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1.  Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases 
Nature Communications  2015;6:7520.
Dominant mutations in five tRNA synthetases cause Charcot–Marie–Tooth (CMT) neuropathy, suggesting that altered aminoacylation function underlies the disease. However, previous studies showed that loss of aminoacylation activity is not required to cause CMT. Here we present a Drosophila model for CMT with mutations in glycyl-tRNA synthetase (GARS). Expression of three CMT-mutant GARS proteins induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan. Mutant GARS proteins display normal subcellular localization but markedly reduce global protein synthesis in motor and sensory neurons, or when ubiquitously expressed in adults, as revealed by FUNCAT and BONCAT. Translational slowdown is not attributable to altered tRNAGly aminoacylation, and cannot be rescued by Drosophila Gars overexpression, indicating a gain-of-toxic-function mechanism. Expression of CMT-mutant tyrosyl-tRNA synthetase also impairs translation, suggesting a common pathogenic mechanism. Finally, genetic reduction of translation is sufficient to induce CMT-like phenotypes, indicating a causal contribution of translational slowdown to CMT.
Charcot–Marie–Tooth (CMT) neuropathy is associated with dominant mutations in five tRNA synthetase genes. Niehues et al. use BONCAT and FUNCAT to monitor proteome dynamics in a Drosophila CMT model, and reveal that these mutations result in translational slowdown.
PMCID: PMC4506996  PMID: 26138142
2.  Single Chain Variable Fragment Against Aβ Expressed in Baculovirus Inhibits Abeta Fibril Elongation and Promotes its Disaggregation 
PLoS ONE  2015;10(4):e0124736.
Alzheimer’s disease (AD) is the most common form of age-related dementia, and the most urgent problem is that it is currently incurable. Amyloid-β (Aβ) peptide is believed to play a major role in the pathogenesis of AD. We previously reported that an Aβ N-terminal amino acid targeting monoclonal antibody (MAb), A8, inhibits Aβ fibril formation and has potential as an immunotherapy for AD based on a mouse model. To further study the underlying mechanisms, we tested our hypothesis that the single chain fragment variable (scFv) without the Fc fragment is capable of regulating either Aβ aggregation or disaggregation in vitro. Here, a model of cell-free Aβ “on-pathway” aggregation was established and identified using PCR, Western blot, ELISA, transmission electron microscopy (TEM) and thioflavin T (ThT) binding analyses. His-tagged A8 scFvs was cloned and solubly expressed in baculovirus. Our data demonstrated that the Ni-NTA agarose affinity-purified A8 scFv inhibited the forward reaction of “on-pathway” aggregation and Aβ fibril maturation. The effect of A8 scFv on Aβ fibrillogenesis was markedly more significant when administered at the start of the Aβ folding reaction. Furthermore, the results also showed that pre-formed Aβ fibrils could be disaggregated via incubation with purified A8 scFv, which suggested that A8 scFv is involved in the reverse reaction of Aβ aggregation. Therefore, A8 scFv was capable of both inhibiting fibrillogenesis and disaggregating matured fibrils. Our present study provides valuable insight into the regulators of ultrastructural dynamics of cell-free “on-pathway” Aβ aggregation and will assist in the development of therapeutic strategies for AD.
PMCID: PMC4412524  PMID: 25919299
3.  The selective tRNA aminoacylation mechanism based on a single G•U pair 
Nature  2014;510(7506):507-511.
Ligation of tRNAs with their cognate amino acids, by aminoacyl-tRNA synthetases, establishes the genetic code. Throughout evolution, tRNAAla selection by alanyl-tRNA synthetase (AlaRS) has depended predominantly on a single wobble base pair in the acceptor stem, G3•U70, mainly on the kcat level. Here we report the crystal structures of an archaeal AlaRS in complex with tRNAAla with G3•U70 and its A3•U70 variant. AlaRS interacts with both the minor- and major-groove sides of G3•U70, widening the major groove. The geometry difference between G3•U70 and A3•U70 is transmitted along the acceptor stem to the 3′-CCA region. Thus, the 3′-CCA region of tRNAAla with G3•U70 is oriented to the reactive route that reaches the active site, whereas that of the A3•U70 variant is folded back into the “non-reactive route”. This novel mechanism enables the single wobble pair to dominantly determine the specificity of tRNA selection, by an approximate 100-fold difference in kcat.
PMCID: PMC4323281  PMID: 24919148
4.  Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration 
Science (New York, N.Y.)  2014;345(6195):455-459.
In higher eukaryotes, tRNAs with the same anticodon are encoded by multiple nuclear genes and little is known about how mutations in these genes affect translation and cellular homeostasis. Similarly, the surveillance systems that respond to such defects in higher eukaryotes are not clear. Here, we discover that loss of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, in mice with a mutation in a tRNA gene that is specifically expressed in the central nervous system causes ribosome stalling and widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes.
PMCID: PMC4281038  PMID: 25061210
5.  Human tRNA Synthetase Catalytic Nulls with Diverse Functions 
Science (New York, N.Y.)  2014;345(6194):328-332.
Genetic efficiency in higher organisms depends on mechanisms to create multiple functions from single genes. To investigate this question for an enzyme family, we chose aminoacyl tRNA synthetases (AARSs). They are exceptional in their progressive and accretive proliferation of noncatalytic domains as the Tree of Life is ascended. Here we report discovery of a large number of natural catalytic nulls (CNs) for each human AARS. Splicing events retain noncatalytic domains while ablating the catalytic domain (CD) to create CNs with diverse functions. Each synthetase is converted into several new signaling proteins with biological activities ‘orthogonal’ to that of the catalytic parent. We suggest that splice variants with non-enzymatic functions may be more general, as evidenced by recent findings of other catalytically inactive splice-variant enzymes.
PMCID: PMC4188629  PMID: 25035493
6.  Associations between breakfast eating habits and health-promoting lifestyle, suboptimal health status in Southern China: a population based, cross sectional study 
Suboptimal health status (SHS) is the intermediate health state between health and disease, refers to medically undiagnosed or functional somatic syndromes, and has been a major global public health challenge. However, both the etiology and mechanisms associated with SHS are still unclear. Breakfast eating behavior is a dietary pattern marker and previous studies have presented evidence of associations between failure to consume breakfast and increased diseases. Accordingly, in view of the significance of breakfast eating behaviors with respect to health status, the associations between breakfast eating habits and healthy lifestyle, SHS require further elucidation.
A cross-sectional survey was conducted within a clustered sample of 24,159 individuals aged 12–80 years in 2012–13 within the population of Southern China. Breakfast eating habits were categorically defined by consumption frequency (‘scarcely, sometimes or always’). Health-promoting lifestyle was assessed via the health-promoting lifestyle profile (HPLP-II). SHS was evaluated using the medical examination report and Sub-health Measurement Scale V1.0 (SHMS V1.0).
Of the 24,159 participants, the prevalence rates for the ‘health’ , ‘SHS’ , and ‘disease’ were 18.8%, 46.0%, and 35.2%, respectively. Overall, 19.6% of participants reported ‘scarce’ breakfast eating habits, with frequent breakfast eaters scoring higher on both HPLP-II and SHMS V1.0. After demographic adjustment, regression analyses revealed a significant association between breakfast eating habits and healthy lifestyle (p <0.001). There were lower levels of breakfast consumption regularity amongst individuals with SHS than those with disease. Categorically ‘scarce’ breakfast eaters were approximately three times more likely to be assigned SHS (OR: 2.745, 95% CI: 2.468-3.053), while infrequent breakfast eaters (‘sometimes’) were just less than twice as likely to be assessed as being of SHS (OR: 1.731, 95% CI: 1.595-1.879).
Breakfast eating habits are significantly associated with a healthy lifestyle, and appear to be a useful predictor of a healthy lifestyle. Irregular breakfast eating habits are related to an increased risk of SHS; increased breakfast eating frequency may contribute to lowering the prevalence of SHS in Southern China.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0348-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4269950  PMID: 25496597
Breakfast eating habits; Suboptimal health status(SHS); Healthy lifestyle; Cross sectional study
7.  Crystal structure of human seryl-tRNA synthetase and Ser-SA complex reveals a molecular lever specific to higher eukaryotes 
Structure (London, England : 1993)  2013;21(11):10.1016/j.str.2013.08.021.
Seryl-tRNA synthetase (SerRS), an essential enzyme for translation, also regulates vascular development. This “gain-of-function” has been linked to the UNE-S domain added to vertebrate SerRS during evolution. However, the significance of two insertions also specific to higher eukaryotic SerRS remains elusive. Here we determined the crystal structure of human SerRS in complex with Ser-SA, an aminoacylation reaction intermediate analog, at 2.9-Å resolution. Despite a 70-Å distance, binding of Ser-SA in the catalytic domain dramatically leverages the position of Insertion I in the tRNA binding domain. Importantly, this leverage is unique to higher eukaryotes and not seen in bacterial, archaeal and lower eukaryotic SerRSs. Deletion of Insertion I does not affect tRNA binding but instead reduce the catalytic efficiency of the synthetase. Thus, a long-range conformational and functional communication specific to higher eukaryotes is found in human SerRS, possibly to coordinate translation with vasculogenesis.
PMCID: PMC3825832  PMID: 24095058
8.  Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2 
Charcot–Marie–Tooth (CMT) disease is a genetically heterogeneous condition with >50 genes now being identified. Thanks to new technological developments, namely, exome sequencing, the ability to identify additional rare genes in CMT has been drastically improved. Here we present data suggesting that MARS is a very rare novel cause of late-onset CMT2. This is supported by strong functional and evolutionary evidence, yet the absence of additional unrelated cases warrant future studies to substantiate this conclusion.
PMCID: PMC3796032  PMID: 23729695
9.  Structural disorder in expanding the ‘functionome’ of aminoacyl-tRNA synthetases 
Chemistry & biology  2013;20(9):1093-1099.
Over the last decade, aminoacyl-tRNA synthetases (AARSs) have emerged as a new class of regulatory proteins with widespread functions beyond their classic role in protein synthesis. The functional expansion concurs with the incorporation of new domains and motifs to AARSs and coincides with the emergence of the multi-synthetase complex (MSC) during the course of eukaryotic evolution. Notably, the new domains in AARSs are often found to be structurally disordered or to be linked to the enzyme cores via unstructured linkers. Further bioinformatic analysis performed here classifies the 20 human cytoplasmic AARSs into 3 groups based on their propensities for structural disorder. The analysis also suggests that, while the assembly of the MSC mainly involves ordered structural domains, structurally disordered regions play an important role in activating and expanding the regulatory functions of AARSs.
PMCID: PMC3782743  PMID: 24054183
10.  Prevalence of Cognitive Impairment No Dementia in a Rural Area of Northern China 
Neuroepidemiology  2014;42(4):197-203.
Few data are available on the prevalence of cognitive impairment no dementia (CIND) in rural China. The aim of this study was to estimate the prevalence of CIND in individuals aged 60 years and older in a large rural community, and to analyze the associated risk factors.
A two-phase, door-to-door epidemiological study was used for residents aged 60 years and older in Ji County, a rural county near Tianjin in Northern China. In phase 1 of the study, the Mini-Mental State Examination and Clinical Dementia Rating were administered for screening purposes. In phase 2, the subjects who screened positive were further examined by neurologists. A total of 5,744 individuals underwent the home visit interview, where demographic variables and comorbidities were recorded; 5,550 individuals completed the two phases. CIND was diagnosed by the Aging, Demographics and Memory Study on CIND criteria. The odds ratio (OR) for each risk factor was calculated by logistic regression analysis.
The prevalence of CIND among those aged 60 years and older was 23.3%. The prevalence of CIND was lower among those with a higher level of education or social involvement. CIND was more prevalent in fe males, older individuals, those with a past history of stroke, and those living without a partner. Significant risk factors were found by multivariate analyses: past history of stroke (OR = 1.889; 95% CI: 1.437–2.483); being female (OR = 1.546; 95% CI: 1.305–1.832); and having no partner (divorced, widowed or single; OR = 1.250; 95% CI: 1.042–1.499). In turn, level of education (OR = 0.560; 95% CI: 0.460–0.681) and engagement in social activities (OR = 0.339; 95% CI: 0.258–0.404) were protective factors.
This is the first large-scale community-based epidemiological study assessing the prevalence of cognitive loss in the rural Chinese population. The total prevalence of CIND observed was 23.3%, which was higher than in other studies in Western and Asian countries. Living without a partner, female gender and previous stroke increased the risk of CIND, whereas a higher level of education and engagement in social activities reduced the risk of CIND.
PMCID: PMC4074439  PMID: 24751796
Cognitive impairment no dementia; China; Prevalence
11.  Clinical analysis and etiology of porokeratosis 
The present study was performed in order to define the clinical manifestations of porokeratosis, with particular emphasis on genital porokeratosis. A total of 55 cases of porokeratosis were retrospectively reviewed between 2000 and 2007 from Huashan Hospital (Shanghai, China). Out of 55 cases, there were 22 cases of porokeratosis of Mibelli, 17 cases of disseminated superficial actinic porokeratosis (DSAP), 15 cases of disseminated superficial porokeratosis and one case of linear porokeratosis. The ratio of males to females was 39:16. Among them, 12 cases had a family history of porokeratosis. During the five-year follow-up period, no malignant transformation was observed and no further aggravation of lesions was detected. The results indicated that the initial region of DSAP in the Chinese population may differ from Caucasians. In combination with other studies, the present study found that genital porokeratosis in the Chinese population is often associated with pruritus. Since no recurrence was observed in cases treated with surgical excision, it was suggested that surgical excision is a viable treatment strategy and should be used for porokeratotic lesions if possible. In addition, regular follow-ups are required, since the aggravation of porokeratosis may cause the development of malignancy transformation.
PMCID: PMC4113647  PMID: 25120591
genital porokeratosis; clinical manifestation; etiology; pruritus; lesions
12.  tRNA synthetase counteracts c-Myc to develop functional vasculature 
eLife  2014;3:e02349.
Recent studies suggested an essential role for seryl-tRNA synthetase (SerRS) in vascular development. This role is specific to SerRS among all tRNA synthetases and is independent of its well-known aminoacylation function in protein synthesis. A unique nucleus-directing domain, added at the invertebrate-to-vertebrate transition, confers this novel non-translational activity of SerRS. Previous studies showed that SerRS, in some unknown way, controls VEGFA expression to prevent vascular over-expansion. Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. Thus, vertebrate SerRS and c-Myc is a pair of ‘Yin-Yang’ transcriptional regulator for proper development of a functional vasculature. Our results also discover an anti-angiogenic activity for SIRT2.
eLife digest
The network of blood vessels is one of the earliest structures to develop in a vertebrate embryo. A protein called Vascular Endothelial Growth Factor A (or VEGFA for short) is needed to promote the growth of these blood vessels, but too much VEGFA can cause blood vessels to grow too much and to grow abnormally.
Like most of the DNA in the nucleus, the gene for VEGFA is tightly wrapped around proteins called histones and must be unwrapped before it can be expressed as a protein. For the VEGFA gene, this unwrapping process starts when a protein called c-Myc adds chemical tags to the histones.
Recent research suggested that an enzyme called seryl-tRNA synthetase (or SerRS for short) also controls the expression of VEGFA. This came as a surprise because no other tRNA synthetase has a similar role during development. And although SerRS is known to enter the cell nucleus in vertebrates, researchers did not know what SerRS did in the nucleus to control the expression of VEGFA.
Now, Shi et al. have discovered that SerRS controls blood vessel development in zebrafish embryos by counteracting the activity of c-Myc. It does this in two different ways: first, it directly blocks c-Myc from binding to and unpacking the DNA; and second, SerRS works with another enzyme to remove tags that are already on the histones. Shi et al. found that if the expression of this other enzyme (called SIRT2) was reduced in zebrafish, the fish expressed more VEGFA and their blood vessels grew too much.
Since blood vessel growth is important in the development of cancers, the findings of Shi et al. could also lead to a better understanding of how tumors develop, as well as how blood vessels develop normally.
PMCID: PMC4057782  PMID: 24940000
seryl-tRNA synthetase; c-Myc; VEGFA; SIRT2; angiogenesis; vasculature; human; zebrafish
13.  IMP3 expression is associated with epithelial-mesenchymal transition in breast cancer 
IMP3 plays an important role in tumor invasion and metastasis, to which epithelial to mesenchymal transition (EMT) also contributes. The purpose of this study was to investigate whether IMP3 can regulate invasion and metastasis through EMT in breast cancers. The protein expression levels of IMP3 and EMT markers were analyzed by immunohistochemistry in 180 paraffin-embedded human breast tissue samples. There was an inverse correlation of IMP3 with E-cadherin protein expression (P = 0.042). IMP3 expression directly correlated with both Slug (P = 0.004) and vimentin (P < 0.001). Changes in E-cadherin, vimentin, and Slug mRNA and protein levels were examined by quantitative real-time reverse polymerase chain reaction (qRT-PCR) and western blotting. Overexpression of IMP3 reduced the expression of E-cadherin and upregulated Slug and vimentin in transfected cells. In contrast, knocking down IMP3 had the opposite expression of the three proteins. Ribo-immunoprecipitation qPCR revealed that IMP3 binds Slug mRNA directly. In a transwell assay, overexpression of Slug rescued the cell migration and invasion caused by silencing IMP3 in MDA-MB-231 cells. On the other hand, knockdown of Slug in T47D-IMP3 cells could also have the opposite change. Our results strengthen the association of IMP3 with the regulation of EMT. Slug is a functional target of IMP3. IMP3 could therefore promote invasion and migration through the EMT in breast cancer cells.
PMCID: PMC4097240  PMID: 25031719
Insulin-like growth factor II (IGF-II) mRNA binding protein 3 (IMP3); epithelial-mesenchymal transition; ribo-immunoprecipitation; metastasis; breast cancer
14.  Architecture and Metamorphosis 
Topics in current chemistry  2014;344:89-118.
When compared to other conserved housekeeping protein families, such as ribosomal proteins, during the evolution of higher eukaryotes, aminoacyl-tRNA synthetases (aaRSs) show an apparent high propensity to add new sequences, and especially, new domains. The stepwise emergence of those new domains is consistent with their involvement in a broad range of biological functions beyond protein synthesis, and correlates with the increasing biological complexity of higher organisms. The new domains have been extensively characterized based on their evolutionary origins and their sequence, structural and functional features. While some of the domains are uniquely found in aaRSs and may have originated from nucleic acid binding motifs, others are common domain modules mediating protein-protein interactions that play a critical role in the assembly of the multi-synthetase complex (MSC). Interestingly, the MSC has emerged from a miniature complex in yeast, to a large, stable complex in insects to humans. The human MSC consists of 9 aaRSs (LysRS, ArgRS, GlnRS, AspRS, MetRS, IleRS, LeuRS and GluProRS) and 3 scaffold proteins (AIMP1/p43, AIMP2/p38 and AIMP3/p18), and has a molecular weight of 1.5 million Da. The MSC has been proposed to have a functional dualism: both facilitating protein synthesis and serving as a reservoir of non-canonical functions associated with its synthetase and non-synthetase components. Importantly, domain additions and functional expansions are not limited to the components of the MSC and are found in almost all aaRS proteins. From a structural perspective, multi-functionalities are represented by multiple conformational states. In fact, alternative conformations of aaRSs have been generated by various mechanisms from proteolysis to alternative splicing and posttranslational modifications, as well as by disease-causing mutations. Therefore, the metamorphosis between different conformational states is connected to the activation and regulation of the novel functions of aaRSs in higher eukaryotes.
PMCID: PMC3864538  PMID: 23536245
Domain expansion; Evolution; Novel function; Structural metamorphosis; tRNA synthetase
15.  Protective Effect of Glycyrrhizin, a Direct HMGB1 Inhibitor, on Focal Cerebral Ischemia/Reperfusion-Induced Inflammation, Oxidative Stress, and Apoptosis in Rats 
PLoS ONE  2014;9(3):e89450.
Glycyrrhizin (GL) has been reported to protect against ischemia and reperfusion (I/R)-induced injury by inhibiting the cytokine activity of high mobility group box 1 (HMGB1). In the present study, the protective effects of GL against I/R injury, as well as the related molecular mechanisms, were investigated in rat brains.
Focal cerebral I/R injury was induced by intraluminal filamentous occlusion of the middle cerebral artery (MCA) in Male Sprague-Dawley rats. GL alone or GL and rHMGB1 were administered intravenously at the time of reperfusion. Serum levels of HMGB1 and inflammatory mediators were quantified via enzyme-linked immunosorbent assay (ELISA). Histopathological examination, immunofluorescence, RT-PCR and western blotting analyses were performed to investigate the protective and anti-apoptotic effects and related molecular mechanisms of GL against I/R injury in rat brains.
Pre-treatment with GL significantly reduced infarct volume and improved the accompanying neurological deficits in locomotor function. The release of HMGB1 from the cerebral cortex into the serum was inhibited by GL administration. Moreover, pre-treatment with GL alleviated apoptotic injury resulting from cerebral I/R through the inhibition of cytochrome C release and caspase 3 activity. The expression levels of inflammation- and oxidative stress-related molecules including TNF-α, iNOS, IL-1β, and IL-6, which were over-expressed in I/R, were decreased by GL. P38 and P-JNK signalling were involved in this process. All of the protective effects of GL could be reversed by rHMGB1 administration.
GL has a protective effect on ischemia-reperfusion injury in rat brains through the inhibition of inflammation, oxidative stress and apoptotic injury by antagonising the cytokine activity of HMGB1.
PMCID: PMC3942385  PMID: 24594628
16.  Reexpression of Let-7g MicroRNA Inhibits the Proliferation and Migration via K-Ras/HMGA2/Snail Axis in Hepatocellular Carcinoma 
BioMed Research International  2014;2014:742417.
Let-7 family microRNAs have been reported to be downregulated in human hepatocellular carcinoma in comparison with normal hepatic tissues. Among them, let-7g was identified as the lowest expression using real-time RT-PCR. However, the mechanism by which let-7g works in hepatocellular carcinoma remains unknown. Here, in our present study, we have had let-7g reexpressed in vitro in hepatocellular carcinoma cell lines MHCC97-H and HCCLM3 via transfection. The proliferation after reexpression of let-7g was assayed using MTT method; the migration and invasion after restoration were detected by wound-healing and Transwell assay, respectively. We found using Western-blotting that let-7g can regulate epithelial-mesenchymal transition (EMT) by downregulating K-Ras and HMGA2A after reexpresssion. Xenografted nude mice were used to observe whether or not reexpression of let-7g could have potential therapeutic ability. In vivo, to observe the association with let-7g expression and overall prognosis, 40 paired cases of hepatocellular carcinoma were analyzed using in situ hybridization (ISH). It was found that reexpression of let-7g can inhibit the proliferation, migration, and invasion significantly, and that low expression of let-7g was significantly associated with poorer overall survival. Taken together, let-7g could be used as a promising therapeutic agent in vivo in the treatment of hepatocellular carcinoma at the earlier stage.
PMCID: PMC3960551  PMID: 24724096
17.  Neutrophils Infiltration in the Tongue Squamous Cell Carcinoma and Its Correlation with CEACAM1 Expression on Tumor Cells 
PLoS ONE  2014;9(2):e89991.
The present study aimed to explore the clinical significance of neutrophils infiltration and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1) expression in the tongue squamous cell carcinoma (TSCC), and to probe the possible relationship between them.
Materials and Methods
Tissue microarray and immunohistochemistry were used to detect neutrophils density and CEACAM1 expression in 74 cases of primary TSCC specimens and 17 cases of corresponding peritumoral tissues. The relationship of CEACAM1 expression and neutrophils density with clinicopathologic parameters and cancer-related survival of TSCC patients were evaluated. The correlation between CEACAM1 expression and neutrophils density was also evaluated. Real-time quantitative transcription polymerase chain reaction (qRT-PCR) was used to explore the possible molecular mechanisms between CEACAM1 expression and neutrophils infiltration.
Immunohistochemistry evaluation revealed that there was more neutrophils infiltration in TSCC tissues than in peritumoral tissues. High neutrophil density was associated with LN metastasis (P = 0.01), higher clinical stage (P = 0.037) and tumor recurrence (P = 0.024). CEACAM1 overexpression was also associated with lymph node metastasis (P = 0.000) and higher clinical stage (P = 0.001). Survival analysis revealed that both neutrophils infiltration and CEACAM1 overexpression were associated with poorer cancer-related survival of TSCC patients (P<0.05), and neutrophils infiltration was an independent prognostic factor for TSCC (P<0.05). Furthermore, overexpression of CEACAM1 was correlated with more neutrophils infiltration in TSCC tissues (P<0.01). qRT-PCR results showed that CEACAM1-4L can upregulate the mRNA expression of IL-8 and CXCL-6, which were strong chemotactic factors of neutrophils.
Our results demonstrated that more neutrophils infiltration and overexpression of CEACAM1 were associated with poor clinical outcomes in TSCC tissues. Overexpression of CEACAM1 on tumor cells correlated with more neutrophils infiltration to some extent through upregulating mRNA expression of IL-8 and CXCL-6.
PMCID: PMC3937421  PMID: 24587171
18.  Suggestion of GLYAT gene underlying variation of bone size and body lean mass as revealed by a bivariate genome-wide association study 
Human genetics  2012;132(2):189-199.
Bone and muscle, two major tissue types of musculoskeletal system, have strong genetic determination. Abnormality in bone and/or muscle may cause musculoskeletal diseases such as osteoporosis and sarcopenia. Bone size phenotypes (BSPs), such as hip bone size (HBS), appendicular bone size (ABS), are genetically correlated with body lean mass (mainly muscle mass). However, the specific genes shared by these phenotypes are largely unknown. In this study, we aimed to identify the specific genes with pleiotropic effects on BSPs and appendicular lean mass (ALM).
We performed a bivariate genome-wide association study (GWAS) by analyzing ~690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) followed by a replication study in 2,286 unrelated US Caucasians (558 males and 1728 females).
We identified 14 interesting single nucleotide polymorphisms (SNPs) that may contribute to variation of both BSPs and ALM, with p values <10−6 in discovery stage. Among them, the association of three SNPs (rs2507838, rs7116722, and rs11826261) in/near GLYAT (glycine-N-acyltransferase) gene was replicated in US Caucasians, with p values ranging from 1.89×10−3 to 3.71×10−4 for ALM-ABS, from 5.14×10−3 to 1.11×10−2 for ALM-HBS, respectively. Meta-analyses yielded stronger association signals for rs2507838, rs7116722, and rs11826261, with pooled p values of 1.68×10−8, 7.94×10−8, 6.80×10−8 for ALB-ABS and 1.22×10−4, 9.85×10−5, 3.96×10−4 for ALM-HBS, respectively. Haplotype allele ATA based on these three SNPs were also associated with ALM-HBS and ALM-ABS in both discovery and replication samples. Interestingly, GLYAT was previously found to be essential to glucose metabolism and energy metabolism, suggesting the gene’s dual role in both bone development and muscle growth.
Our findings, together with the prior biological evidence, suggest the importance of GLYAT gene in co-regulation of bone phenotypes and body lean mass.
PMCID: PMC3682481  PMID: 23108985
Bivariate GWAS; Bone size; Lean mass; GLYAT
19.  Influence of Preferred Orientation on the Electrical Conductivity of Fluorine-Doped Tin Oxide Films 
Scientific Reports  2014;4:3679.
Current development of high-performance transparent conductive oxide (TCO) films is limited with tradeoff between carrier mobility and concentration since none of them can be improved without sacrificing the other. In this study, we prepare fluorine doped tin oxide (FTO) films by chemical vapor deposition with inclusions of different additives and report that the mobility can be varied from 0.65 to 28.5 cm2 V−1 s−1 without reducing the achieved high carrier concentration of 4 × 1020 cm−3. Such an increase in mobility is shown to be clearly associated with the development of (200) preferred orientation (PO) but concurrent degradation of (110) PO in films. Thus, at a constant high carrier concentration, the electrical conductivity can be improved via carrier mobility simply by PO control. Such a one-step approach avoiding conventional post-deposition treatment is suggested for developing next-generation FTO as well as other TCO films with better than ever conductivities.
PMCID: PMC3890905  PMID: 24419455
20.  Gold-Free Ternary III–V Antimonide Nanowire Arrays on Silicon: Twin-Free down to the First Bilayer 
Nano Letters  2013;14(1):326-332.
With the continued maturation of III–V nanowire research, expectations of material quality should be concomitantly raised. Ideally, III–V nanowires integrated on silicon should be entirely free of extended planar defects such as twins, stacking faults, or polytypism, position-controlled for convenient device processing, and gold-free for compatibility with standard complementary metal–oxide–semiconductor (CMOS) processing tools. Here we demonstrate large area vertical GaAsxSb1–x nanowire arrays grown on silicon (111) by molecular beam epitaxy. The nanowires’ complex faceting, pure zinc blende crystal structure, and composition are mapped using characterization techniques both at the nanoscale and in large-area ensembles. We prove unambiguously that these gold-free nanowires are entirely twin-free down to the first bilayer and reveal their three-dimensional composition evolution, paving the way for novel infrared devices integrated directly on the cost-effective Si platform.
PMCID: PMC3890218  PMID: 24329502
Nanowire; III−V; antimonide; GaAsSb; crystal structure; silicon; zinc blende; twin-free; transmission electron microscopy; energy dispersive X-ray spectroscopy; molecular beam epitaxy; X-ray diffraction; synchrotron radiation
21.  Structural Switch of Lysyl-tRNA Synthetase Between Translation and Transcription 
Molecular cell  2012;49(1):30-42.
Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207-phosphorylation provokes a new conformer of LysRS that inactivates its translational, but activates its transcriptional function. The crystal structure of an MSC sub-complex established that LysRS is held in the MSC by binding to the N-terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap4A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.
PMCID: PMC3766370  PMID: 23159739
tRNA synthetase; Structure; Phosphorylation; H/D Exchange; Hydrogen/Deuterium Exchange; Mass Spectrometry; Fourier Transform; Ion Cyclotron Resonance; FTMS; Conformational Change
22.  Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 Signaling 
Nature chemical biology  2012;8(6):547-554.
IFN-γ engenders strong anti-proliferative responses, in part through activation of p53. However, the long-known IFN-γ-dependent upregulation of human Trp-tRNA synthetase (TrpRS), a cytoplasmic enzyme that activates tryptophan to form Trp-AMP in the first step of protein synthesis, is unexplained. Here we report a nuclear complex of TrpRS with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and with poly (ADP-ribose) polymerase 1 (PARP-1), the major PARP in human cells. The IFN-γ-dependent poly (ADP-ribosyl)ation of DNA-PKcs (which activates its kinase function) and concomitant activation of p53 were specifically prevented by Trp-SA, an analog of Trp-AMP that disrupted the TrpRS/DNA-PKcs/PARP-1 complex. The connection of TrpRS to p53 signaling in vivo was confirmed in a vertebrate system. These and further results suggest a surprising evolutionary expansion of the protein synthesis apparatus to a nuclear role that links major signaling pathways.
PMCID: PMC3780985  PMID: 22504299
23.  Internally deleted human tRNA synthetase suggests evolutionary pressure for repurposing 
Structure (London, England : 1993)  2012;20(9):1470-1477.
Aminoacyl-tRNA synthetases (AARSs) catalyze aminoacylation of tRNAs in the cytoplasm. Surprisingly, AARSs also have critical extracellular and nuclear functions. Evolutionary pressure for new functions might be manifested by splice variants that skip only an internal catalytic domain (CD) and link non-catalytic N- and C-terminal polypeptides. Using disease-associated histidyl-tRNA synthetase (HisRS) as an example, we discovered an expressed 171 amino acid protein (HisRSΔCD) that deleted the entire CD, and joined an N-terminal WHEP to the C-terminal anticodon-binding domain (ABD). X-ray crystallographic and 3-D NMR methods revealed the first structures of human HisRS and HisRSΔCD. In contrast to homodimeric HisRS, HisRSΔCD is monomeric, where rupture of the ABD’s packing with CD resulted in a dumbbell-like structure of flexibly linked WHEP and ABD domains. In addition, the ABD of HisRSΔCD presents a new local conformation. This natural internally deleted HisRS suggests evolutionary pressure to reshape AARS tertiary and quaternary structures for repurposing.
PMCID: PMC3485694  PMID: 22958643
24.  ATP-Directed Capture of Bioactive Herbal-Based Medicine on Human tRNA Synthetase 
Nature  2012;494(7435):121-124.
PMCID: PMC3569068  PMID: 23263184
25.  Intranasal immunization with a helper-dependent adenoviral vector expressing the codon-optimized fusion glycoprotein of human respiratory syncytial virus elicits protective immunity in BALB/c mice 
Virology Journal  2013;10:183.
Human respiratory syncytial virus (RSV) is a serious pediatric pathogen of the lower respiratory tract. Currently, there is no clinically approved vaccine against RSV infection. Recent studies have shown that helper-dependent adenoviral (HDAd) vectors may represent effective and safe vaccine vectors. However, viral challenge has not been investigated following mucosal vaccination with HDAd vector vaccines.
To explore the role played by HDAd as an intranasally administered RSV vaccine vector, we constructed a HDAd vector encoding the codon optimized fusion glycoprotein (Fsyn) of RSV, designated HDAd-Fsyn, and delivered intranasally HDAd-Fsyn to mice.
RSV-specific humoral and cellular immune responses were generated in BALB/c mice, and serum IgG with neutralizing activity was significantly elevated after a homologous boost with intranasal (i.n.) application of HDAd-Fsyn. Humoral immune responses could be measured even 14 weeks after a single immunization. Immunization with i.n. HDAd-Fsyn led to effective protection against RSV infection on challenge.
The results indicate that HDAd-Fsyn can induce powerful systemic immunity against subsequent i.n. RSV challenge in a mouse model and is a promising candidate vaccine against RSV infection.
PMCID: PMC3685604  PMID: 23742026
Human respiratory syncytial virus; Helper-dependent adenovirus vectors; Fusion glycoprotein; Protective immunity; Immune responses

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