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1.  A New Synthetic Allotetraploid (A1A1G2G2) between Gossypium herbaceum and G. australe: Bridging for Simultaneously Transferring Favorable Genes from These Two Diploid Species into Upland Cotton 
PLoS ONE  2015;10(4):e0123209.
Gossypium herbaceum, a cultivated diploid cotton species (2n = 2x = 26, A1A1), has favorable traits such as excellent drought tolerance and resistance to sucking insects and leaf curl virus. G. australe, a wild diploid cotton species (2n = 2x = 26, G2G2), possesses numerous economically valuable characteristics such as delayed pigment gland morphogenesis (which is conducive to the production of seeds with very low levels of gossypol as a potential food source for humans and animals) and resistance to insects, wilt diseases and abiotic stress. Creating synthetic allotetraploid cotton from these two species would lay the foundation for simultaneously transferring favorable genes into cultivated tetraploid cotton. Here, we crossed G. herbaceum (as the maternal parent) with G. australe to produce an F1 interspecific hybrid and doubled its chromosome complement with colchicine, successfully generating a synthetic tetraploid. The obtained tetraploid was confirmed by morphology, cytology and molecular markers and then self-pollinated. The S1 seedlings derived from this tetraploid gradually became flavescent after emergence of the fifth true leaf, but they were rescued by grafting and produced S2 seeds. The rescued S1 plants were partially fertile due to the existence of univalents at Metaphase I of meiosis, leading to the formation of unbalanced, nonviable gametes lacking complete sets of chromosomes. The S2 plants grew well and no flavescence was observed, implying that interspecific incompatibility, to some extent, had been alleviated in the S2 generation. The synthetic allotetraploid will be quite useful for polyploidy evolutionary studies and as a bridge for transferring favorable genes from these two diploid species into Upland cotton through hybridization.
PMCID: PMC4400159  PMID: 25879660
2.  Zfra activates memory Hyal-2+ CD3− CD19− spleen cells to block cancer growth, stemness, and metastasis in vivo 
Oncotarget  2015;6(6):3737-3751.
Zfra is a 31-amino-acid zinc finger-like protein, which participates in the tumor necrosis factor signaling. Here, we determined that when nude mice and BALB/c mice were pre-injected with nanogram levels of a synthetic Zfra1–31 or truncated Zfra4–10 peptide via tail veins, these mice became resistant to the growth, metastasis and stemness of melanoma cells, and many malignant cancer cells. The synthetic peptides underwent self-polymerization in phosphate-buffered saline. Alteration of the Ser8 phosphorylation site to Gly8 abolished Zfra aggregation and its-mediated cancer suppression in vivo. Injected Zfra peptide autofluoresced due to polymerization and was trapped mainly in the spleen. Transfer of Zfra-stimulated spleen cells to naïve mice conferred resistance to cancer growth. Zfra-binding cells, designated Hyal-2+ CD3− CD19− Z cells, are approximately 25–30% in the normal spleen, but are significantly downregulated (near 0–3%) in tumor-growing mice. Zfra prevented the loss of Z cells caused by tumors. In vitro stimulation or education of naïve spleen cells with Zfra allowed generation of activated Z cells to confer a memory anticancer response in naïve or cancer-growing mice. In particular, Z cells are abundant in nude and NOD-SCID mice, and can be readily activated by Zfra to mount against cancer growth.
PMCID: PMC4414150  PMID: 25686832
Zfra; skin cancer; melanoma; metastasis; stemness
3.  Ultra-Localized Single Cell Electroporation Using Silicon Nanowires 
Lab on a chip  2013;13(3):10.1039/c2lc40837f.
Analysis of cell-to-cell variation can further the understanding of intracellular processes and the role of individual cell function within a larger cell population. The ability to precisely lyse single cells can be used to release cellular components to resolve cellular heterogeneity that might be obscured when whole populations are examined. We report a method to position and lyse individual cells on silicon nanowire and nanoribbon biological field effect transistors. In this study, HT-29 cancer cells were positioned on top of transistors by manipulating magnetic beads using external magnetic fields. Ultra-rapid cell lysis was subsequently performed by applying 600–900 mVpp at 10 MHz for as little as 2 ms across the transistor channel and the bulk substrate. We show that the fringing electric field at the device surface disrupts the cell membrane, leading to lysis from irreversible electroporation. This methodology allows rapid and simple single cell lysis and analysis with potential applications in medical diagnostics, proteome analysis and developmental biology studies.
PMCID: PMC3535553  PMID: 23179093
4.  Pectinesterase Inhibitor from Jelly Fig (Ficus awkeotsang Makino) Achene Inhibits Surface Antigen Expression by Human Hepatitis B Virus 
Pectinesterase inhibitor (PEI) isolated from jelly fig (Ficus awkeotsang Makino) is an edible component of a popular drink consumed in Asia. Hepatitis B virus (HBV) infection is prevalent in Asia, and current treatments for HBV infection need improvement. This study aimed to evaluate the effect of PEI on the surface antigen expression by HBV (HBsAg). Human hepatoma cell lines Hep3B and Huh7 served as in vitro models for assessing the cytotoxicity and HBsAg expression. A culture of primary hepatocytes cultured from mice served as the normal counterpart. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. HBsAg expression was evaluated by measuring HBsAg secretion into the culture medium using an enzyme-linked immunosorbent assay. The results showed that PEI did not affect the viability of the human hepatoma cell lines or primary mouse hepatocytes. PEI inhibited the expression of HBsAg in hepatoma cell lines harboring endogenous (Hep3B) and integrated (Huh7) HBV genomes in a concentration- and time-dependent manner, thus implicating a universal activity against HBV gene expression. In conclusion, it suggests that PEI from jelly fig inhibits the expression of human HBsAg in host cells without toxic effects on normal primary hepatocytes.
PMCID: PMC3834976  PMID: 24302965
5.  Cardiopulmonary Profile in Streptozotocin-Induced Type 1 Diabetic Rats during Systemic Endotoxemia 
Journal of Diabetes Research  2013;2013:494179.
This study was designed to determine the severity of cardiopulmonary dysfunction during systemic endotoxemia in type 1 diabetes. Thirty-two adult male Wistar rats were randomly assigned to a control group or to a group treated with streptozotocin (STZ) to create an animal model of type 1 diabetes. Survival time and cardiovascular parameters were continually monitored in urethane anaesthetized animals receiving intravenous infusion of endotoxin (lipopolysaccharide (LPS)) or saline. We also determined arterial blood gases, lung injury, and tumor necrosis factor-alpha (TNF-α) levels in serum and bronchoalveolar lavage fluid. Before LPS administration, the mean arterial pressure in STZ rats was significantly higher than that in normal rats. After LPS injection, the heart rate drop significantly in STZ rats than that in the control group. Also, the increased levels of TNF-α in serum and lavage fluid after LPS treatment were significantly higher in STZ rats than those in normal rats. Survival time in STZ rats was shorter than that in normal rats after LPS application. Albumin content, wet/dry weight ratio of lung, and lung injury were indistinguishable between STZ and normal rats. These results indicate that the cardiopulmonary change which occurs during LPS-induced endotoxemia is minor in STZ-induced diabetic rats.
PMCID: PMC3647548  PMID: 23671873
6.  The novel application of artificial neural network on bioelectrical impedance analysis to assess the body composition in elderly 
Nutrition Journal  2013;12:21.
This study aims to improve accuracy of Bioelectrical Impedance Analysis (BIA) prediction equations for estimating fat free mass (FFM) of the elderly by using non-linear Back Propagation Artificial Neural Network (BP-ANN) model and to compare the predictive accuracy with the linear regression model by using energy dual X-ray absorptiometry (DXA) as reference method.
A total of 88 Taiwanese elderly adults were recruited in this study as subjects. Linear regression equations and BP-ANN prediction equation were developed using impedances and other anthropometrics for predicting the reference FFM measured by DXA (FFMDXA) in 36 male and 26 female Taiwanese elderly adults. The FFM estimated by BIA prediction equations using traditional linear regression model (FFMLR) and BP-ANN model (FFMANN) were compared to the FFMDXA. The measuring results of an additional 26 elderly adults were used to validate than accuracy of the predictive models.
The results showed the significant predictors were impedance, gender, age, height and weight in developed FFMLR linear model (LR) for predicting FFM (coefficient of determination, r2 = 0.940; standard error of estimate (SEE) = 2.729 kg; root mean square error (RMSE) = 2.571kg, P < 0.001). The above predictors were set as the variables of the input layer by using five neurons in the BP-ANN model (r2 = 0.987 with a SD = 1.192 kg and relatively lower RMSE = 1.183 kg), which had greater (improved) accuracy for estimating FFM when compared with linear model. The results showed a better agreement existed between FFMANN and FFMDXA than that between FFMLR and FFMDXA.
When compared the performance of developed prediction equations for estimating reference FFMDXA, the linear model has lower r2 with a larger SD in predictive results than that of BP-ANN model, which indicated ANN model is more suitable for estimating FFM.
PMCID: PMC3662169  PMID: 23388042
Back Propagation Artificial Neural Network (BP-ANN); Body composition; Bioelectrical impedance analysis (BIA); Elderly; Dual-energy X-ray absorptiometry
7.  Assessing Current Therapeutic Approaches to Decode Potential Resistance Mechanisms in Glioblastomas 
Unique astrocytic cell infiltrating growth and glial tumor growth in the confined skull make human glioblastoma (GBM) one of the most difficult cancers to treat in modern medicine. Prognosis for patients is very poor, as they die more or less within 12 months. Patients either die of the cancer itself, or secondary complications such as cerebral edema, herniations, or hemorrhages. GBMs rarely metastasize to other organs. However, GBM recurrence associated with resistance to therapeutic drugs is common. Patients die shortly after relapse. GBM is indeed an outstanding cancer model to search for potential mechanisms for drug resistance. Here, we reviewed the current cancer biology of gliomas and their pathophysiological events that contribute to the development of therapeutic resistance. We have addressed the potential roles of cancer stem cells, epigenetic modifications, and epithelial mesenchymal transition (EMT) in the development of resistance to inhibitor drugs in GBMs. The potential role of TIAF1 (TGF-β-induced antiapoptotic factor) overexpression and generation of intratumor amyloid fibrils for conferring drug resistance in GBMs is discussed.
PMCID: PMC3601334  PMID: 23516171
glioblastoma multiforme; temozolomide; resistance mechanisms; cancer stem cell; TIAF1 expression; extracellular matrix
8.  Lapatinib Induces Autophagy, Apoptosis and Megakaryocytic Differentiation in Chronic Myelogenous Leukemia K562 Cells 
PLoS ONE  2011;6(12):e29014.
Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted.
PMCID: PMC3245247  PMID: 22216158
9.  Increased expression of angiogenin in gastric carcinoma in correlation with tumor angiogenesis and proliferation 
AIM: To investigate the implication of angiogenin (ANG) in the neovascularizaton and growth of human gastric carcinoma (HGC).
METHODS: ANG mRNA expression in HGC specimens obtained by surgical resection from patients with HGC were examined by RT-PCR. ANG, Ki-67, VEGF protein expression and microvessel density (MVD) in HGC specimens were detected by immunohistochemistry.
RESULTS: RT-PCR showed significantly higher ANG mRNA expression (0.482 ± 0.094) in HGC tissues than in the surrounding nontumorous tissues (0.276 ± 0.019, P = 0.03). MVD within tumorous tissues increased significantly with ANG mRNA expression (r = 0.380, P = 0.001) and ANG protein expression (P < 0.01). The ANG expression levels of cancer tissues were positively correlated with VEGF (P < 0.01) and the proliferation index of cancer cells (P < 0.01).
CONCLUSION: ANG is one of the neovascularization factors of HGC. ANG may work in coordination with VEGF, and promote the proliferation of HGC cells.
PMCID: PMC4088009  PMID: 16937522
Angiogenin; Gastric carcinoma; Vascular endothelial growth factor; Angiogenesis
10.  Association between betel quid chewing and carotid intima-media thickness in rural Bangladesh 
Background: Areca nut, more commonly known as betel nut, is the fourth most commonly used addictive substance in the world. Though recent evidence suggests it may play a role in the development of cardiovascular disease, no studies have investigated whether betel nut use is related to subclinical atherosclerosis.
Methods: We evaluated the association between betel nut use and subclinical atherosclerosis in 1206 participants randomly sampled from the Health Effects of Arsenic Longitudinal Study (HEALS). Frequency and duration of betel nut use were assessed at baseline, and carotid IMT was measured on average 6.65 years after baseline.
Results: A positive association was observed between duration and cumulative exposure (function of duration and frequency) of betel nut use and IMT, with above-median use for duration (7 or more years) and cumulative exposure (30 or more quid-years) corresponding to a 19.1 μm [95% confidence interval (CI): 5.3-32.8; P ≤ 0.01] and 16.8 μm (95% CI: 2.9-30.8; P < 0.05) higher IMT in an adjusted model, respectively. This association was more pronounced in men [32.8 μm (95% CI: 10.0-55.7) and 30.9 μm (95% CI: 7.4-54.2)]. There was a synergy between cigarette smoking and above-median betel use such that the joint exposure was associated with a 42.4 μm (95% CI: 21.6-63.2; P ≤ 0.01) difference in IMT.
Conclusion: Betel nut use at long duration or high cumulative exposure levels is associated with subclinical atherosclerosis as manifested through carotid IMT. This effect is especially pronounced among men and cigarette smokers.
PMCID: PMC4121551  PMID: 24550247
Areca nut; Bangladesh; betel nut; cardiovascular disease; carotid intima-media thickness
11.  A prospective study of arm circumference and risk of death in Bangladesh 
Background: Epidemiological studies have observed protective effects of mid-upper arm circumference (MUAC) against all-cause mortality mostly in Western populations. However, evidence on cause-specific mortality is limited.
Methods: The sample included 19 575 adults from a population-based cohort study in rural Bangladesh, who were followed up for an average of 7.9 years for mortality. Cox proportional hazards regression was used to evaluate the effect of MUAC, as well as the joint effect of body mass index (BMI) and MUAC, on the risk of death from any cause, cancer and cardiovascular disease (CVD).
Results: During 154 664 person-years of follow-up, 744 deaths including 312 deaths due to CVD and 125 deaths due to cancer were observed. There was a linear inverse relationship of MUAC with total and CVD mortality. Each 1-cm increase in MUAC was associated a reduced risk of death from any cause [hazard ratio (HR) = 0.85; 95% confidence interval (C), 0.81–0.89) and CVD (HR = 0.87; 95% CI, 0.80–0.94), after controlling for potential confounders. No apparent relationship between MUAC and the risk of death from cancer was observed. Among individuals with a low BMI (<18.5 kg/m2), a MUAC less than 24 cm was associated with increased risk for all-cause (HR = 1.81; 95% CI, 1.52–2.17) and CVD mortality (HR = 1.45; 95% CI, 1.11–1.91).
Conclusions: MUAC may play a critical role on all-cause and CVD mortality in lean Asians.
PMCID: PMC4121562  PMID: 24713183
Mid-upper arm circumference (MUAC); mortality; cardiovascular diseases; cohort study; epidemiology
12.  Docking to multiple pockets or ligand fields for screening, activity prediction and scaffold hopping 
Future medicinal chemistry  2014;6(16):1741-1755.
Two recent technological advances dramatically reducing the rate of false-negatives in activity prediction by docking flexible 3D models of compounds include multi-conformational docking (mPockDock) and the docking of candidates to atomic property fields derived by co-crystallized ligands (mApfDock).
The mApfDock and mPockDock provide the AUC of 90.4 and 83.8%, respectively. The mApfDock gave better performance when compounds required large induced-fit pocket changes unseen in crystallography, whereas the mPockDock is superior when the co-crystallized ligands do not represent sufficient chemical and binding location diversity.
Both approaches proved to be efficient for scaffold hopping; they are complementary when the coverage of the co-crystallized complexes is poor but become convergent when the complexes are diverse enough.
PMCID: PMC4285145  PMID: 25407367
13.  Crystallization and preliminary X-ray diffraction analysis of the α subdomain of Lon protease from Brevibacillus thermoruber  
The α subdomain of Lon protease from B. thermoruber WR-249 has been expressed, purified and crystallized. Preliminary X-ray diffraction experiments have been undertaken.
DNA-binding ability has previously been reported as a novel function for the thermostable Lon protease from Brevibacillus thermoruber WR-249 (Bt-Lon), and the α subdomain (amino acids 491–605) of Bt-Lon has been identified as being responsible for DNA binding. However, the physiological role and DNA-recognition mode of Bt-Lon still remain unclear. In this study, the crystallization and preliminary crystallographic analysis of the Bt-Lon α subdomain are presented. Native diffraction data to 2.88 Å resolution were obtained from a vitrified crystal at 100 K on the BL13C1 beamline at the NSRRC (National Synchrotron Radiation Research Center), Taiwan. The crystals belonged to space group P23, with unit-cell parameters a = b = c = 94.28 Å. Solvent-content calculations and molecular-replacement results suggest that there are two molecules of Bt-Lon α subdomain per asymmetric unit.
PMCID: PMC3729169  PMID: 23908038
Lon protease; DNA binding; Brevibacillus thermoruber
14.  Plasma ATP is required for neutrophil activation in a mouse sepsis model 
Shock (Augusta, Ga.)  2014;42(2):142-147.
Our previous work has shown that polymorphonuclear neutrophils (PMN) require cellular ATP release and autocrine purinergic signaling for their activation. Here we studied in a mouse model of cecal ligation and puncture (CLP) whether sepsis affects this purinergic signaling process and thereby alters PMN responses after sepsis. Using high performance liquid chromatography, we found that plasma ATP, ADP, and AMP concentrations increased up to 6 fold during the first 8 h after CLP, reaching top levels that were significantly higher than those in sham control animals without CLP. While leukocyte and PMN counts in sham animals increased significantly after 4 h, these blood cell counts decreased in sepsis animals. CD11b expression on the cell surface of PMN of septic animals was significantly higher compared to sham and untreated control animals. These findings suggest increased PMN activation and sequestration of PMN from the circulation after sepsis. Plasma ATP levels correlated with CD11b expression, suggesting that increased ATP concentrations in plasma contribute to PMN activation. We found that treatment of septic mice with the ATP receptor antagonist suramin diminished CD11b expression, indicating that plasma ATP contributs to PMN activation by stimulating P2 receptors of PMN. Increased PMN activation can protect the host from invading microorganisms. However, increased PMN activation can also be detrimental by promoting secondary organ damage. We conclude that pharmacological targeting of P2 receptors may allow modulation of PMN responses in sepsis.
PMCID: PMC4107005  PMID: 24675414
Cecal ligation and puncture; CD11b expression; purinergic signaling; P2 receptor antagonist; suramin
15.  VEGF, not VEGFR2, is associated with the angiogenesis effect of mini-TyrRS/mini-TrpRS in human umbilical vein endothelial cells in hypoxia 
Cytotechnology  2013;66(4):655-665.
The purpose of this study was to determine the relationship between VEGF and mini-TyrRS/mini-TrpRS in angiogenesis in hypoxic culture and to begin to comprehend their mechanism in angiogenesis. We designed a VEGF gene silencing assay by using lentivirus vectors, and then western blotting was used to determine the protein expression of VEGF, VEGFR2 and pVEGFR2 in three groups in hypoxic culture at 3, 6, 12, or 24 h: (1) untransfected human umbilical vein endothelial cells (HUVECs) (Control); (2) pGCSIL-GFP lentivirus vector-transduced HUVECs (Mock); and (3) pGCSIL-shVEGF lentivirus vector-transduced HUVECs (Experimental). We also detected the effects of mini-TyrRS/mini-TrpRS peptides on HUVEC proliferation, migration and tube formation after lentivirus vector transfection and VEGFR2 antibody injection. The results indicated that expression of the mini-TyrRS protein was increased, whereas that of mini-TrpRS was specifically decreased in hypoxic culture both in control and mock groups. However, this trend in protein levels of mini-TyrRS and mini-TrpRS was lost in the experimental group after transduction with the pGCSIL-shVEGF lentivirus vector. The protein expression of VEGF was increased in hypoxic culture both in control and mock groups. After transduction with the pGCSIL-shVEGF lentivirus vector, the protein level of VEGF was noticeably decreased in the experimental group; however, for VEGFR2, the results showed no significant difference in VEGFR2 protein expression in any of the groups. For pVEGFR2, we found a distinct trend from that seen with VEGF. The protein expression of pVEGFR2 was sharply increased in hypoxic culture in the three groups. The addition of mini-TyrRS significantly promoted proliferation, migration and tube formation of HUVECs, while mini-TrpRS inhibited these processes in both control and mock groups in hypoxic culture. However, these effects disappeared after transduction with the pGCSIL-shVEGF lentivirus vector in the experimental group, but no significant difference was observed after VEGFR2 antibody injection. The protein expression of VEGF is similar to that of mini-TyrRS in hypoxic culture and plays an important role in the mini-TyrRS/mini-TrpRS-stimulated proliferation, migration and tube formation of HUVECs in hypoxia. These results also suggest that the change in mini-TyrRS and mini-TrpRS expression in hypoxic culture is not related to VEGFR2 and that some other possible mechanisms, are involved in the phosphorylation of VEGFR2.
PMCID: PMC4082773  PMID: 23896703
Mini-TyrRS; Mini-TrpRS; Angiogenesis; VEGF; VEGFR2; Hypoxia; HUVEC
16.  Positive correlation of serum adipocyte fatty acid binding protein levels with carotid–femoral pulse wave velocity in geriatric population 
BMC Geriatrics  2015;15:88.
Adipocyte fatty acid binding protein (A-FABP) is a novel fat-derived circulating protein, which is independently and positively associated with atherosclerosis. The present study evaluated the relationship between fasting serum A-FABP and central arterial stiffness in geriatric adults.
Fasting blood samples were obtained from 87 geriatric patients and the serum A-FABP levels were measured using an enzyme immunoassay. Carotid-femoral pulse wave velocity (cfPWV) was determined using the SphygmoCor system. cfPWV values of >10 m/s represented the high arterial stiffness group, while values ≤10 m/s defined the low arterial stiffness group.
High arterial stiffness group comprised of 42 geriatric adults (48.3 %). When compared to those in the low arterial stiffness group, the high arterial stiffness group had a higher rate of diabetes mellitus (P = 0.044) and hypertension (P = 0.043). Body weight (P = 0.027), waist circumference (P = 0.035), body mass index (P = 0.001), systolic blood pressure (P = 0.005), diastolic blood pressure (P = 0.045), pulse pressure (P = 0.038), and serum A-FABP level (P < 0.001) were also higher in the high arterial stiffness group than in the low arterial stiffness group. Multivariate logistic regression analysis of the factors significantly associated with arterial stiffness revealed that A-FABP (odds ratio: 1.833, 95 % confidence interval 1.123–2.993, P = 0.015) was an independent predictor of arterial stiffness in geriatric adults.
Serum A-FABP levels constitute a major risk factor in the development of central arterial stiffness in the geriatric population.
PMCID: PMC4513955  PMID: 26205896
Adipocyte fatty acid binding protein; Arterial stiffness; Geriatric adults; Pulse wave velocity
17.  The creation of modulated monoclinic aperiodic composites in n-alkane/urea compounds 
n-Dodecane/urea is a member of the prototype series of n-alkane/urea inclusion compounds. At room temperature, it presents a quasi-one dimensional liquid-like state for the confined guest molecules within the rigid, hexagonal framework of the urea host. At lower temperatures, we report the existence of two other phases. Below Tc=248 K there appears a phase with rank four superspace group P6122(00γ), the one typically observed at room temperature in n-alkane/urea compounds with longer guest molecules. A misfit parameter, defined by the ratio γ=ch/cg (chost/cguest), is found to be 0.632±0.005. Below Tc1=123 K, a monoclinic modulated phase is created with a constant shift along c of the guest molecules in adjacent channels. The maximal monoclinic space group for this structure is P1211(α0γ). Analogies and differences with n-heptane/urea, which also presents a monoclinic, modulated low-temperature phase, are discussed.
PMCID: PMC4512510  PMID: 26213678
alkane/urea crystals; aperiodic crystals; crystallographic superspace; diffraction; phase transitions
18.  Axin Regulates Dendritic Spine Morphogenesis through Cdc42-Dependent Signaling 
PLoS ONE  2015;10(7):e0133115.
During development, scaffold proteins serve as important platforms for orchestrating signaling complexes to transduce extracellular stimuli into intracellular responses that regulate dendritic spine morphology and function. Axin (“axis inhibitor”) is a key scaffold protein in canonical Wnt signaling that interacts with specific synaptic proteins. However, the cellular functions of these protein–protein interactions in dendritic spine morphology and synaptic regulation are unclear. Here, we report that Axin protein is enriched in synaptic fractions, colocalizes with the postsynaptic marker PSD-95 in cultured hippocampal neurons, and interacts with a signaling protein Ca2+/calmodulin-dependent protein kinase II (CaMKII) in synaptosomal fractions. Axin depletion by shRNA in cultured neurons or intact hippocampal CA1 regions significantly reduced dendritic spine density. Intriguingly, the defective dendritic spine morphogenesis in Axin-knockdown neurons could be restored by overexpression of the small Rho-GTPase Cdc42, whose activity is regulated by CaMKII. Moreover, pharmacological stabilization of Axin resulted in increased dendritic spine number and spontaneous neurotransmission, while Axin stabilization in hippocampal neurons reduced the elimination of dendritic spines. Taken together, our findings suggest that Axin promotes dendritic spine stabilization through Cdc42-dependent cytoskeletal reorganization.
PMCID: PMC4512687  PMID: 26204446
19.  Specialised emission pattern of leaf trace in a late Permian (253 million-years old) conifer 
Scientific Reports  2015;5:12405.
Leaf traces are important structures in higher plants that connect leaves and the stem vascular system. The anatomy and emission pattern of leaf traces are well studied in extant vascular plants, but remain poorly understood in fossil lineages. We quantitatively analysed the leaf traces in the late Permian conifer Ningxiaites specialis from Northwest China based on serial sections through pith, primary and secondary xylems. A complete leaf traces emission pattern of a conifer is presented for the first time from the late Palaeozoic. Three to five monarch leaf traces are grouped in clusters, arranged in a helical phyllotaxis. The leaf traces in each cluster can be divided into upper, middle and lower portions, and initiate at the pith periphery and cross the wood horizontally. The upper leaf trace increases its diameter during the first growth increment and then diminishes completely, which indicates leaf abscission at the end of the first year. The middle trace immediately bifurcates once or twice to form two or three vascular bundles. The lower trace persists as a single bundle during its entire length. The intricate leaf trace dynamics indicates this fossil plant had a novel evolutionary habit by promoting photosynthetic capability for the matured plant.
PMCID: PMC4510520  PMID: 26198410
20.  Digital quantum simulation of fermionic models with a superconducting circuit 
Nature Communications  2015;6:7654.
One of the key applications of quantum information is simulating nature. Fermions are ubiquitous in nature, appearing in condensed matter systems, chemistry and high energy physics. However, universally simulating their interactions is arguably one of the largest challenges, because of the difficulties arising from anticommutativity. Here we use digital methods to construct the required arbitrary interactions, and perform quantum simulation of up to four fermionic modes with a superconducting quantum circuit. We employ in excess of 300 quantum logic gates, and reach fidelities that are consistent with a simple model of uncorrelated errors. The presented approach is in principle scalable to a larger number of modes, and arbitrary spatial dimensions.
Quantum simulation offers an unparalleled computational resource, but realizing it for fermionic systems is challenging due to their particle statistics. Here the authors report on the time evolutions of fermionic interactions implemented with digital techniques on a nine-qubit superconducting circuit.
PMCID: PMC4510643  PMID: 26153660
21.  ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning 
Nature communications  2015;6:6023.
The ciliary kinase NEK8 plays a critical role in situs determination and cystic kidney disease, yet its exact function remains unknown. In this study we identify ANKS6 as a target and activator of NEK8. ANKS6 requires NEK8 for localizing to the ciliary inversin compartment (IC) and activates NEK8 by binding to its kinase domain. Here we demonstrate the functional importance of this interaction through the analysis of two novel mouse mutations, Anks6Streaker and Nek8Roc. Both display heterotaxy, cardiopulmonary malformations and cystic kidneys, a syndrome also characteristic of mutations in Invs and Nphp3, the other known components of the IC. The Anks6Strkr mutation decreases ANKS6 interaction with NEK8, precluding NEK8 activation. The Nek8Roc mutation inactivates NEK8 kinase function while preserving ANKS6 localization to the IC. Together, these data reveal the crucial role of NEK8 kinase activation within the IC, promoting proper left-right patterning, cardiopulmonary development and renal morphogenesis.
PMCID: PMC4361001  PMID: 25599650
22.  Electric-field-induced strong enhancement of electroluminescence in multilayer molybdenum disulfide 
Nature Communications  2015;6:7509.
The layered transition metal dichalcogenides have attracted considerable interest for their unique electronic and optical properties. While the monolayer MoS2 exhibits a direct bandgap, the multilayer MoS2 is an indirect bandgap semiconductor and generally optically inactive. Here we report electric-field-induced strong electroluminescence in multilayer MoS2. We show that GaN–Al2O3–MoS2 and GaN–Al2O3–MoS2–Al2O3-graphene vertical heterojunctions can be created with excellent rectification behaviour. Electroluminescence studies demonstrate prominent direct bandgap excitonic emission in multilayer MoS2 over the entire vertical junction area. Importantly, the electroluminescence efficiency observed in multilayer MoS2 is comparable to or higher than that in monolayers. This strong electroluminescence can be attributed to electric-field-induced carrier redistribution from the lowest energy points (indirect bandgap) to higher energy points (direct bandgap) in k-space. The electric-field-induced electroluminescence is general for other layered materials including WSe2 and can open up a new pathway towards transition metal dichalcogenide-based optoelectronic devices.
The layer-number-dependent optical and electronic properties of transition metal dichalcogenides are promising in optoelectronics. Here, Li et al. demonstrate greatly enhanced electroluminescence emission in multi-layer MoS2 attributed to the electric-field-induced carrier redistribution.
PMCID: PMC4507000  PMID: 26130491
23.  Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study 
Nature Communications  2015;6:7633.
Graves' disease is the leading cause of hyperthyroidism affecting 1.0–1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10−32) and HLA-DRB1*08:03 (Pcombined=1.83 × 10−9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13–41.48) and 6.13 (95% confidence interval=3.28–11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10−21, 95% confidence interval=21.66–108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.
Graves' disease is the leading cause of hyperthyroidism but treatment options can cause life-threatening complications. Chen et al. conduct two-stage direct HLA genotyping and genome-wide association studies to identify HLA-B*38:02 and HLA-DRB1*08:03 as major pharmacogenetic determinants.
PMCID: PMC4506516  PMID: 26151496
24.  A dendritic nano-sized hexanuclear ruthenium(II) complex as a one- and two-photon luminescent tracking non-viral gene vector 
Scientific Reports  2015;5:10707.
Fluorescent tracking gene delivery could provide us with a better understanding of the critical steps in the transfection process. However, for in vivo tracking applications, a small diameter (<10 nm) is one of the rigorous requirements for tracking vectors. Herein, we have demonstrated a new paradigm for two-photon tracking gene delivery based on a dendritic nano-sized hexanuclear ruthenium(II) polypyridyl complex. Because this metallodendrimer has a multivalent periphery, the complex, which is 6.1 nm, showed high stability and excellent dispersibility and could stepwise condense DNA in vitro. With the outstanding photochemical properties of Ru(II) polypyridyl, this complex could track gene delivery in vivo using one- and two-photon imaging.
PMCID: PMC4505312  PMID: 26185052
25.  Progression of Large Lymphoma Is Significantly Impeded with a Combination of Gemcitabine Chemotherapy and Dendritic Cells Intra-Tumor Vaccination 
PLoS ONE  2015;10(7):e0132799.
Relapsed, refractory lymphoma remains to be a challenge and lacks efficient treatment. Some tumor cells escape from treatment, become resistant to chemotherapeutic agents, and rapidly regenerate into large tumors. Lymphoma cells induce accumulation of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) in lymphatic organs and their vicinity. MDSCs enable tumor cells to escape from immune cells mediated surveillance and attack. Gemcitabine is a chemotherapeutic agent that eliminates both tumor cells and MDSCs, improving the immune environment favorable for subsequent treatment. We evaluated the effects of low dose gemcitabine combined with intra-tumorally delivered dendritic cells (DCs) for the treatment of A20 large-size lymphoma. We showed that MDSCs increased markedly in lymphoma-bearing mice, and that gemcitabine significantly increased the apoptosis of MDSCs. Treatment of lymphoma with either gemcitabine or intra-tumoral DCs alone could not inhibit tumor growth or rescue lymphoma-bearing mice. Treatment of lymphoma with small dose gemcitabine followed by intra-tumorally injected DCs significantly improved the efficacy of either individual treatment by reducing MDSCs, inducing onsite DCs maturation, eliminating tumor cells, inhibiting tumor growth and relapse, and extending the survival of the lymphoma-bearing mice, partly through the induction of the IFNγ secreting cells and the activation of cytotoxic lymphocytes. We showed that NK cells and CD8+ T cells were the major effectors to mediate the inhibition of tumor growth. Thus, the observation that gemcitabine synergizes DCs mediated immunotherapy to improve the efficacy of large size lymphoma treatment provides an experimental basis for the combination of chemotherapy and immunotherapy for the efficient treatment of relapsed or refractory lymphoma.
PMCID: PMC4504496  PMID: 26181041

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