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1.  IL-6 mediates differentiation disorder during spermatogenesis in obesity-associated inflammation by affecting the expression of Zfp637 through the SOCS3/STAT3 pathway 
Scientific Reports  2016;6:28012.
Zfp637 is a recently identified zinc finger protein, and its functions remain largely unknown. Here, we innovatively demonstrate the effects of Zfp637 on the differentiation of mouse spermatogonia and on its downstream target gene SOX2 in vitro. Obesity has been recognized as a chronic inflammatory disease that leads to decreased sexual function and sexual development disorders. We observed higher levels of IL-6 in serum and testis homogenates from obese mice compared with control mice. We also demonstrated that high levels of IL-6 inhibited Zfp637 expression, and we elucidated the underlying mechanisms. SOCS3 overexpression and STAT3 phosphorylation inhibitor (AG490) were used to investigate the function of the SOCS3/STAT3 pathway during this process. Our results showed that exposure of mouse spermatogonial cells to high levels of IL-6 inhibited Zfp637 expression by increasing SOCS3 expression and inhibiting the phosphorylation of STAT3, further reducing cellular differentiation. Consistent with the in vitro results, we observed increasing expression levels of SOCS3 and SOX2, but a reduction of Zfp637 expression, in obese mouse testes. In conclusion, Zfp637 plays a crucial role in spermatogenesis by downregulating SOX2 expression, and IL-6 can decrease the expression of Zfp637 through the SOCS3/STAT3 signaling pathway.
doi:10.1038/srep28012
PMCID: PMC4916425  PMID: 27329259
2.  Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells 
Molecular pharmaceutics  2016;13(6):2010-2025.
Glutathione transferases (GSTs) are often overexpressed in tumors and frequently correlated to bad prognosis and resistance against a number of different anticancer drugs. To selectively target these cells and to overcome this resistance we previously have developed prodrugs that are derivatives of existing anticancer drugs (e.g., doxorubicin) incorporating a sulfonamide moiety. When cleaved by GSTs, the prodrug releases the cytostatic moiety predominantly in GST overexpressing cells, thus sparing normal cells with moderate enzyme levels. By modifying the sulfonamide it is possible to control the rate of drug release and specifically target different GSTs. Here we show that the newly synthesized compounds, 4-acetyl-2-nitro-benzenesulfonyl etoposide (ANS–etoposide) and 4-acetyl-2-nitro-benzenesulfonyl doxorubicin (ANS–DOX), function as prodrugs for GSTA1 and MGST1 overexpressing cell lines. ANS–DOX, in particular, showed a desirable cytotoxic profile by inducing toxicity and DNA damage in a GST-dependent manner compared to control cells. Its moderate conversion of 500 nmol/min/mg, as catalyzed by GSTA1, seems hereby essential since the more reactive 2,4-dinitrobenzenesulfonyl doxorubicin (DNS–DOX) (14000 nmol/min/mg) did not display a preference for GSTA1 overexpressing cells. DNS–DOX, however, effectively killed GSTP1 (20 nmol/min/mg) and MGST1 (450 nmol/min/mg) overexpressing cells as did the less reactive 4-mononitrobenzenesulfonyl doxorubicin (MNS–DOX) in a MGST1-dependent manner (1.5 nmol/min/mg) as shown previously. Furthermore, we show that the mechanism of these prodrugs involves a reduction in GSH levels as well as inhibition of the redox regulatory enzyme thioredoxin reductase 1 (TrxR1) by virtue of their electrophilic sulfonamide moiety. TrxR1 is upregulated in many tumors and associated with resistance to chemotherapy and poor patient prognosis. Additionally, the prodrugs potentially acted as a general shuttle system for DOX, by overcoming resistance mechanisms in cells. Here we propose that GST-dependent prodrugs require a conversion rate “window” in order to selectively target GST overexpressing cells, while limiting their effects on normal cells. Prodrugs are furthermore a suitable system to specifically target GSTs and to overcome various drug resistance mechanisms that apply to the parental drug.
Graphical abstract
doi:10.1021/acs.molpharmaceut.6b00140
PMCID: PMC5241094  PMID: 27093577
glutathione transferases; prodrugs; MGST1; GSTA1; doxorubicin; etoposide; redox; TrxR1
3.  Changes in event-related potentials in patients with first-episode schizophrenia and their siblings 
BMC Psychiatry  2017;17:20.
Background
This study aimed to explore the characteristics of event-related potentials induced by facial emotion recognition in patients with first-episode schizophrenia and in their siblings.
Methods
In this case-control study, 30 first-episode schizophrenia patients, 26 siblings, and 30 healthy controls were enrolled. They completed facial emotion recognition tasks from the Ekman Standard Faces Database as an induction for evoked potentials. Evoked potential data were obtained using a 64-channel electroencephalography system. Average evoked potential waveforms were computed from epochs for each stimulus type. The amplitudes and latency of the event-related potentials for P100 (positive potential 100 ms after stimulus onset), N170 (negative potential 170 ms after stimulus onset), and N250 (fronto-central peak) were investigated at O1, O2, P7, and P8 electrode locations.
Results
There were significant differences between the groups for P100 amplitude (F = 11.526, P < 0.001), electrode position (F = 450.592, P < 0.001), emotion (disgust vs. happiness vs. fear) (F = 1722.467, P < 0.001), and emotion intensity (low vs. moderate vs. high) (F = 1737.169, P < 0.001). Post hoc analysis showed significantly larger amplitudes in the schizophrenia group at the O1, O2, P7, and P8 electrode positions. There were no significant differences between the siblings of schizophrenia patients and the healthy controls.
Conclusions
Patients with schizophrenia showed abnormalities in P100 amplitude, but similar results were not observed in their siblings. These results provide evidence of dysfunctional event-related potential patterns underlying facial emotion processing in patients with schizophrenia. P100 may be a characteristic index of schizophrenia.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-016-1189-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-016-1189-7
PMCID: PMC5240372  PMID: 28095817
First-episode schizophrenia; Event-related potential; Genetic high-risk population
4.  HNRNPA2B1 regulates the epithelial–mesenchymal transition in pancreatic cancer cells through the ERK/snail signalling pathway 
Background
Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) is closely related to tumour occurrence and development, oncogene expression, apoptosis inhibition and invasion and metastasis capacities. However, its function in the epithelial–mesenchymal transition (EMT) of pancreatic cancer is not fully understood.
Methods
By comparing various wild-type pancreatic cancer cell lines, we determined which have a higher expression level of HNRNPA2B1 accompanied by the higher expression of N-cadherin and vimentin and lower expression of E-cadherin. Therefore, to elucidate the role of HNRNPA2B1 in EMT, we generated models of HNRNPA2B1 knockdown and overexpression in different types of pancreatic cancer cell lines (MIA Paca-2, PANC-1 and Patu-8988) and examined changes in expression of EMT-related factors, including CDH1, CDH2, vimentin and snail.
Results
The results show that HNRNPA2B1 promotes EMT development by down-regulating E-cadherin and up-regulating N-cadherin and vimentin, and also stimulates the invasion capacity and inhibits viability in human pancreatic cancer cell lines, the similar results in vivo experiments. Moreover, we found that HNRNPA2B1 likely regulates EMT progression in pancreatic carcinoma via the ERK/snail signalling pathway.
Conclusions
The results of this work suggest that HNRNPA2B1 inhibition has potential antitumour effects, which warrants in-depth investigation.
doi:10.1186/s12935-016-0368-4
PMCID: PMC5223355  PMID: 28077929
Epithelial–mesenchymal transition; HNRNPA2B1; ERK/snail; Pancreatic cancer
5.  Hyperbolic Space Sparse Coding with Its Application on Prediction of Alzheimer’s Disease in Mild Cognitive Impairment 
Mild Cognitive Impairment (MCI) is a transitional stage between normal age-related cognitive decline and Alzheimer’s disease (AD). Here we introduce a hyperbolic space sparse coding method to predict impending decline of MCI patients to dementia using surface measures of ventricular enlargement. First, we compute diffeomorphic mappings between ventricular surfaces using a canonical hyperbolic parameter space with consistent boundary conditions and surface tensor-based morphometry is computed to measure local surface deformations. Second, ring-shaped patches of TBM features are selected according to the geometric structure of the hyperbolic parameter space to initialize a dictionary. Sparse coding is then applied on the patch features to learn sparse codes and update the dictionary. Finally, we adopt max-pooling to reduce the feature dimensions and apply Adaboost to predict AD in MCI patients (N = 133) from the Alzheimer’s Disease Neuroimaging Initiative baseline dataset. Our work achieved an accuracy rate of 96.7% and outperformed some other morphometry measures. The hyperbolic space sparse coding method may offer a more sensitive tool to study AD and its early symptom.
doi:10.1007/978-3-319-46720-7_38
PMCID: PMC5217478  PMID: 28066843
Mild Cognitive Impairment; Hyperbolic Parameter Space; Ring-shaped Patches; Sparse Coding and Dictionary Learning
6.  Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype 
Scientific Reports  2017;7:39011.
Glioblastoma is an aggressive tumor that is associated with distinctive infiltrating microglia/macrophages populations. Previous studies demonstrated that chlorogenic acid (5-caffeoylquinic acid, CHA), a phenolic compound with low molecular weight, has an anti-tumor effect in multiple malignant tumors. In the present study, we focused on the macrophage polarization to investigate the molecular mechanisms behind the anti-glioma response of CHA in vitro and in vivo. We found that CHA treatment increased the expression of M1 markers induced by LPS/IFNγ, including iNOS, MHC II (I-A/I-E subregions) and CD11c, and reduced the expression of M2 markers Arg and CD206 induced by IL-4, resulting in promoting the production of apoptotic-like cancer cells and inhibiting the growth of tumor cells by co-culture experiments. The activations of STAT1 and STAT6, which are two crucial signaling events in M1 and M2-polarization, were significantly promoted and suppressed by CHA in macrophages, respectively. Furthermore, In G422 xenograft mice, CHA increased the proportion of CD11c-positive M1 macrophages and decreased the distribution of CD206-positive M2 macrophages in tumor tissue, consistent with the reduction of tumor weight observed in CHA-treated mice. Overall these findings indicated CHA as a potential therapeutic approach to reduce glioma growth through promoting M1-polarized macrophage and inhibiting M2 phenotypic macrophage.
doi:10.1038/srep39011
PMCID: PMC5206721  PMID: 28045028
7.  Dose-rate plays a significant role in synchrotron radiation X-ray-induced damage of rodent testes 
Synchrotron radiation (SR) X-ray has significant potential for applications in medical imaging and cancer treatment. However, the mechanisms underlying SR X-ray-induced tissue damage remain unclear. Previous studies on regular X-ray-induced tissue damage have suggested that dose-rate could affect radiation damage. Because SR X-ray has exceedingly high dose-rate compared to regular X-ray, it remains to be determined if dose-rate may affect SR X-ray-induced tissue damage. We used rodent testes as a model to investigate the role of dose-rate in SR X-ray-induced tissue damage. One day after SR X-ray irradiation, we determined the effects of the irradiation of the same dosage at two different dose-rates, 0.11 Gy/s and 1.1 Gy/s, on TUNEL signals, caspase-3 activation and DNA double-strand breaks (DSBs) of the testes. Compared to those produced by the irradiation at 0.11 Gy/s, irradiation at 1.1 Gy/s produced higher levels of DSBs, TUNEL signals, and caspase-3 activation in the testes. Our study has provided the first evidence suggesting that dose-rate could be a significant factor in SR X-ray-induced tissue damage, which may establish a valuable base for utilizing this factor to manipulate the tissue damage in SR X-ray-based medical applications.
PMCID: PMC5209442  PMID: 28078052
Synchrotron radiation X-ray; dose-rate; tissue damage; rodent testes
8.  Predictors of elevational biodiversity gradients change from single taxa to the multi-taxa community level 
Nature Communications  2016;7:13736.
The factors determining gradients of biodiversity are a fundamental yet unresolved topic in ecology. While diversity gradients have been analysed for numerous single taxa, progress towards general explanatory models has been hampered by limitations in the phylogenetic coverage of past studies. By parallel sampling of 25 major plant and animal taxa along a 3.7 km elevational gradient on Mt. Kilimanjaro, we quantify cross-taxon consensus in diversity gradients and evaluate predictors of diversity from single taxa to a multi-taxa community level. While single taxa show complex distribution patterns and respond to different environmental factors, scaling up diversity to the community level leads to an unambiguous support for temperature as the main predictor of species richness in both plants and animals. Our findings illuminate the influence of taxonomic coverage for models of diversity gradients and point to the importance of temperature for diversification and species coexistence in plant and animal communities.
Explaining species richness patterns is a key question in ecology. Peters et al. sample diverse plant and animal groups across elevation on Mt. Kilimanjaro to show that, while disparate factors drive distributions of individual taxa, diversity overall decreases with elevation, mostly driven by effects of temperature.
doi:10.1038/ncomms13736
PMCID: PMC5192166  PMID: 28004657
9.  High expression of GFAT1 predicts poor prognosis in patients with pancreatic cancer 
Scientific Reports  2016;6:39044.
Pancreatic cancer is one of the most lethal of all types of cancer, with the 5-year survival rate ranging only at 6–7%. The aberrant glucose metabolism is one of the hallmarks of cancer cells, and as a branch of glucose metabolism, hexosamine biosynthesis pathway (HBP) has been reported to play a critical role in the insulin resistance and progression of cancer. Glutamine:fructose-6-phosphate amidotransferase (GFAT1) is the rate-limiting enzyme of the HBP; nevertheless, the prognostic value of GFAT1 in pancreatic cancer remains elusive. In this study, we found that the expression of GFAT1 was increased in pancreatic cancer samples compared to peri-tumor tissues. High expression of GFAT1 was positively associated with lymph node metastasis, pTNM stage and shorter overall survival (OS) in pancreatic cancer patients. GFAT1 was identified as an independent prognosticator for OS, and combining GFAT1 expression with pTNM stage generated a predictive nomogram, which showed better prognostic efficiency for OS in patients with pancreatic cancer. In summary, high GFAT1 expression is identified as an independent predictor of adverse clinical outcome in our small number of pancreatic cancer patients, and the practical prognostic nomogram model may help clinicians in decision making and the design of clinical studies.
doi:10.1038/srep39044
PMCID: PMC5172351  PMID: 27996048
10.  Effects of retinoic acid receptor-γ on the Aspergillus fumigatus induced innate immunity response in human corneal epithelial cells 
AIM
To explore the effects of retinoic acid receptor-γ (RARγ) on innate immune responses against Aspergillus fumigatus (A. fumigatus) in cultured human corneal epithelial cells (HCECs).
METHODS
The HCECs were stimulated with A. fumigatus hyphae for 0, 2, 4, 8, 12 and 16h. RARγ mRNA and protein levels were tested by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Then HCECs were pretreated with or without BMS961 (RARγ agonist, 1 µg/mL). The mRNA and protein expression of Dectin-1 and the downstream cytokines (TNF-α and IL-6) were determined by qRT-PCR, Western blot and enzyme-linked immunosorbent assay (ELISA).
RESULTS
The expression of RARγ was upregulated after stimulation with A. fumigatus. RARγ mRNA began to rise at 4h and peaked at 8h (P<0.001). The protein of RARγ reached to the peak at 16h (P<0.001). Pretreated with BMS961 before A. fumigatus hyphae stimulation, expression of Dectin-1, TNF-α and IL-6 decreased dramatically at mRNA and protein levels.
CONCLUSION
HCECs can express RARγ and A. fumigatus hyphae infection can increase RARγ expression. BMS961 can inhibit the expression of Dectin-1 and pro-inflammatory cytokines, and play an anti-inflammatory role in innate immune responses against A. fumigatus.
doi:10.18240/ijo.2016.12.02
PMCID: PMC5154981  PMID: 28003968
retinoic acid receptor-γ; innate immunity; Aspergillus fumigatus; corneal epithelium
11.  Host Cellular Protein TRAPPC6AΔ Interacts with Influenza A Virus M2 Protein and Regulates Viral Propagation by Modulating M2 Trafficking 
Journal of Virology  2016;91(1):e01757-16.
ABSTRACT
Influenza A virus (IAV) matrix protein 2 (M2) plays multiple roles in the early and late phases of viral infection. Once synthesized, M2 is translocated to the endoplasmic reticulum (ER), travels to the Golgi apparatus, and is sorted at the trans-Golgi network (TGN) for transport to the apical plasma membrane, where it functions in virus budding. We hypothesized that M2 trafficking along with its secretory pathway must be finely regulated, and host factors could be involved in this process. However, no studies examining the role of host factors in M2 posttranslational transport have been reported. Here, we used a yeast two-hybrid (Y2H) system to screen for host proteins that interact with the M2 protein and identified transport protein particle complex 6A (TRAPPC6A) as a potential binding partner. We found that both TRAPPC6A and its N-terminal internal-deletion isoform, TRAPPC6A delta (TRAPPC6AΔ), interact with M2. Truncation and mutation analyses showed that the highly conserved leucine residue at position 96 of M2 is critical for mediating this interaction. The role of TRAPPC6AΔ in the viral life cycle was investigated by the knockdown of endogenous TRAPPC6AΔ with small interfering RNA (siRNA) and by generating a recombinant virus that was unable to interact with TRAPPC6A/TRAPPC6AΔ. The results indicated that TRAPPC6AΔ, through its interaction with M2, slows M2 trafficking to the apical plasma membrane, favors viral replication in vitro, and positively modulates virus virulence in mice.
IMPORTANCE The influenza A virus M2 protein regulates the trafficking of not only other proteins but also itself along the secretory pathway. However, the host factors involved in the regulation of the posttranslational transport of M2 are largely unknown. In this study, we identified TRAPPC6A and its N-terminal internal-deletion isoform, TRAPPC6AΔ, as interacting partners of M2. We found that the leucine (L) residue at position 96 of M2 is critical for mediating this interaction, which leads us to propose that the high level of conservation of 96L is a consequence of M2 adaptation to its interacting host factor TRAPPC6A/TRAPPC6AΔ. Importantly, we discovered that TRAPPC6AΔ can positively regulate viral replication in vitro by modulating M2 trafficking to the plasma membrane.
doi:10.1128/JVI.01757-16
PMCID: PMC5165196  PMID: 27795429
influenza A virus; M2; TRAPPC6AΔ; transport
12.  Use of Redundant Exclusion PCR To Identify a Novel Bacillus thuringiensis Cry8 Toxin Gene from Pooled Genomic DNA 
Applied and Environmental Microbiology  2016;82(13):3808-3815.
ABSTRACT
With the aim of optimizing the cloning of novel genes from a genomic pool containing many previously identified homologous genes, we designed a redundant exclusion PCR (RE-PCR) technique. In RE-PCR, a pair of generic amplification primers are combined with additional primers that are designed to specifically bind to redundant, unwanted genes that are a subset of those copied by the amplification primers. During RE-PCR, the specific primer blocks amplification of the full-length redundant gene. Using this method, we managed to clone a number of cry8 or cry9 toxin genes from a pool of Bacillus thuringiensis genomic DNA while excluding amplicons for cry9Da, cry9Ea, and cry9Eb. The method proved to be very efficient at increasing the number of rare genes in the resulting library. One such rare (and novel) cry8-like gene was expressed, and the encoded toxin was shown to be toxic to Anomala corpulenta.
IMPORTANCE Protein toxins from the bacterium Bacillus thuringiensis are being increasingly used as biopesticides against a wide range of insect pests, yet the search for new or improved toxins is becoming more difficult, as traditional methods for gene discovery routinely isolate previously identified clones. This paper describes an approach that we have developed to increase the success rate for novel toxin gene identification through reducing or eliminating the cloning of previously characterized genes.
doi:10.1128/AEM.00862-16
PMCID: PMC4907210  PMID: 27084017
13.  Potassium Aspartate Attenuates Brain Injury Induced by Controlled Cortical Impact in Rats Through Increasing Adenosine Triphosphate (ATP) Levels, Na+/K+-ATPase Activity and Reducing Brain Edema 
Background
Potassium aspartate (PA), as an electrolyte supplement, is widely used in clinical practice. In our previous study, we found PA had neuroprotective effects against apoptosis after cerebral ischemia/reperfusion in rats. In this study, we examine whether PA has protective effects on traumatic brain injury (TBI).
Material/Methods
TBI was induced by controlled cortical impact (CCI) in rats. Vehicle treatment (control) or PA treatment was administered intraperitoneally at 30 minutes after CCI. The modified neurological severity score (mNSS) and cortical lesion volume were examined. Brain edema and blood-brain barrier (BBB) integrity were measured, as well as brain ATP contents, lactic acid levels, and Na+/K+-ATPase activities.
Results
We found that CCI induced cortical injury in rats. Acute PA treatment at the dose of 62.5 mg/kg and 125 mg/kg significantly improved neurological deficits (p<0.05 and p<0.001, respectively) and decreased the cortical lesion volume (p<0.05 and p<0.001, respectively) compared with vehicle-only treatment. PA treatment at the dose of 125 mg/kg attenuated brain edema and ameliorated BBB integrity. In addition, PA treatment significantly reduced the loss of ATP (p<0.01), reduced lactic acid levels (p<0.001), and increased the activity of Na+/K+-ATPase (p<0.01).
Conclusions
Our results indicate PA has neuroprotective effects on TBI through increasing ATP levels, Na+/K+-ATPase activity, and reducing brain edema. It provides experimental evidence for the clinical application of PA.
doi:10.12659/MSM.898185
PMCID: PMC5175720  PMID: 27959885
Aspartic Acid; Brain Injuries; Myosins
14.  The Effect of Iron Fortification on Iron (Fe) Status and Inflammation: A Randomized Controlled Trial 
PLoS ONE  2016;11(12):e0167458.
Background
Iron deficiency (ID) is common in toddlers in developing countries. Iron fortified or meat-based complementary foods may be effective to prevent ID.
Objective
Our objective was to compare iron status at 18 months and growth from 6 to 18 months in rural poor toddlers fed 3 different complementary foods.
Methods
The study was nested within a larger trial in which 6-month-old infants were randomized to receive 50g/d meat (MG), an equi-caloric fortified cereal supplement (FG) or local cereal supplement (LG) for 1 year. Hb, sTfR, HsCRP, ferritin and AGP were measured in 410 blood samples collected by a random sampling (MG, 137; FG, 140; LG, 133); calprotectin was measured in feces. Body iron = -[log (sTfR ×1000/ferritin)-2.8229] /0.1207. ID = ferritin<12ug/L.
Results
The toddlers in FG had the significantly highest levels in serum ferritin and body iron (P = 0.043, 0.004), and the rates of both ID and iron deficiency anemia (IDA) were the lowest in FG (P = 0.010, 0.021). The rate of systemic inflammation in FG was 30.71%, which was the highest among three groups (P = 0.042). No intervention effects on either the rates of ID and IDA or iron stores (serum ferritin and body iron) were shown in MG. The change in length-for-age z scores (LAZ) from 6 to 18 months among three groups was significantly different (P = 0.021) and a smaller decrease of LAZ in MG and a larger decrease of LAZ in FG were observed.
Conclusion
Iron fortified cereal improved iron status of poor rural toddlers but was also associated with systemic inflammation which was likely to impair their growth.
doi:10.1371/journal.pone.0167458
PMCID: PMC5140064  PMID: 27923057
15.  Lobular capillary hemangioma of the tracheobronchial tree 
Medicine  2016;95(48):e5499.
Abstract
Rationale:
Lobular capillary hemangioma (LCH) of the tracheobronchial tree is a rare benign tumor, whose characteristics and treatments remain relatively unknown.
Patient concerns:
A 39-year-old man with hemoptysis caused by neoplasm in the bronchus intermedius was admitted to our hospital.
Diagnoses:
The patient was diagnosed with LCH.
Interventions:
The lesions were removed with biopsy forceps, and cryotherapy was performed.
Outcomes:
After follow up for more than 2 years, no recurrence was found.
Lessons:
Airway LCH can be treated by excisional biopsy, cryotherapy, APC, laser, radiotherapy, and surgery. Cryotherapy is worthy of recommendation.
doi:10.1097/MD.0000000000005499
PMCID: PMC5134768  PMID: 27902613
bronchoscopy; case report; cryotherapy; hemoptysis; lobular capillary hemangioma
16.  Infusion with Human Bone Marrow-derived Mesenchymal Stem Cells Improves β-cell Function in Patients and Non-obese Mice with Severe Diabetes 
Scientific Reports  2016;6:37894.
Mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for type 1 diabetes (T1D). However, little is known on whether MSC transplantation can benefit T1D patients with ketoacidosis and its potential actions. Here, we show that infusion with bone marrow MSCs preserves β-cell function in some T1D patients with ketoacidosis by decreasing exogenous insulin requirement and increasing plasma C-peptide levels up to 1–2 years. MSC transplantation increased plasma and islet insulin contents in non-obese diabetic (NOD) mice with severe diabetes. In comparison with severe diabetes controls, MSC infusion reduced insulitis, decreased pancreatic TNF-α, and increased IL-10 and TGF-β1 expression in NOD mice. MSC infusion increased the percentages of splenic Tregs and levels of plasma IL-4, IL-10 and TGF-β1, but reduced the percentages of splenic CD8+ T and levels of plasma IFN-γ, TNF-α and IL-17A in NOD mice. Finally, infused MSCs predominantly accumulated in pancreatic tissues at 28 days post infusion. The effects of MSCs on preserving β-cell function and modulating inflammation tended to be dose-dependent and multiple doses of MSCs held longer effects in NOD mice. Hence, MSC transplantation preserved β-cell function in T1D patients and NOD mice with severe diabetes by enhancing Treg responses.
doi:10.1038/srep37894
PMCID: PMC5131346  PMID: 27905403
17.  Hot electron induced non-saturation current behavior at high electric field in InAlN/GaN heterostructures with ultrathin barrier 
Scientific Reports  2016;6:37415.
The high-field transport characteristics of nearly lattice-matched InAlN/GaN heterostructures with different barrier thickness were investigated. It is found that the current in the InAlN/GaN heterostructures with ultrathin barrier shows unsaturated behaviors (or secondary rising) at high voltage, which is different from that of AlGaN/GaN heterostructures. This phenomenon is more obvious if the barrier thickness is thinner and the channel width is narrower. The experimental results demonstrate that it is the increasing carrier density excited from the more defect states by the hot electrons with larger electron saturation velocity that results in the unsaturated current behaviors in InAlN/GaN heterostructures. Our results pave a way for further optimizing InAlN barrier design and improving the reliability of InAlN/GaN HEMTs.
doi:10.1038/srep37415
PMCID: PMC5120260  PMID: 27876766
18.  Navigation by anomalous random walks on complex networks 
Scientific Reports  2016;6:37547.
Anomalous random walks having long-range jumps are a critical branch of dynamical processes on networks, which can model a number of search and transport processes. However, traditional measurements based on mean first passage time are not useful as they fail to characterize the cost associated with each jump. Here we introduce a new concept of mean first traverse distance (MFTD) to characterize anomalous random walks that represents the expected traverse distance taken by walkers searching from source node to target node, and we provide a procedure for calculating the MFTD between two nodes. We use Lévy walks on networks as an example, and demonstrate that the proposed approach can unravel the interplay between diffusion dynamics of Lévy walks and the underlying network structure. Moreover, applying our framework to the famous PageRank search, we show how to inform the optimality of the PageRank search. The framework for analyzing anomalous random walks on complex networks offers a useful new paradigm to understand the dynamics of anomalous diffusion processes, and provides a unified scheme to characterize search and transport processes on networks.
doi:10.1038/srep37547
PMCID: PMC5120342  PMID: 27876855
19.  DNA barcoding of Mobulid Ray Gill Rakers for Implementing CITES on Elasmobranch in China 
Scientific Reports  2016;6:37567.
The Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) has been counted on for conserving threatened marine fish since it regulates the commercial international trade of these species. Implementation of the international treaty for Mantas included on CITES Appendix II is challenging due to insufficient information on species identification and markets management. To fill the gap in such aspects, we identified five species of Mobulid rays (Mobula spps. and Manta spp) by using COI and NADH2 mtDNA markers in dried ray gill rakers from Chinese markets, namely, Mobula japonica (representing 54.8% of the sample set), M. tarapacana (14.4%), M. kuhlii (13.3%), M. thurstoni (6.4%), along with Manta birostris (11.2%; CITES Appendix II). The utilization and conservation statuses of these species were discussed. Based on combination of DNA barcodes and key morphological characters, we developed a three-step process for identifying the gill rakers of Mobulid rays which has been adopted by frontline enforcement in China. We hope that our work can serve as a foundation and basis to reinforce objectives of international treaties, regulation of consumer-driven markets, regional cooperation, and national fishery management on endangered elasmobranchs in China as well as related countries.
doi:10.1038/srep37567
PMCID: PMC5120345  PMID: 27876850
20.  Main Effects of Diagnoses, Brain Regions, and their Interaction Effects for Cerebral Metabolites in Bipolar and Unipolar Depressive Disorders 
Scientific Reports  2016;6:37343.
Previous studies suggested patients with bipolar depressive disorder (BDd) or unipolar depressive disorder (UDd) have cerebral metabolites abnormalities. These abnormalities may stem from multiple sub-regions of gray matter in brain regions. Thirteen BDd patients, 20 UDd patients and 20 healthy controls (HC) were enrolled to investigate these abnormalities. Absolute concentrations of 5 cerebral metabolites (glutamate-glutamine (Glx), N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), parietal cortex (PC)) were measured from 4 subregions (the medial frontal cortex (mPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and parietal cortex (PC)) of gray matter. Main and interaction effects of cerebral metabolites across subregions of gray matter were evaluated. For example, the Glx was significantly higher in BDd compared with UDd, and so on. As the interaction analyses showed, some interaction effects existed. The concentrations of BDds’ Glx, Cho, Cr in the ACC and HCs’ mI and Cr in the PC were higher than that of other interaction effects. In addition, the concentrations of BDds’ Glx and Cr in the PC and HCs’ mI in the ACC were statistically significant lower than that of other interaction effects. These findings point to region-related abnormalities of cerebral metabolites across subjects with BDd and UDd.
doi:10.1038/srep37343
PMCID: PMC5116758  PMID: 27869127
21.  Pneumomediastinum Secondary to Foreign Body Aspiration: Clinical Features and Treatment Explorement in 39 Pediatric Patients 
Chinese Medical Journal  2016;129(22):2691-2696.
Background:
Pneumomediastinum (PM) secondary to foreign body aspiration (FBA) is rare in children. Although it is mainly benign, some cases may be fatal. Due to the rare nature of this clinical entity, proper assessment and management have been poorly studied so far. Here, we characterized the presentation and management of this clinical entity and provided an evaluation system for the management.
Methods:
We retrospectively reviewed children with PM secondary to FBA, who were treated in Beijing Children's Hospital from January 2010 to December 2015. All patients were stratified according to the degree of dyspnea on admission, and interventions were given accordingly. Bronchoscopic removals of airway foreign bodies (FBs) were performed on all patients. For patients in acute respiratory distress, emergent air evacuation and/or resuscitations were performed first. Admission data, interventions, and clinical outcomes were recorded.
Results:
A total of 39 patients were included in this study. The clinical severity was divided into three grades (Grades I, II, and III) according to the degree of dyspnea. Thirty-one patients were in Grade I dyspnea, and they simply underwent bronchoscopic FBs removals. PM resolved spontaneously and all patients recovered uneventfully. Six patients were in Grade II dyspnea, and emergent drainage preceded rigid bronchoscopy. They all recovered uneventfully under close observation. Two exhausted patients were in Grade III dyspnea. They died from large PM and bilateral pneumothorax, respectively, despite of aggressive interventions in our hospital.
Conclusions:
PM secondary to FBA could be life-threatening in some patients. The degree of dyspnea should be evaluated immediately, and patients in different dyspnea should be treated accordingly. For patients in Grade I dyspnea, simple bronchoscopic FBs removals could promise a good outcome. For patients in Grade II dyspnea, emergent air evacuation and/or resuscitation should precede a bronchoscopy before the children become exhausted.
doi:10.4103/0366-6999.193450
PMCID: PMC5126160  PMID: 27824001
Children; Foreign Body Aspiration; Pneumomediastinum; Pneumothorax; Subcutaneous Emphysema
22.  Paclitaxel Drug-eluting Tracheal Stent Could Reduce Granulation Tissue Formation in a Canine Model 
Chinese Medical Journal  2016;129(22):2708-2713.
Background:
Currently available silicone and metallic stents for tracheal stenosis are associated with many problems. Granulation proliferation is one of the main complications. The present study aimed to evaluate the efficacy of paclitaxel drug-eluting tracheal stent in reducing granulation tissue formation in a canine model, as well as the pharmacokinetic features and safety profiles of the coated drug.
Methods:
Eight beagles were randomly divided into a control group (bare-metal stent group, n = 4) and an experimental group (paclitaxel-eluting stent group, n = 4). The observation period was 5 months. One beagle in both groups was sacrificed at the end of the 1st and 3rd months, respectively. The last two beagles in both groups were sacrificed at the end of 5th month. The proliferation of granulation tissue and changes in tracheal mucosa were compared between the two groups. Blood routine and liver and kidney function were monitored to evaluate the safety of the paclitaxel-eluting stent. The elution method and high-performance liquid chromatography were used to characterize the rate of in vivo release of paclitaxel from the stent.
Results:
Compared with the control group, the proliferation of granulation tissue in the experimental group was significantly reduced. The drug release of paclitaxel-eluting stent was the fastest in the 1st month after implantation (up to 70.9%). Then, the release slowed down gradually. By the 5th month, the release reached up to 98.5%. During the observation period, a high concentration of the drug in the trachea (in the stented and adjacent unstented areas) and lung tissue was not noted, and the blood test showed no side effect.
Conclusions:
The paclitaxel-eluting stent could safely reduce the granulation tissue formation after stent implantation in vivo, suggesting that the paclitaxel-eluting tracheal stent might be considered for potential use in humans in the future.
doi:10.4103/0366-6999.193461
PMCID: PMC5126163  PMID: 27824004
Canine; Drug-eluting Stent; Paclitaxel; Tracheal Stenosis
23.  Liraglutide Enhances the Efficacy of Human Mesenchymal Stem Cells in Preserving Islet β-cell Function in Severe Non-obese Diabetic Mice 
Molecular Medicine  2016;22:800-808.
Glucagon-like peptide 1 (GLP-1) can promote islet β cell replication and function, and mesenchymal stem cells (MSCs) can inhibit T cell autoimmunity. The aim of this study was to test the dynamic distribution of infused human MSCs and the therapeutic effect of combined MSCs and liraglutide, a long-acting GLP-1 analog, on preserving β cell function in severe nonobese diabetic (NOD) mice. We found that infused MSCs accumulated in the pancreas at 4 wks post infusion, which was not affected by liraglutide treatment. Liraglutide significantly enhanced the function of MSCs to preserve islet β cells by reducing glucose levels 30 min post glucose challenge and increasing the content and secretion of insulin by islet β cells in severely diabetic mice. Infusion with MSCs significantly reduced insulitis scores but increased the frequency of splenic Tregs, accompanied by a reduction in plasma IFN-γ and TNF-α levels and an elevation of plasma IL-10 and transforming growth factor-β1 (TGF-β1) levels in NOD mice. Although liraglutide mitigated MSC-mediated changes in the frequency of Tregs and the level of plasma IL-10, it significantly increased the plasma TGF-β1 levels in severely diabetic mice. Therefore, our findings suggest that liraglutide could enhance the therapeutic efficacy of MSCs in the treatment of severe type 1 diabetes.
doi:10.2119/molmed.2016.00168
PMCID: PMC5193422  PMID: 27878211
24.  A competing-risk-based score for predicting twenty-year risk of incident diabetes: the Beijing Longitudinal Study of Ageing study 
Scientific Reports  2016;6:37248.
Few risk tools have been proposed to quantify the long-term risk of diabetes among middle-aged and elderly individuals in China. The present study aimed to develop a risk tool to estimate the 20-year risk of developing diabetes while incorporating competing risks. A three-stage stratification random-clustering sampling procedure was conducted to ensure the representativeness of the Beijing elderly. We prospectively followed 1857 community residents aged 55 years and above who were free of diabetes at baseline examination. Sub-distribution hazards models were used to adjust for the competing risks of non-diabetes death. The cumulative incidence function of twenty-year diabetes event rates was 11.60% after adjusting for the competing risks of non-diabetes death. Age, body mass index, fasting plasma glucose, health status, and physical activity were selected to form the score. The area under the ROC curve (AUC) was 0.76 (95% Confidence Interval: 0.72–0.80), and the optimism-corrected AUC was 0.78 (95% Confidence Interval: 0.69–0.87) after internal validation by bootstrapping. The calibration plot showed that the actual diabetes risk was similar to the predicted risk. The cut-off value of the risk score was 19 points, marking mark the difference between low-risk and high-risk patients, which exhibited a sensitivity of 0.74 and specificity of 0.65.
doi:10.1038/srep37248
PMCID: PMC5110955  PMID: 27849048
25.  Increased CD4+CD45RA-FoxP3low cells alter the balance between Treg and Th17 cells in colitis mice 
World Journal of Gastroenterology  2016;22(42):9356-9367.
AIM
To investigate the role of regulatory T cell (Treg) subsets in the balance between Treg and T helper 17 (Th17) cells in various tissues from mice with dextran sulfate sodium-induced colitis.
METHODS
Treg cells, Treg cell subsets, Th17 cells, and CD4+CD25+FoxP3+IL-17+ cells from the lamina propria of colon (LPC) and other ulcerative colitis (UC) mouse tissues were evaluated by flow cytometry. Forkhead box protein 3 (FoxP3), interleukin 17A (IL-17A), and RORC mRNA levels were assessed by real-time PCR, while interleukin-10 (IL-10) and IL-17A levels were detected with a Cytometric Beads Array.
RESULTS
In peripheral blood monocytes (PBMC), mesenteric lymph node (MLN), lamina propria of jejunum (LPJ) and LPC from UC mice, Treg cell numbers were increased (P < 0.05), and FoxP3 and IL-10 mRNA levels were decreased. Th17 cell numbers were also increased in PBMC and LPC, as were IL-17A levels in PBMC, LPJ, and serum. The number of FrI subset cells (CD4+CD45RA+FoxP3low) was increased in the spleen, MLN, LPJ, and LPC. FrII subset cells (CD4+CD45RA-FoxP3high) were decreased among PBMC, MLN, LPJ, and LPC, but the number of FrIII cells (CD4+CD45RA-FoxP3low) and CD4+CD25+FoxP3+IL-17A+ cells was increased. FoxP3 mRNA levels in CD4+CD45RA-FoxP3low cells decreased in PBMC, MLN, LPJ, and LPC in UC mice, while IL-17A and RORC mRNA increased. In UC mice the distribution of Treg, Th17 cells, CD4+CD45RA-FoxP3high, and CD4+CD45RA-FoxP3low cells was higher in LPC relative to other tissues.
CONCLUSION
Increased numbers of CD4+CD45RA-FoxP3low cells may cause an imbalance between Treg and Th17 cells that is mainly localized to the LPC rather than secondary lymphoid tissues.
doi:10.3748/wjg.v22.i42.9356
PMCID: PMC5107699  PMID: 27895423
Ulcerative colitis; Regulatory T cells; Treg cells subsets; T helper 17 cells

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