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1.  Local hyperthermia treatment of tumors induces CD8+ T cell-mediated resistance against distal and secondary tumors 
Combinatorial use of iron oxide nanoparticles (IONPs) and an alternating magnetic filed (AMF) can induce local hyperthermia in tumors in a controlled and uniform manner. Heating B16 primary tumors at 43°C for 30 minutes activated dendritic cells (DCs) and subsequently CD8+ T cells in the draining lymph node (dLN) and conferred resistance against rechallenge with B16 (but not unrelated Lewis Lung carcinoma) given 7 days post hyperthermia on both the primary tumor side and the contralateral side in a CD8+ T cell-dependent manner. Mice with heated primary tumors also resisted rechallenge given 30 days post hyperthermia. Mice with larger heated primary tumors had greater resistance to secondary tumors. No rechallenge resistance occurred when tumors were heated at 45°C. Our results demonstrate the promising potential of local hyperthermia treatment applied to identified tumors in inducing anti-tumor immune responses that reduce the risk of recurrence and metastasis.
PMCID: PMC4119841  PMID: 24566274
ironoxide; nanoparticle; local hyperthermia; heat; anti-tumor immune
2.  Interleukin-18 genetic polymorphisms contribute differentially to the susceptibility to Crohn’s disease 
AIM: To investigate the correlation between interleukin-18 (IL-18) gene polymorphisms and the risk of developing Crohn’s disease (CD).
METHODS: The PubMed, CISCOM, CINAHL, Web of Science, EBSCO, Cochrane Library, MEDLINE, EMBASE and CBM databases were searched without any language restrictions using combinations of keywords relating to CD and IL-18 for relevant articles published before November 1st, 2013. Screening of the published studies retrieved from searches was based on our stringent inclusion and exclusion criteria and resulted in seven eligible studies for meta-analysis. A meta-analysis was conducted using a random-effects model with STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95%CI) were calculated.
RESULTS: Seven case-control studies, with a total of 1930 CD cases and 1930 healthy subjects, met our inclusion criteria. The results of our meta-analysis indicated that the IL-18 rs1946518 A>C and rs187238 G>C polymorphisms may correlate with an increased risk of CD under five genetic models (all P < 0.05). Furthermore, we observed positive associations between the IL-18 rs360718 A>C polymorphism and CD risk under three genetic models (C allele vs A allele: OR = 2.03, 95%CI: 1.20-3.43, P = 0.008; CC vs AA+AC: OR = 2.39, 95%CI: 1.2-4.43, P = 0.006; CC vs AC: OR = 2.31, 95%CI: 1.22-4.38, P = 0.010). However, such associations were not found for the IL-18 rs917997 C>T, codon 35 A>C and rs1946519 G>T polymorphisms (all P > 0.05). A subgroup analysis was conducted to investigate the effect of ethnicity on an individual’s susceptibility to CD. Our results revealed positive correlations between IL-18 genetic polymorphisms and an increased risk of CD among Asians and Africans (all P < 0.05), but not among Caucasians (all P > 0.05).
CONCLUSION: This meta-analysis indicated that the IL-18 rs1946518 A>C, rs187238 G>C and rs360718 A>C polymorphisms may contribute to susceptibility to CD, especially among Asians and Africans. These polymorphisms are known to reduce IL-18 mRNA and protein levels.
PMCID: PMC4515852
Interleukin-18; Single nucleotide polymorphism; Crohn’s disease; Meta-analysis
3.  Massive interstitial copy-neutral loss-of-heterozygosity as evidence for cancer being a disease of the DNA-damage response 
BMC Medical Genomics  2015;8:42.
The presence of loss-of-heterozygosity (LOH) mutations in cancer cell genomes is commonly encountered. Moreover, the occurrences of LOHs in tumor suppressor genes play important roles in oncogenesis. However, because the causative mechanisms underlying LOH mutations in cancer cells yet remain to be elucidated, enquiry into the nature of these mechanisms based on a comprehensive examination of the characteristics of LOHs in multiple types of cancers has become a necessity.
We performed next-generation sequencing on inter-Alu sequences of five different types of solid tumors and acute myeloid leukemias, employing the AluScan platform which entailed amplification of such sequences using multiple PCR primers based on the consensus sequences of Alu elements; as well as the whole genome sequences of a lung-to-liver metastatic cancer and a primary liver cancer. Paired-end sequencing reads were aligned to the reference human genome to identify major and minor alleles so that the partition of LOH products between homozygous-major vs. homozygous-minor alleles could be determined at single-base resolution. Strict filtering conditions were employed to avoid false positives. Measurements of LOH occurrences in copy number variation (CNV)-neutral regions were obtained through removal of CNV-associated LOHs.
We found: (a) average occurrence of copy-neutral LOHs amounting to 6.9 % of heterologous loci in the various cancers; (b) the mainly interstitial nature of the LOHs; and (c) preference for formation of homozygous-major over homozygous-minor, and transitional over transversional, LOHs.
The characteristics of the cancer LOHs, observed in both AluScan and whole genome sequencings, point to the formation of LOHs through repair of double-strand breaks by interhomolog recombination, or gene conversion, as the consequence of a defective DNA-damage response, leading to a unified mechanism for generating the mutations required for oncogenesis as well as the progression of cancer cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-015-0104-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4515014  PMID: 26208496
Copy number variation; Double strand break repair; Gain-of-heterozygosity; Gene conversion; Inter-homologous recombination; Loss-of-heterozygosity
4.  Pathogenesis of X-Linked Charcot-Marie-Tooth Disease: Differential Effects of Two Mutations in Connexin 32 
X-Linked Charcot-Marie-Tooth disease is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding connexin 32 (Cx32). Cx32 is expressed at the paranodes and Schmidt–Lantermann incisures of myelinating Schwann cells in which it is believed to form a reflexive pathway between the abaxonal and adaxonal cytoplasmic domains. Patients with the Val181Ala (V181A) mutation have a severe peripheral neuropathy. Experiments using a nude mouse xenograft system show that Schwann cells expressing only this mutant form of Cx32 are profoundly impaired in their ability to support the earliest stages of regeneration of myelinated fibers. Coupling between paired Xenopus oocytes expressing V181A is reduced compared with the coupling between oocytes expressing wild-type human Cx32 (32WT), and protein levels assayed by Western blot are substantially lower. Immunocytochemisty shows that Neuro2a cells expressing theV181Amutant have very few gap junction plaques compared with cells expressing 32WT; Cx32 protein levels are lower in these cells than in those expressing 32WT. Because failure of normal regeneration is evident before formation of myelin, loss of function of Cx32 may impact on the function of precursors of the myelinating Schwann cell before the formation of the hypothesized reflexive pathway. The Glu102Gly (E102G) mutation leads to a milder phenotype. Early regeneration is normal in grafts with Schwann cells expressing the E102G mutant. The only abnormality detected in the behavior of its channel is increased sensitivity to acidification-induced closure, a property that may lead to reduced gap junction coupling during periods of metabolic stress. This restricted functional abnormality may explain the relatively mild phenotype seen in the xenograft model and in E102G patients.
PMCID: PMC4513672  PMID: 14627639
connexin 32; xenograft myelin; Charcot–Marie–Tooth disease; peripheral neuropathy; myelin regeneration
5.  Relationship between Diabetic Retinopathy and Subclinical Hypothyroidism: a meta-analysis 
Scientific Reports  2015;5:12212.
Several epidemiological studies have found a positive association between diabetic retinopathy (DR) and subclinical hypothyroidism (SCH), but the findings are varied or even contradictory. In the work, we performed a meta-analysis to ascertain the relationship between DR and SCH. We searched relevant studies on the relationship between DR and SCH. All English reports were used Medline, EMbase, Web of Science, Google scholar, and all Chinese ones used CBMDisc (Chinese Biochemical Literature on Disc) and CNKI (China National Knowledge Infrastructure) database. Meta-analysis was performed using RevMan 5.1 software. We obtained eight observational studies. Random-effects meta-analysis indicated a significant association between DR and SCH (odds ratio = 2.13, 95% confidence interval = 1.41 – 3.23, p < 0.001). Based on currently evidence, SCH is probably a significant risk factor for DR.
PMCID: PMC4507396  PMID: 26193340
6.  Prognostic value of the primary lesion apparent diffusion coefficient (ADC) in nasopharyngeal carcinoma: a retrospective study of 541 cases 
Scientific Reports  2015;5:12242.
The prognostic value of the primary lesion pretreatment apparent diffusion coefficient (ADC), which is obtained by diffusion-weighted magnetic resonance imaging (MR-DWI), remains unknown in nasopharyngeal carcinoma (NPC). Thus, to investigate whether the pretreatment ADC value as measured from the primary site on MR-DWI is an independent prognostic factor in NPC, we retrospectively reviewed a cohort of 541 patients with histologically-proven stage I-IVB NPC. All patients underwent MRI using a 3-Tesla system (Trio Tim; Siemens, Erlangen Germany). To calculate ADC, the primary lesion was designated on the ADC map at the level of the largest tumor diameter to cover most of the lesion, avoiding cystic or necrotic components. Median and mean (±SD) pretreatment ADC were 0.713 and 0.716 ± 0.079 × 10−3 mm2/s, respectively. Univariate and multivariate analysis confirmed high pretreatment ADC was a good prognostic factor for poor local relapse-free survival and disease-free survival. Furthermore, the area under the ROC curve for prediction of local failure significantly increased when pretreatment ADC was combined with T classification (P = 0.004). Thus, pretreatment ADC might provide useful information for predicting outcome and selecting high-risk patients appropriate for more aggressive therapy. Further studies are warranted to investigate the biological basis of this observation.
PMCID: PMC4505330  PMID: 26184509
7.  SLX2 interacting with BLOS2 is differentially expressed during mouse oocyte meiotic maturation 
Cell Cycle  2014;13(14):2230-2236.
Gametogenesis is a complex biological process of producing cells for sexual reproduction. Xlr super family members containing a conserved COR1 domain play essential roles in gametogenesis. In the present study, we identified that Slx2, a novel member of Xlr super family, is specifically expressed in the meiotic oocytes, which is demonstrated by western blotting and immunohistochemistry studies. In the first meiotic prophase, SLX2 is unevenly distributed in the nuclei of oocytes, during which phase SLX2 is partly co-localized with SYCP3 in synaptonemal complex and γH2AX in the nucleus of oocytes. Interestingly, the localization of SLX2 was found to be switched into the cytoplasm of oocytes after prometaphase I during oocyte maturation. Furthermore, yeast two-hybrid and coimmunoprecipitation studies demonstrated that SLX2 interacts with BLOS2, which is a novel centrosome-associated protein, and co-localized with γ-Tubulin, which is a protein marker of chromosome segregation in meiosis. These results indicated that SLX2 might get involved in chromosomes segregation during meiosis by interaction with BLOS2. In conclusion, SLX2 might be a novel gametogenesis-related protein that could play multiple roles in regulation of meiotic processes including synaptonemal complex assembly and chromosome segregation.
PMCID: PMC4111678  PMID: 24870619
SLX2; BLOS2; Spindle; Meiosis; Oocyte
8.  Charge deformation and orbital hybridization: intrinsic mechanisms on tunable chromaticity of Y3Al5O12:Ce3+ luminescence by doping Gd3+ for warm white LEDs 
Scientific Reports  2015;5:11514.
The deficiency of Y3Al5O12:Ce (YAG:Ce) luminescence in red component can be compensated by doping Gd3+, thus lead to it being widely used for packaging warm white light-emitting diode devices. This article presents a systematic study on the photoluminescence properties, crystal structures and electronic band structures of (Y1−xGdx)3Al5O12: Ce3+ using powerful experimental techniques of thermally stimulated luminescence, X-ray diffraction, X-ray absorption near edge structure (XANES), extended X-ray absorption fine structure (EXAFS) and ultraviolet photoelectron spectra (UPS) of the valence band, assisted with theoretical calculations on the band structure, density of states (DOS), and charge deformation density (CDD). A new interpretation from the viewpoint of compression deformation of electron cloud in a rigid structure by combining orbital hybridization with solid-state energy band theory together is put forward to illustrate the intrinsic mechanisms that cause the emission spectral shift, thermal quenching, and luminescence intensity decrease of YAG: Ce upon substitution of Y3+ by Gd3+, which are out of the explanation of the classic configuration coordinate model. The results indicate that in a rigid structure, the charge deformation provides an efficient way to tune chromaticity, but the band gaps and crystal defects must be controlled by comprehensively accounting for luminescence thermal stability and efficiency.
PMCID: PMC4502399  PMID: 26175141
10.  Incidence Density and Risk Factors of Diabetic Retinopathy Within Type 2 Diabetes: A Five-Year Cohort Study in China (Report 1) 
A prospective study was carried out from August 2010 to August 2014 in the community of Fengyutan (China). Six hundred and twenty two T2D subjects were collected. The incidence density of diabetic retinopathy (DR) was 1.81% person-year (95% confidence interval, CI: 1.21–2.43% person-year). After a Cox regression model analysis and adjusted confounding factors, independent predictors related to the incidence of DR including male gender (adjusted hazard ratios, aHR: 1.47, 95% CI: 1.21–1.62), with hypertension (aHR: 1.49, 95%: 1.12–1.73), duration of diabetes > 10 years (aHR: 2.28, 95%: 2.05–2.42), uncontrolled diabetes (aHR: 1.76, 95%: 1.41–2.01), total cholesterol ≥ 200 mg/dL (aHR: 1.54, 95%: 1.34–1.72) and HbA1c ≥ 7% (mmol/mol) (aHR: 2.12, 95%: 1.87–2.32). Duration of T2D revealed the significantly dose-response relationship to the onset of DR. The incidence density of DR in the Chinese community was relatively low in comparison with other studies. More attention should be paid to the T2D patients, especially of male gender, with hypertension, longer duration of diabetes, uncontrolled diabetes, total cholesterol ≥ 200mg/dL and HbA1c ≥ 7% (mmol/mol).
PMCID: PMC4515698  PMID: 26184262
community; diabetic retinopathy; epidemiology; incidence density; risk factors
11.  Incidence of and Risk Factors for Mastoiditis after Intensity Modulated Radiotherapy in Nasopharyngeal Carcinoma 
PLoS ONE  2015;10(6):e0131284.
To report the incidence of and risk factors for mastoiditis after intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC).
Patients and Methods
Retrospective analysis of pretreatment and follow-up magnetic resonance imaging (MRI) data for 451 patients with NPC treated with IMRT at a single institution. The diagnosis of mastoiditis was based on MRI; otomastoid opacification was rated as Grade 0 (none), 1 (mild), 2 (moderate) or 3 (severe) by radiologists blinded to clinical outcome. This study mainly focused on severe mastoiditis; patients were divided into three groups: the G0M (Grade 0 mastoiditis before treatment) group, G1-2M (Grade 1 to 2 mastoiditis before treatment) group and G3M (Grade 3 mastoiditis before treatment) group. The software SAS9.3 program was used to analyze the data.
For the entire cohort, the incidence of Grade 3 mastoiditis was 20% before treatment and 31%, 19% and 17% at 3, 12 and 24 months after radiotherapy, respectively. In the G0M group, the incidence of severe mastoiditis was 0% before treatment and 23%, 15% and 13% at 3, 12 and 24 months after radiotherapy, respectively. Multivariate analysis revealed T category (OR=0.68, 95% CI = 0.469 to 0.984), time (OR=0.668, 95% CI = 0.59 to 0.757) and chemotherapy (OR=0.598, 95% CI = 0.343 to 0.934) were independent factors associated with severe mastoiditis in the G0M group after treatment.
Mastoiditis, as diagnosed by MRI, occurs as a progressive process that regresses and resolves over time in patients with NPC treated using IMRT.
PMCID: PMC4483256  PMID: 26114761
12.  A Cysteine Zipper Stabilizes a Pre-Fusion F Glycoprotein Vaccine for Respiratory Syncytial Virus 
PLoS ONE  2015;10(6):e0128779.
Recombinant subunit vaccines should contain minimal non-pathogen motifs to reduce potential off-target reactivity. We recently developed a vaccine antigen against respiratory syncytial virus (RSV), which comprised the fusion (F) glycoprotein stabilized in its pre-fusion trimeric conformation by “DS-Cav1” mutations and by an appended C-terminal trimerization motif or “foldon” from T4-bacteriophage fibritin. Here we investigate the creation of a cysteine zipper to allow for the removal of the phage foldon, while maintaining the immunogenicity of the parent DS-Cav1+foldon antigen. Constructs without foldon yielded RSV F monomers, and enzymatic removal of the phage foldon from pre-fusion F trimers resulted in their dissociation into monomers. Because the native C terminus of the pre-fusion RSV F ectodomain encompasses a viral trimeric coiled-coil, we explored whether introduction of cysteine residues capable of forming inter-protomer disulfides might allow for stable trimers. Structural modeling indicated the introduced cysteines to form disulfide “rings”, with each ring comprising a different set of inward facing residues of the coiled-coil. Three sets of rings could be placed within the native RSV F coiled-coil, and additional rings could be added by duplicating portions of the coiled-coil. High levels of neutralizing activity in mice, equivalent to that of the parent DS-Cav1+foldon antigen, were elicited by a 4-ring stabilized RSV F trimer with no foldon. Structure-based alteration of a viral coiled-coil to create a cysteine zipper thus allows a phage trimerization motif to be removed from a candidate vaccine antigen.
PMCID: PMC4476739  PMID: 26098893
13.  Burden and correlates of non-communicable-diseases among rural residents: a cross-sectional study in Hebei, China 
BMC Public Health  2015;15:571.
Burden of non-communicable diseases (NCDs) is increasing rapidly in most of the developing countries including China, even in rural areas. Dearth of representative data called for an investigation to estimate the burden and identify the correlates of NCDs in rural China.
A cross-sectional study was conducted involving a representative sample of 6003 consenting randomly selected rural residents aged 15 years or more, from 36 villages of Shijiazhuang in Hebei province of China between July 2010 and June 2011. Information on demographics and behavior were collected, body mass index (BMI) and blood pressure were measured and blood samples were tested to diagnose diabetes and hyperlipidemia.
Majority participants were aged < 30 year, married and educated up to junior/senior high school level. Mean age for the 6003 participants was 37.4 ± 14.8. About 55.7 % had BMI of 18.6-24.9. In past 12 months: 19.8 % smoked daily, 41.6 % were exposed to passive smoking, 28.5 % drank alcohol, 10.4 % skipped breakfasts frequently, 82.8 % did never exercise and 25.3 % had psychological disturbances. 51.1 % were hypertensive, 6.7 % were diabetic and 9.2 % had hyperlipidemia. Based on self-reports, cardiovascular diseases (4.5 %), cerebrovascular diseases (2.3 %), cancers (0.2 %), chronic obstructive pulmonary diseases (2 %), orthopedic problems (12.1 %) and gastrointestinal NCDs (7.8 %) were identified among the participants, while proportion of subjects with one, two and three or more NCDs were 43 %, 14.4 % and 5.5 % respectively. Higher odds of having more NCDs were associated with higher BMI (Kg/M2), family history of NCDs, daily and past history of smoking and drinking, passive smoking, lack of exercise, skipping breakfast and psychological disturbances.
Despite limitations associated with cross-sectional design and self-reporting, observation in this large sample of rural residents could develop important insights regarding high burden of NCDs in this population. Based on the identified correlates, targeted intervention strategies seem to be required urgently to control NCDs in rural China.
PMCID: PMC4473846  PMID: 26088558
Non-communicable diseases; Demographic correlates; NCDs; Chronic diseases; Unhealthy behaviors
14.  Magnetic Resonance Force Microscopy Detected Long-Lived Spin Magnetization 
IEEE transactions on magnetics  2013;49(7):3528-3532.
Magnetic resonance force microscopy (MRFM), which combines magnetic resonance imaging with scanning probe microscopy together, is capable of performing ultra-sensitive detection of spin magnetization. In an attempt to observe dynamic nuclear polarization (DNP) in an MRFM experiment, which could possibly further improve its sensitivity towards a single proton spin, a film of perdeuterated polystyrene doped with a nitroxide electron-spin probe was prepared. A high-compliance cantilever with a 4 μm diameter magnetic tip was brought near the film at a temperature of 7.3 K and in a background magnetic field of ~0.6 T. The film was irradiated with 16.7 GHz microwaves while the resulting transient change in cantilever frequency was recorded in real time. In addition to observing the expected prompt change in cantilever frequency due to saturation of the nitroxide’s electron-spin magnetization, we observed a persistent cantilever frequency change. Based on its magnitude, lifetime, and field dependence, we tentatively attribute the persistent signal to polarized deuteron magnetization created via transfer of magnetization from electron spins. Further measurements of the persistent signal’s dependence on the cantilever amplitude and tip-sample separation are presented and explained by the cross-effect DNP mechanism in high magnetic field gradients.
PMCID: PMC4474500  PMID: 26097251
15.  Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation 
Scientific Reports  2015;5:11445.
Excessive microglial activation often contributes to inflammation-mediated neurotoxicity in the ischemic penumbra during the acute stage of ischemic stroke. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation via the NF-κB pathway. Isoflurane preconditioning (IP) can provide neuroprotection and inhibit microglial activation. In this study, we investigated the roles of the TLR4 signalling pathway in IP to exert neuroprotection following ischemic stroke in vivo and in vitro. The results showed that 2% IP alleviated neurological deficits, reduced the infarct volume, attenuated apoptosis and weakened microglial activation in the ischemic penumbra. Furthermore, IP down-regulated the expression of HSP 60, TLR4 and MyD88 and up-regulated inhibitor of IκB-α expression compared with I/R group in vivo. In vitro, 2% IP and a specific inhibitor of TLR4, CLI-095, down-regulated the expression of TLR4, MyD88, IL-1β, TNF-α and Bax, and up-regulated IκB-α and Bcl-2 expression compared with OGD group. Moreover, IP and CLI-095 attenuated microglial activation-induced neuronal apoptosis, and overexpression of the TLR4 gene reversed the neuroprotective effects of IP. In conclusion, IP provided neuroprotection by regulating TLR4 expression directly, alleviating microglial activation and neuroinflammation. Thus, inhibiting the activation of microglial activation via TLR4 may be a new avenue for stroke treatment.
PMCID: PMC4471883  PMID: 26086415
16.  Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately 
Wnt and Notch signaling pathways are critically involved in relative cell fate decisions within the development of cutaneous tissues. Moreover, several studies identified the above two pathways as having a significant role during wound healing. However, their biological effects during cutaneous tissues repair are unclear.
We employed a self-controlled model (Sprague–Dawley rats with full-thickness skin wounds) to observe the action and effect of Wnt/β-catenin and Notch signalings in vivo. The quality of wound repair relevant to the gain/loss-of-function Wnt/β-catenin and Notch activation was estimated by hematoxylin-and-eosin and Masson staining. Immunofluorescence analysis and Western blot analysis were used to elucidate the underlying mechanism of the regulation of Wnt and Notch signaling pathways in wound healing. Meanwhile, epidermal stem cells (ESCs) were cultured in keratinocyte serum-free medium with Jaggedl or in DAPT (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl) to investigate whether the interruption of Notch signaling contributes to the expression of Wnt/β-catenin signaling.
The results showed that in vivo the gain-of-function Wnt/β-catenin and Notch activation extended the ability to promote wound closure. We further determined that activation or inhibition of Wnt signaling and Notch signaling can affect the proliferation of ESCs, the differentiation and migration of keratinocytes, and follicle regeneration by targeting c-Myc and Hes1, which ultimately lead to enhanced or delayed wound healing. Furthermore, Western blot analysis suggested that the two pathways might interact in vivo and in vitro.
These results suggest that Wnt and Notch signalings play important roles in cutaneous repair by targeting c-Myc and Hes1 separately. What’s more, interaction between the above two pathways might act as a vital role in regulation of wound healing.
PMCID: PMC4501079  PMID: 26076648
17.  Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus 
Science (New York, N.Y.)  2013;342(6158):592-598.
Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under five years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F-crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
PMCID: PMC4461862  PMID: 24179220
18.  Maternal Caffeine Consumption and Risk of Congenital Limb Deficiencies 
Animal studies have shown that high doses of caffeine might cause congenital limb deficiencies (LDs); however, no epidemiologic studies have explored this relation.
This case-control study assessed associations between maternal dietary caffeine and congenital LDs using data from the National Birth Defects Prevention Study (NBDPS), with 844 LD cases and 8069 controls from 1997 to 2007. Caffeine intakes from beverages (coffee, tea, and soda) and chocolate combined and by beverage type were examined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated for subtypes of isolated LDs (no additional major anomalies) and LDs with other major anomalies separately, comparing the odds of 10 to <100, 100 to <200, 200 to <300, and 300+ mg/day total caffeine intake to 0 to <10 mg/day.
All total dietary caffeine intake categories of 10 mg/day and above were marginally associated with odds of all isolated LDs combined (aOR, 1.4–1.7), isolated longitudinal LDs (aOR, 1.2–1.6), and isolated transverse LDs (aOR, 1.3–1.8) compared to the lowest intake category. A dose-response pattern for total dietary caffeine intake was not observed.
A weak increased risk of congenital LDs associated with maternal dietary caffeine consumption was observed in this study; however, risk did not vary by amount of caffeine consumed.
PMCID: PMC4457310  PMID: 22903936
caffeine; coffee; tea; soda; congenital limb deficiencies
19.  The Use of Chemical-Chemical Interaction and Chemical Structure to Identify New Candidate Chemicals Related to Lung Cancer 
PLoS ONE  2015;10(6):e0128696.
Lung cancer causes over one million deaths every year worldwide. However, prevention and treatment methods for this serious disease are limited. The identification of new chemicals related to lung cancer may aid in disease prevention and the design of more effective treatments. This study employed a weighted network, constructed using chemical-chemical interaction information, to identify new chemicals related to two types of lung cancer: non-small lung cancer and small-cell lung cancer. Then, a randomization test as well as chemical-chemical interaction and chemical structure information were utilized to make further selections. A final analysis of these new chemicals in the context of the current literature indicates that several chemicals are strongly linked to lung cancer.
PMCID: PMC4457841  PMID: 26047514
20.  Phenotypic and Genotypic Analysis of Clostridium difficile Isolates: a Single-Center Study 
Journal of Clinical Microbiology  2014;52(12):4260-4266.
Clostridium difficile infections (CDI) are a growing concern in North America, because of their increasing incidence and severity. Using integrated approaches, we correlated pathogen genotypes and host clinical characteristics for 46 C. difficile infections in a tertiary care medical center during a 6-month interval from January to June 2010. Multilocus sequence typing (MLST) demonstrated 21 known and 2 novel sequence types (STs), suggesting that the institution's C. difficile strains are genetically diverse. ST-1 (which corresponds to pulsed-field gel electrophoresis strain type NAP1/ribotype 027) was the most prevalent (32.6%); 43.5% of the isolates were binary toxin gene positive, of which 75% were ST-1. All strains were ciprofloxacin resistant and metronidazole susceptible, and 8.3% and 13.0% of the isolates were resistant to clindamycin and tetracycline, respectively. The corresponding resistance loci, including potential novel mutations, were identified from the whole-genome sequencing (WGS) of the resistant strains. Core genome single nucleotide polymorphisms (SNPs) determining the phylogenetic relatedness of the 46 strains recapitulated MLST types and provided greater interstrain differentiation. The disease severity was greatest in patients infected with ST-1 and/or binary gene-positive strains, but genome-wide SNP analysis failed to provide additional associations with CDI severity within the same STs. We conclude that MLST and core genome SNP typing result in the same phylogenetic grouping of the 46 C. difficile strains collected in a single hospital. WGS also has the capacity to differentiate those strains within STs and allows the comparison of strains at the individual gene level and at the whole-genome level.
PMCID: PMC4313296  PMID: 25275005
21.  Post-transcriptional Regulation of Keratinocyte Progenitor Cell Expansion, Differentiation and Hair Follicle Regression by miR-22 
PLoS Genetics  2015;11(5):e1005253.
Hair follicles (HF) undergo precisely regulated recurrent cycles of growth, cessation, and rest. The transitions from anagen (growth), to catagen (regression), to telogen (rest) involve a physiological involution of the HF. This process is likely coordinated by a variety of mechanisms including apoptosis and loss of growth factor signaling. However, the precise molecular mechanisms underlying follicle involution after hair keratinocyte differentiation and hair shaft assembly remain poorly understood. Here we demonstrate that a highly conserved microRNA, miR-22 is markedly upregulated during catagen and peaks in telogen. Using gain- and loss-of-function approaches in vivo, we find that miR-22 overexpression leads to hair loss by promoting anagen-to-catagen transition of the HF, and that deletion of miR-22 delays entry to catagen and accelerates the transition from telogen to anagen. Ectopic activation of miR-22 results in hair loss due to the repression a hair keratinocyte differentiation program and keratinocyte progenitor expansion, as well as promotion of apoptosis. At the molecular level, we demonstrate that miR-22 directly represses numerous transcription factors upstream of phenotypic keratin genes, including Dlx3, Foxn1, and Hoxc13. We conclude that miR-22 is a critical post-transcriptional regulator of the hair cycle and may represent a novel target for therapeutic modulation of hair growth.
Author Summary
Up to 60% people suffer from hair loss throughout their lifetime. Hair growth undergoes recurrent cycling of growth, regression, and resting phases with a defined periodicity. The main cause of human hair loss is due to the premature transition from growth to regression. Understanding of the molecular basis underlying hair regression is important to elucidate the mechanisms of hair loss. Here, we demonstrated that miR-22, a highly conserved microRNA, is critical for the transition from growth to regression of the hair follicle. Importantly, miR-22 could be a novel target for therapeutic therapy of hair loss disorders.
PMCID: PMC4447420  PMID: 26020521
22.  Oligonucleotide Probes for ND-FISH Analysis to Identify Rye and Wheat Chromosomes 
Scientific Reports  2015;5:10552.
Genomic in situ hybridization (GISH) has been widely used to detect rye (Secale cereale L.) chromosomes in wheat (Triticum aestivum L.) introgression lines. The routine procedure of GISH using genomic DNA of rye as a probe is time-consuming and labor-intensive because of the preparation and labeling of genomic DNA of rye and denaturing of chromosomes and probes. In this study, new oligonucleotide probes Oligo-1162, Oligo-pSc200 and Oligo-pSc250 were developed. The three new probes can be used for non-denaturing fluorescence in situ hybridization (ND-FISH) assays and replace genomic DNA of rye as a probe to discriminate rye chromosomes in wheat backgrounds. In addition, previously developed oligonucleotide probes Oligo-pSc119.2-1, Oligo-pSc119.2-2, Oligo-pTa535-1, Oligo-pTa535-2, Oligo-pTa71-2, Oligo-pAWRC.1 and Oligo-CCS1 can also be used for ND-FISH of wheat and rye. These probes have provided an easier, faster and more cost-effective method for the FISH analysis of wheat and hybrids derived from wheat × rye.
PMCID: PMC4440213  PMID: 25994088
23.  Fabrication of 200 nm Period Hard X-ray Phase Gratings 
Nano Letters  2014;14(6):3453-3458.
Far field X-ray grating interferometry achieves extraordinary phase sensitivity in imaging weakly absorbing samples, provided that the grating period is within the transverse coherence length of the X-ray source. Here we describe a cost-efficient process to fabricate large area, 100 nm half-pitch hard X-ray phase gratings with an aspect ratio of 32. The nanometric gratings are suitable for ordinary compact X-ray sources having low spatial coherence, as demonstrated by X-ray diffraction experiments.
PMCID: PMC4055044  PMID: 24845537
X-ray grating far-field interferometer; X-ray phase contrast imaging; nanoimprint lithography; cryogenic reactive ion etch; atomic layer deposition; electroplating
24.  Tumor Grafting Induces Changes of Gut Microbiota in Athymic Nude Mice in the Presence and Absence of Medicinal Gynostemma Saponins 
PLoS ONE  2015;10(5):e0126807.
Recent findings have revealed that gut microbiota plays a substantial role in modulating diseases such as autism, rheumatoid arthritis, allergies, and cancer that occur at sites distant to the gut. Athymic nude mice have been employed for tumorigenic research for decades; however, the relationships between the gut microbiome and host’s response in drug treatment to the grafted tumors have not been explored. In this study, we analyzed the fecal microbiome of nonxenograft and xenograft nude mice treated with phytosaponins from a popular medicinal plant, Gynostemma pentaphyllum (Gp). Analysis of enterobacterial repetitive intergenic consensus (ERIC)-PCR data showed that the microbiota profile of xenograft mice departed from that of the nonxenograft mice. After ten days of treatment with Gp saponins (GpS), the microbiota of the treated mice was closer to the microbiota at Day 0 before the implantation of the tumor. Data obtained from 16S pyrosequencing of fecal samples reiterates the differences in microbiome between the nonxenograft and xenograft mice. GpS markedly increased the relative abundance of Clostridium cocleatum and Bacteroides acidifaciens, for which the beneficial effects on the host have been well documented. This study, for the first time, characterizes the properties of gut microbiome in nude mice responding to tumor implant and drug treatment. We also demonstrate that dietary saponins such as GpS can potentially regulate the gut microbial ecosystem by increasing the number of symbionts. Interestingly, this regulation of the gut ecosystem might, at least in part, be responsible for or contribute to the anticancer effect of GpS.
PMCID: PMC4439139  PMID: 25992551
25.  Identification of a transporter Slr0982 involved in ethanol tolerance in cyanobacterium Synechocystis sp. PCC 6803 
Cyanobacteria have been engineered to produce ethanol through recent synthetic biology efforts. However, one major challenge to the cyanobacterial systems for high-efficiency ethanol production is their low tolerance to the ethanol toxicity. With a major goal to identify novel transporters involved in ethanol tolerance, we constructed gene knockout mutants for 58 transporter-encoding genes of Synechocystis sp. PCC 6803 and screened their tolerance change under ethanol stress. The efforts allowed discovery of a mutant of slr0982 gene encoding an ATP-binding cassette transporter which grew poorly in BG11 medium supplemented with 1.5% (v/v) ethanol when compared with the wild type, and the growth loss could be recovered by complementing slr0982 in the Δslr0982 mutant, suggesting that slr0982 is involved in ethanol tolerance in Synechocystis. To decipher the tolerance mechanism involved, a comparative metabolomic and network-based analysis of the wild type and the ethanol-sensitive Δslr0982 mutant was performed. The analysis allowed the identification of four metabolic modules related to slr0982 deletion in the Δslr0982 mutant, among which metabolites like sucrose and L-pyroglutamic acid which might be involved in ethanol tolerance, were found important for slr0982 deletion in the Δslr0982 mutant. This study reports on the first transporter related to ethanol tolerance in Synechocystis, which could be a useful target for further tolerance engineering. In addition, metabolomic and network analysis provides important findings for better understanding of the tolerance mechanism to ethanol stress in Synechocystis.
PMCID: PMC4440267  PMID: 26052317
ethanol; tolerance; transporter; metabolomics; Synechocystis

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