5-bromouridine. Using Dyrec-seq, we quantified the transcription and degradation rates of 4,702 genes in HeLa cells. Functional enrichment analysis showed that the transcription and degradation rates of genes are actually determined by the genes biological functions. Comparison of theoretical and experimental analysis results revealed that the amount of RNA was determined by the ratio of transcription to degradation rates, while the rapidity of responses to external stimuli was determined only by the degradation rate. This study emphasizes that degradation as well as transcription is important in determining the behavior of RNA.

systems biology↗

Implementation of Bayesian Multiple Comparison Correction in the Second-Level Analysis of fMRI Data: With Pilot Analyses of Simulation and Real fMRI Datasets Based on Voxelwise Inference

We developed and tested Bayesian multiple comparison correction method for Bayesian voxelwise second-level fMRI analysis with R. The performance of the developed method was tested with simulation and real image datasets. First, we compared false alarm and hit rates, which were used as proxies for selectivity and sensitivity, respectively, between Bayesian and classical inference were conducted. For the comparison, we created simulated images, added noise to the created images, and analyzed the noise-added images while applying Bayesian and classical multiple comparison correction methods. Second, we analyzed five real image datasets to examine how our Bayesian method worked in realistic settings. When the performance assessment was conducted, Bayesian correction method demonstrated good sensitivity (hit rate [&ge;] 75%) and acceptable selectivity (false alarm rate < 10%) when N [&le;] 8. Furthermore, Bayesian correction method showed better sensitivity compared with classical correction method while maintaining the aforementioned acceptable selectivity.

neuroscience↗

The Hippo pathway origin and its oncogenic alteration in evolution

The Hippo pathway is a central regulator of organ size and a key tumor suppressor via coordinating cell proliferation and death. Initially discovered in Drosophila, the Hippo pathway has been implicated as an evolutionarily conserved pathway in mammals; however, how this pathway was evolved to be functional from its origin is still largely unknown. In this study, we traced the Hippo pathway in premetazoan species, characterized the intrinsic functions of its ancestor components, and unveiled the evolutionary history of this key signaling pathway from its unicellular origin. In addition, we elucidated the paralogous gene history for the mammalian Hippo pathway components and characterized their cancer-derived somatic mutations from an evolutionary perspective. Taken together, our findings not only traced the conserved function of the Hippo pathway to its unicellular ancestor components, but also provided novel evolutionary insights into the Hippo pathway organization and oncogenic alteration.

evolutionary biology↗

Genomic inbreeding trends in the global Thoroughbred horse population driven by influential sire lines and selection for exercise trait-related genes

The Thoroughbred horse is a highly valued domestic animal population under strong selection for athletic phenotypes. Here we present a high resolution genomics-based analysis of inbreeding in the population that may form the basis for evidence-based discussion amid concerns in the breeding industry over the increasing use of small numbers of popular sire lines, which may accelerate a loss of genetic diversity. In the most comprehensive globally representative sample of Thoroughbreds to-date (n = 10,118), including prominent stallions (n = 305) from the major bloodstock regions of the world, we show using pan-genomic SNP genotypes that there has been a highly significant decline in global genetic diversity during the last five decades (FIS R2 = 0.942, P = 2.19 x 10-13; FROH R2 = 0.88, P = 1.81 x 10-10) that has likely been influenced by the use of popular sire lines. Estimates of effective population size in the global and regional populations indicate that there is some level of regional variation that may be exploited to improve global genetic diversity. Inbreeding is often a consequence of selection, which in managed animal populations tends to be driven by preferences for cultural, aesthetic or economically advantageous phenotypes. Using a composite selection signals approach, we show that centuries of selection for favourable athletic traits among Thoroughbreds acts on genes with functions in behaviour, musculoskeletal conformation and metabolism. As well as classical selective sweeps at core loci, polygenic adaptation for functional modalities in cardiovascular signalling, organismal growth and development, cellular stress and injury, metabolic pathways and neurotransmitters and other nervous system signalling has shaped the Thoroughbred athletic phenotype. Our results demonstrate that genomics-based approaches to identify genetic outcrosses will add valuable objectivity to augment traditional methods of stallion selection and that genomics-based methods will be beneficial to actively monitor the population to address the marked inbreeding trend.\n\nAuthor SummaryIn the highly valuable global Thoroughbred horse industry, there is no systematic industry-mediated genetic population management. Purposeful inbreeding is common practice and there is an increasing use of popular sires. Inbreeding can lead to population health and fertility decline, but there is little objective genomics-based data for the Thoroughbred to catalyse action and support changes in breeding practices. Here, we describe the most comprehensive genetic analysis in the population among 10,000 Thoroughbreds from the major bloodstock regions of the world and reveal a highly significant increase in inbreeding during the last five decades. The main drivers of genetic diversity are the most influential breed-shaping sire lines, Sadlers Wells, Danehill and A.P. Indy. We identified genomic regions subject to positive selection containing genes for athletic traits. Our results highlight the need for population-wide efforts to proactively avert the potential increase of deleterious alleles that may impact on animal health in order to safeguard the future of a breed that is admired for its athleticism and enjoyed for sport worldwide.

genetics↗

Admistration of Exogenous Melatonin Improves the Diurnal Rhythms of Gut Microbiota in High Fat Diet-Fed Mice

Melatonin, a circadian hormone, has been reported to improve host lipid metabolism by reprogramming gut microbiota, which also exhibits rhythmicity in a light/dark cycle. However, the effect of admistartion of exogenous melatonin on the diurnal variation in gut microbiota in high fat diet (HFD)-fed mice is obscure. Here, we further confirmed the anti-obesogenic effect of melatonin on in mice feed with HFD for two weeks. Samples were collected every 4 h within a 24-h period and diurnal rhythms of clock genes expression (Clock, Cry1, Cry2, Per1, and Per2) and serum lipid indexes varied with diurnal time. Notably, Clock and triglycerides (TG) showed a marked rhythm only in the control and melatonin treated mice, but not in the HFD-fed mice. Rhythmicity of these parameters were similar between control and melatonin treated HFD mice compared with the HFD group, indicating an improvement of melatonin in the diurnal clock of host metabolism in HFD-fed mice. 16S rDNA sequencing showed that most microbiota exhibited a daily rhythmicity and the trends differentiated at different groups and different time points. We also identified several specific microbiota correlating with the circadian clock genes and serum lipid indexes, which might contribute the potential mechanism of melatonin in HFD-fed mice. Interestingly, administration of exogenous melatonin only at daytime exhibited higher resistance to HFD-induced lipid dysmetabolism than nighttime treatment companying with altered gut microbiota (Lactobacillus, Intestinimonas, and Oscillibacter). Importantly, the responses of microbiota transplanted mice to HFD feeding also varied at different transplanting times (8:00 and 16:00) and different microbiota donors. In summary, daily oscillations in the expression of circadian clock genes, serum lipid indexes, and gut microbiota, appears to be driven by a short-time feeding of an HFD. Administration of exogenous melatonin improved the compositions and diurnal rhythmicity of gut microbiota, which might be linked to host diurnal rhythm and metabolism.\n\nImportancePrevious studies show that a circadian hormone, melatonin, involves in host lipid metabolism by reprogramming gut microbiota, which also exhibits rhythmicity in a light/dark cycle. However, the effect of melatonin drinking on the diurnal variation in gut microbiota in high fat diet-fed mice is obscure. Here, we found that 24-h oscillations were widely occurred in circadian clock genes, serum lipid indexes, and gut microbiota. Melatonin drinking improved the compositions and circadian rhythmicity of gut microbiota, which might be linked to host circadian rhythm and metabolism.

microbiology↗

Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis

The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases (IBDs); however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin not only establishes a first-line barrier against pathogens, but also serves as a niche for microbial growth. We hypothesized that dysbiosis may cause abnormal mucin utilization and microbial metabolic dysfunction. To test this hypothesis, we analyzed short-chain fatty acids (SCFAs) and mucin components in the stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohns disease (CD) patients from Japan. The levels of n-butyrate were significantly lower in the stools of both the CD and UC patients than in those of the healthy subjects. Correlation analysis identified 7 bacterial species positively correlated with n-butyrate levels, among which the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans act as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in the colonic lamina propria. Importantly, the availability of mucin-associated O-glycans to the microbiota was significantly reduced in n-butyrate-deficient UC patients. Taken together, our findings highlight the biological significance of the symbiosynthesis pathway in the production of n-butyrate, which maintains gut immune homeostasis.

microbiology↗

NGSEA: network-based gene set enrichment analysis for interpreting gene expression phenotypes with functional gene sets

Gene set enrichment analysis (GSEA) is a popular tool to identify underlying biological processes in clinical samples using their gene expression phenotypes. GSEA measures the enrichment of annotated gene sets that represent biological processes for differentially expressed genes (DEGs) in clinical samples. GSEA may be suboptimal for functional gene sets, however, because DEGs from the expression dataset may not be functional genes per se but dysregulated genes perturbed by bona fide functional genes. To overcome this shortcoming, we developed network-based GSEA (NGSEA), which measures the enrichment score of functional gene sets using the expression difference of not only individual genes but also their neighbors in the functional network. We found that NGSEA outperformed GSEA in identifying pathway gene sets for matched gene expression phenotypes. We also observed that NGSEA substantially improved the ability to retrieve known anti-cancer drugs from patient-derived gene expression data using drug-target gene sets compared with another method, Connectivity Map. We also repurposed FDA-approved drugs using NGSEA and experimentally validated budesonide as a chemical with anti-cancer effects for colorectal cancer. We, therefore, expect that NGSEA will facilitate both pathway interpretation of gene expression phenotypes and anti-cancer drug repositioning. NGSEA is freely available at www.inetbio.org/ngsea.

bioinformatics↗

Drosophila ribosomal protein S5b is essential for oogenesis and interacts with distinct RNAs

In Drosophila melanogaster there are two genes encoding ribosomal protein S5, RpS5a and RpS5b. Here, we demonstrate that RpS5b is required for oogenesis. Females lacking RpS5b produce ovaries with numerous developmental defects that undergo widespread apoptosis in mid-oogenesis. Females lacking germline RpS5a are fully fertile, but germline expression of interfering RNA targeting germline RpS5a in an RpS5b mutant background worsened the RpS5b phenotype and blocked oogenesis before egg chambers form. A broad spectrum of mRNAs co-purified in immunoprecipitations with RpS5a, while RpS5b-associated mRNAs were specifically enriched for GO terms related to mitochondrial electron transport and cellular metabolic processes. Consistent with this, RpS5b mitochondrial fractions are depleted for proteins linked to oxidative phosphorylation and mitochondrial respiration, and RpS5b mitochondria tended to form large clusters and had more heterogeneous morphology than those from controls. We conclude that RpS5b-containing ribosomes preferentially associate with particular mRNAs and serve an essential function in oogenesis.

developmental biology↗

UDCT: Unsupervised data to content transformation with histogram-matching cycle-consistent generative adversarial networks

The segmentation of images is a common task in a broad range of research fields. To tackle increasingly complex images, artificial intelligence (AI) based approaches have emerged to overcome the shortcomings of traditional feature detection methods. Owing to the fact that most AI research is made publicly accessible and programming the required algorithms is now possible in many popular languages, the use of such approaches is becoming widespread. However, these methods often require data labeled by the researcher to provide a training target for the algorithms to converge to the desired result. This labeling is a limiting factor in many cases and can become prohibitively time consuming. Inspired by Cycle-consistent Generative Adversarial Networks (cycleGAN) ability to perform style transfer, we outline a method whereby a computer generated set of images is used to segment the true images. We benchmark our unsupervised approach against a state-of-the-art supervised cell-counting network on the VGG Cells dataset and show that it is not only competitive but can also precisely locate individual cells. We demonstrate the power of this method by segmenting bright-field images of cell cultures, a live-dead assay of C.Elegans and X-ray-computed tomography of metallic nanowire meshes.

bioengineering↗