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1.  Cu(II) Catalytic Reduction of Cr(VI) by Tartaric Acid Under the Irradiation of Simulated Solar Light 
Environmental Engineering Science  2014;31(8):447-452.
Abstract
Cu(II) catalytic reduction of Cr(VI) by tartaric acid under the irradiation of simulated solar light was investigated through batch experiments at pHs from 3 to 6 and at temperatures from 15°C to 35°C. Results demonstrated that introduction of Cu(II) could markedly improve reduction of Cr(VI) in comparison with tartaric acid alone. Optimal removal of Cr(VI) was achieved at pH 4. Reduction of Cr(VI) increased with increasing temperatures and initial concentrations of Cu(II) and tartaric acid. The catalytic role of Cu(II) in the reduction of Cr(VI) was ascribed to the formation of Cu(II)-tartaric acid complex, which generated active reductive intermediates, including Cu(I) and tartaric acid radicals through a pathway of metal–ligand–electron transfer with light. Cu(II) photocatalytic reduction of Cr(VI) by tartaric acid followed pseudo zero-order kinetics with regard to Cr(VI), and the activation energy was calculated to be 21.48 kJ/mol. To date, such a role of Cu(II) has not been reported. The results from the present study are helpful in fully understanding the photochemical reductive behavior of Cr(VI) in the presence of both tartaric acid and Cu(II) in soil and aquatic environments.
doi:10.1089/ees.2013.0407
PMCID: PMC4118708  PMID: 25125941
catalytic reduction; Cr(VI); Cu(II); simulated solar light; tartaric acid
2.  Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased β2-Adrenergic Signaling in Hearts 
Diabetes  2014;63(8):2676-2689.
Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.
doi:10.2337/db13-1763
PMCID: PMC4113065  PMID: 24677713
3.  Tumor regression following intravenous administration of lactoferrin- and lactoferricin-bearing dendriplexes 
Nanomedicine  2015;11(6):1445-1454.
The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors. In this study, we investigated if the conjugation of the polypropylenimine dendrimer to lactoferrin and lactoferricin, whose receptors are overexpressed on cancer cells, could result in a selective gene delivery to tumors and a subsequently enhanced therapeutic efficacy. The conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumor while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumors and up to 50% of B16-F10 tumors over one month. The treatment was well tolerated by the animals. These results suggest that these novel lactoferrin- and lactoferricin-bearing dendrimers are promising gene delivery systems for cancer therapy.
From the Clinical Editor
Specific targeting of cancer cells should enhance the delivery of chemotherapeutic agents. This is especially true for gene delivery. In this article, the authors utilized a dendrimer-based system and conjugated this with lactoferrin and lactoferricin to deliver anti-tumor genes. The positive findings in animal studies should provide the basis for further clinical studies.
Graphical abstract
Tumor regression in a mouse A431 xenograft model after intravenous administration of lactoferrin- and lactoferricin-bearing diaminobutyric polypropylenimine (DAB) dendriplex encoding tumor necrosis factor (TNF) α.
doi:10.1016/j.nano.2015.04.006
PMCID: PMC4509555  PMID: 25933695
Cancer therapy; Gene delivery; Dendrimer; Lactoferrin; Lactoferricin
4.  Serum protein gamma-glutamyl hydrolase, Ig gamma-3 chain C region, and haptoglobin are associated with the syndromes of pulmonary tuberculosis in traditional Chinese medicine 
Background
Traditional Chinese Medicine (TCM) has been applied in treating tuberculosis (TB) based on the TCM syndromes with the effects of inhibiting Mycobacterium, strengthening the body immune system, and reducing the pulmonary toxicity. We used bioinformatic methods to study the clinical and pathological characteristics of pulmonary TB patients with TCM syndromes. Isobaric tags for relative and absolute quantification - coupled two dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2DLC-MS/MS) methods were applied to screen differentially expressed serum proteins.
Methods
Pulmonary TB cases were divided into four distinctive TCM syndromes: pulmonary Yin deficiency (PYD) syndrome, hyperactivity of fire due to Yin deficiency (HFYD) syndrome, deficiency of Qi and Yin (DQY) syndrome, and deficiency of Yin and Yang (DYY) syndrome. The serum samples from 214 pulmonary TB patients were collected, and the clinical and pathological data was analyzed by using iTRAQ-2DLC-MS/MS. Finally, the differentially expressed proteins were screened and tested by ELISA. Only 5 patients with DYY syndrome were recruited in 3 years, which were not enough for further research.
Results
The DQY cases had higher erythrocyte sedimentation rate (ESR) compared to the PYD and HFYD cases (P = 0.0178). 94.44 % (12 PYD, 18 HFYD, and 4 DQY before anti-TB treatment) of 36 treated TB cases were transformed to PYD accompanied with the reduction of ESR and absorption of pulmonary lesions. A total of 39 differentially expressed proteins (ratios of >1.3 or <0.75) were found among the three TCM syndromes. Proteomic studies revealed that gamma-glutamyl hydrolase (GGH), Ig gamma-3 chain C region (IGHG3), and haptoglobin (HPT) were specifically over-expressed in PYD (P < 0.01), HFYD (P < 0.001), and DQY cases (P < 0.01), respectively. Furthermore, GGH was significantly higher in PYD cases compared to the HFYD and DQY cases (P < 0.01, P < 0.001, respectively), whereas IGHG3 was significantly higher in HFYD cases than PYD and DQY cases (P < 0.001, P < 0.01, respectively).
Conclusions
The results suggest that TCM syndromes are significantly correlated with the pulmonary lesions and ESR. GGH was associated with folate metabolism in PYD cases, IGHG3 was linked to the control of Mycobacterium infection in HFYD patients, and HPT was involved in hypoxia in DQY patients. The present study provides new biological basis to understand the pathological changes and proteomic differences of TB syndromes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12906-015-0686-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12906-015-0686-4
PMCID: PMC4509701  PMID: 26198726
Traditional Chinese Medicine Syndrome; Pathology; Erythrocyte sedimentation rate; Serum protein; Tuberculosis
5.  Correction: Comparison of Current Diagnostic Criteria for Acute-On-Chronic Liver Failure 
PLoS ONE  2015;10(7):e0133817.
doi:10.1371/journal.pone.0133817
PMCID: PMC4508032  PMID: 26193100
6.  Hand-Held and Integrated Single-Cell Pipettes 
Journal of the American Chemical Society  2014;136(31):10858-10861.
Successful single-cell isolation is a primary step for subsequent chemical and biological analyses of single cells. Conventional single-cell isolation methods often encounter operational complexity, limited efficiency, deterioration of cell viability, incompetence in the isolation of a single-cell into nanoliter liquid, and/or inability to select single adherent cells with specific phenotypes. Here, we develop a hand-held single-cell pipet (hSCP) that is rapid, operationally simple, highly efficient, and inexpensive for unbiased isolation of single viable suspended cells directly from submicroliter cell suspensions into nanoliter droplets without the assistance of any additional equipment. An integrated SCP (iSCP) has also been developed for selective isolation of single suspended and adherent cells according to the fluorescence imaging and morphological features. The isolated single cells can be conveniently transferred into standard 96-/384-well plates, Petri dishes, or vials for cloning, PCR, and other single-cell biochemical assays.
doi:10.1021/ja5053279
PMCID: PMC4133013  PMID: 25036187
7.  Mechanistic insights into metal ion activation and operator recognition by the ferric uptake regulator 
Nature Communications  2015;6:7642.
Ferric uptake regulator (Fur) plays a key role in the iron homeostasis of prokaryotes, such as bacterial pathogens, but the molecular mechanisms and structural basis of Fur–DNA binding remain incompletely understood. Here, we report high-resolution structures of Magnetospirillum gryphiswaldense MSR-1 Fur in four different states: apo-Fur, holo-Fur, the Fur–feoAB1 operator complex and the Fur–Pseudomonas aeruginosa Fur box complex. Apo-Fur is a transition metal ion-independent dimer whose binding induces profound conformational changes and confers DNA-binding ability. Structural characterization, mutagenesis, biochemistry and in vivo data reveal that Fur recognizes DNA by using a combination of base readout through direct contacts in the major groove and shape readout through recognition of the minor-groove electrostatic potential by lysine. The resulting conformational plasticity enables Fur binding to diverse substrates. Our results provide insights into metal ion activation and substrate recognition by Fur that suggest pathways to engineer magnetotactic bacteria and antipathogenic drugs.
The regulation of iron levels is an important physiological process as excess cellular iron is highly toxic. Here the authors present several structures of a bacterial ferric uptake regulator (Fur) in complex with the Fe2+ transport protein operator and Fur box, shedding light on how iron promotes DNA recognition by Fur.
doi:10.1038/ncomms8642
PMCID: PMC4506495  PMID: 26134419
8.  NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans 
Cardiovascular Research  2014;103(2):228-237.
Aims
Cardiac structural genes have been implicated as causative factors for congenital heart diseases (CHDs). NEXN is an F-actin binding protein and previously identified as a disease gene causing cardiomyopathies. Whether NEXN contributes to CHDs aetiologically remains unknown. Here, we explored the function of NEXN in cardiac development.
Methods and results
First, we determine the role of NEXN in cardiac differentiation using mouse P19cl6 in vitro model; we demonstrated that NEXN inhibited cardiac contractile markers, serving as a negative regulator. Interestingly, we found this effect was mediated by GATA4, a crucial transcription factor that controls cardiac development by knockdown, overexpression, and rescue experiment, respectively. We then generated transgenic mouse models and surprisingly, we discovered cardiac-selective expression of the NEXN gene caused atrial septal defects (ASDs). Next, to search for the mutations in NEXN gene in patients suffering from ASDs, we sequenced the exon and exon–intron joint regions of the NEXN gene in 150 probands with isolated ASDs and identified three mutations in the conserved region of NEXN (c.-52-78C>A, K199E, and L227S), which were not found in 500 healthy controls. Finally, we characterize the related mechanisms and found all mutations inhibited GATA4 expression.
Conclusion
We identify NEXN as a novel gene for ASD and its function to inhibit GATA4 established a critical regulation of an F-actin binding protein on a transcription factor in cardiac development.
doi:10.1093/cvr/cvu134
PMCID: PMC4498134  PMID: 24866383
Atrial septal defect; NEXN; GATA4; Actin; Mutation
9.  Engineering deceleration and acceleration of soliton emitted from Airy pulse with quadratic phase modulation in optical fibers without high-order effects 
Scientific Reports  2015;5:11843.
Soliton propagation direction can be engineered in optical fibers in the presence of high-order effects (HOEs). It is well known that Raman effects can decelerate the soliton. Here we investigate the manipulation of the deceleration or acceleration of soliton emitted from Airy pulse whose spectrum is imposed an initial quadratic phase modulation (QPM) in optical fibers in the absence of HOEs. We show that, under the action of the anomalous second-order dispersion (SOD) and Kerr nonlinearity, Airy pulse with QPM is able to emit soliton with acceleration or deceleration depending on whether the QPM is negative or positive, and at a rate that is determined by the magnitude of QPM. The reason is that the acceleration behaviors of incident Airy pulse is altered depending on whether SOD and QPM have the same or opposite signs. Our study shows the possibility of controlling and manipulating the soliton propagation and interaction in optical fibers without HOEs, by purposely choosing appropriate QPM parameter of an Airy pulse.
doi:10.1038/srep11843
PMCID: PMC4502398  PMID: 26173387
10.  Does functional fitness decline in accordance with our expectation? – a pilot study in healthy female 
Background
Aging may cause various functional abilities gradually deteriorate. With changes in social forms, the trend of functional fitness decline will change accordingly. Therefore, this study endeavored to identify the trends in functional fitness decline by comparing the differences in the functional fitness of females in various age groups.
Methods
Thirty six healthy females were divided into 3 age groups: young healthy females (20 to 30 y); middle-age (45 to 55 y); and older (65 to 75 y). Functional fitness test battery included flexibility, muscle strength/endurance, aerobic endurance, balance and agility.
Results
The performance in the elderly group was significantly worse (P < .05) in all the tests, whereas the muscle strength and endurance, as well as aerobic endurance for the middle-age group showed significantly lower than young groups (P < .05).
Conclusions
The reduction in lower extremity muscle strength occurs in the middle-age group. We recommend that middle-age women be conscious of the reduction in their lower extremity muscle strength and conduct advanced preparations for future aging.
doi:10.1186/s13102-015-0012-y
PMCID: PMC4498516  PMID: 26167287
Elderly people; Lower extremity muscle strength; Exercise activity
11.  A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging 
Science (New York, N.Y.)  2015;348(6239):1160-1163.
Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.
doi:10.1126/science.aaa1356
PMCID: PMC4494668  PMID: 25931448
12.  Transposable elements, mRNA expression level and strand-specificity of small RNAs are associated with non-additive inheritance of gene expression in hybrid plants 
BMC Plant Biology  2015;15:168.
Background
Gene expression inheritance patterns in Arabidopsis hybrid plants were investigated for correlation with the presence of transposable elements (TEs) and small RNA profile.
Results
The presence of TEs in a gene and the expression of small RNA matching a gene were both found to be associated with non-additive mRNA inheritance patterns in hybrids. Expression levels below mid-parent values in the hybrids were associated with low mRNA expression in parents, with the presence of small RNA from both strands, and with the presence of TEs. High-parent dominance of mRNA levels was found to be associated with high parental mRNA expression levels, the absence of TEs, and for some genes, with small RNA fragments that are predominantly from the sense strand. These small RNAs exhibit a broader size distribution than siRNA and reduced nucleotide end bias, which are consistent with an origin from degraded mRNA. Thus, increased as well as decreased gene expression in hybrids relative to the parental mean is associated with gene expression levels, TE presence and small RNA fragments with differing characteristics.
Conclusions
The data presented here is consistent with a role for differential mRNA decay kinetics as one mechanism contributing to high-parent dominance in gene expression. Our evidence is also consistent with trans repression by siRNA and TEs as the cause of low-parent dominance.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0549-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-015-0549-7
PMCID: PMC4490736  PMID: 26139102
Hybrid; Gene expression inheritance; Small RNA; Transposon
13.  Plasminogen regulates cardiac repair after myocardial infarction through its non-canonical function in stem cell homing to the infarcted heart 
Objective
The purpose of this study was to investigate the role of Plasminogen (Plg) in stem cell-mediated cardiac repair and regeneration after myocardial infarction (MI)
Background
MI induces irreversible tissue damage, eventually leading to heart failure. Bone marrow (BM)-derived stem cells promote tissue repair and regeneration after MI. Thrombolytic treatment with Plg activators significantly improves the clinical outcome in MI by restoring cardiac perfusion. However, the role of Plg in stem cell-mediated cardiac repair remains unclear.
Methods
MI was induced in Plg deficient (Plg−/−) and wild-type (Plg+/+) mice by ligation of left anterior descending coronary artery (LAD). Stem cells were visualized by in vivo tracking of GFP-expressing BM cells after BM transplantation. Cardiac function, stem cell homing, signaling pathways downstream of Plg were examined.
Results
G-CSF, a stem cell mobilizer, significantly promoted BM-derived stem cells (GFP+c-kit+ cells) recruitment into infarcted heart and stem cell-meidated cardiac repair in Plg+/+ mice. However, Plg deficiency markedly inhibited stem cell homing and cardiac repair, suggesting that Plg is critical for stem cell-mediated cardiac repair. Moreover, Plg regulated CXCR4 expression in stem cells in vivo and in vitro through MMP-9. Lentiviral reconstitution of CXCR4 expression in BM cells rescued stem cell homing to the infarcted heart in Plg-deficient mice, indicating that a critical role of CXCR4 in Plg-mediated stem cell homing after MI.
Conclusions
These findings have identified a novel role of Plg in stem cell-mediated cardiac repair after MI. Thus, targeting Plg may offer a new therapeutic strategy for stem cell-mediated cardiac repair after MI.
doi:10.1016/j.jacc.2013.11.070
PMCID: PMC4074457  PMID: 24681141
Plasminogen; myocardial infarction; BM-derived stem cells; CXCR4
14.  Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy 
Cardiovascular Research  2014;103(1):60-71.
Aims
To determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy.
Methods and results
Replacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at ≥8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca2+]i, and sarcoplasmic reticulum (SR) Ca2+ content} and ICa-L than age-matched control VMs and than myocytes isolated from 2-month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month-old mdx mice to the same level as in age-matched control VMs. In the VMs of 12-month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseICa-L. No differences were observed in the expression of Cav1.2α1c, Cav1.2β1, Cav1.2β2, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and the Na+/Ca2+ exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2α1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (β1-AR) density and beta-adrenergic sensitivity.
Conclusion
In young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased β1-AR density/sensitivity, leading to blunted cardiac beta-adrenergic response.
doi:10.1093/cvr/cvu119
PMCID: PMC4133593  PMID: 24812281
Duchenne muscular dystrophy; Heart; Beta-adrenergic response; Myocyte contraction; Calcium
15.  TMEM16A-Mediated Mucin Secretion in IL-13-Induced Nasal Epithelial Cells From Chronic Rhinosinusitis Patients 
Purpose
Chronic rhinosinusitis with nasal polyps (CRSwNP), a mainly Th2 cytokine-mediated disease, often involves mucus secretion. Recent evidence suggests that transmembrane protein 16A (TMEM16A), a calcium-activated Cl- channel (CaCC), can regulate mucus secretion from airway epithelium by transepithelial electrolyte transport and hydration. However, the role of TMEM16A in mucin production/secretion in the airway epithelium is not clear. This study was conducted to determine the role of TMEM16A in mediating mucin secretion in human nasal polyp epithelial cells (HNPECs) induced by IL-13.
Methods
Human sinonasal mucosa tissue and dissociated sinonasal epithelium from control subjects and patients with CRSwNP were assessed for the expression of TMEM16A and the secretion of human mucin 5AC (MUC5AC) by immunohistochemistry, Western blot analysis, and enzyme-linked immuno-sorbent assay (ELISA). A model of the Th2 inflammatory environment was created by exposure of primary air-liquid interface (ALI)-cultured HNPECs to interleukin-13 (IL-13) for 14 days, with subsequent assessment of TMEM16A expression in cell lysates by Western blotting and MUC5AC secretion in apical washings of cells by ELISA.
Results
The expressions of TMEM16A and MUC5AC were increased in human nasal polyp tissue and dissociated nasal polyp epithelium. TMEM16A was detected in IL-13-treated HNPECs, specifically in MUC5AC-positive cells but not in ciliated cells. IL-13 treatment increased percentages of TMEM16A-positive cells, MUC5AC-positive cells, and cells coexpressing TMEM16A/MUC5AC, the expression of TMEM16A protein, and the secretion of MUC5AC. T16Ainh-A01, a TMEM16A inhibitor, attenuated these IL-13-induced effects.
Conclusions
The expression of TMEM16A and MUC5AC are increased in CRSwNP, which might be a direct effect of Th2 cytokines present in the sinonasal mucosa in CRSwNP. Down-regulation of TMEM16A expression and MUC5AC secretion in HNPECs by T16Ainh-A01 indicates that TMEM16A might play an important role in mucin secretion in upper airway inflammatory diseases.
doi:10.4168/aair.2015.7.4.367
PMCID: PMC4446635  PMID: 25749771
Chronic rhinosinusitis with nasal polyps; MUC5AC; mucin secretion; nasal epithelial cells; TMEM16A
16.  The Catalytic and Non-catalytic Functions of the Brahma Chromatin-Remodeling Protein Collaborate to Fine-Tune Circadian Transcription in Drosophila 
PLoS Genetics  2015;11(7):e1005307.
Daily rhythms in gene expression play a critical role in the progression of circadian clocks, and are under regulation by transcription factor binding, histone modifications, RNA polymerase II (RNAPII) recruitment and elongation, and post-transcriptional mechanisms. Although previous studies have shown that clock-controlled genes exhibit rhythmic chromatin modifications, less is known about the functions performed by chromatin remodelers in animal clockwork. Here we have identified the Brahma (Brm) complex as a regulator of the Drosophila clock. In Drosophila, CLOCK (CLK) is the master transcriptional activator driving cyclical gene expression by participating in an auto-inhibitory feedback loop that involves stimulating the expression of the main negative regulators, period (per) and timeless (tim). BRM functions catalytically to increase nucleosome density at the promoters of per and tim, creating an overall restrictive chromatin landscape to limit transcriptional output during the active phase of cycling gene expression. In addition, the non-catalytic function of BRM regulates the level and binding of CLK to target promoters and maintains transient RNAPII stalling at the per promoter, likely by recruiting repressive and pausing factors. By disentangling its catalytic versus non-catalytic functions at the promoters of CLK target genes, we uncovered a multi-leveled mechanism in which BRM fine-tunes circadian transcription.
Author Summary
The circadian clock is an endogenous timing system that enables organisms to anticipate daily changes in their external environment and temporally coordinate key biological functions that are important to their survival. Central to Drosophila clockwork is a key transcription factor CLOCK (CLK). CLK activates expression of target genes only during specific parts of the day, thereby orchestrating rhythmic expression of hundreds of clock-controlled genes, which consequently manifest into daily rhythms in physiology and behavior. In this study, we demonstrated that the Brahma (Brm) chromatin-remodeling protein interacts with CLK and fine-tune the levels of CLK-dependent transcription to maintain the robustness of the circadian clock. Specifically, we uncovered two distinct but collaborative functions of Brm. Brm possesses a non-catalytic function that negatively regulates the binding of CLK to target genes and limits transcriptional output, likely by recruiting repressive protein complexes. Catalytically, Brm functions by condensing the chromatin at CLK target genes, specifically when transcription is active. This serves to precisely control the level of repressive factors likely recruited by Brm as well as other transcriptional regulators. By disentangling these two roles of Brm, our study uncovered a multi-layered mechanism in which a chromatin remodeler regulates the circadian clock.
doi:10.1371/journal.pgen.1005307
PMCID: PMC4488936  PMID: 26132408
17.  Postprandial Differences in the Amino Acid and Biogenic Amines Profiles of Impaired Fasting Glucose Individuals after Intake of Highland Barley 
Nutrients  2015;7(7):5556-5571.
The aim of this study was to measure the postprandial changes in amino acid and biogenic amine profiles in individuals with impaired fasting glucose (IFG) and to investigate the changes of postprandial amino acid and biogenic amine profiles after a meal of highland barley (HB). Firstly, 50 IFG and 50 healthy individuals were recruited for the measurement of 2 h postprandial changes of amino acid and biogenic amine profiles after a glucose load. Secondly, IFG individuals received three different loads: Glucose (GL), white rice (WR) and HB. Amino acid and biogenic amine profiles, glucose and insulin were assayed at time zero and 30, 60, 90 and 120 min after the test load. The results showed fasting and postprandial amino acid and biogenic amine profiles were different between the IFG group and the controls. The level of most amino acids and their metabolites decreased after an oral glucose tolerance test, while the postprandial level of γ-aminobutyric acid (GABA) increased significantly in IFG individuals. After three different test loads, the area under the curve for glucose, insulin, lysine and GABA after a HB load decreased significantly compared to GL and WR loads. Furthermore, the postprandial changes in the level of GABA between time zero and 120 min during a HB load were associated positively with 2 h glucose and fasting insulin secretion in the IFG individuals. Thus, the HB load produced low postprandial glucose and insulin responses, which induced changes in amino acid and biogenic amine profiles and improved insulin sensitivity.
doi:10.3390/nu7075238
PMCID: PMC4517015  PMID: 26184292
postprandial status; amino acid and biogenic amine profiles; insulin; highland barley; impaired fasting glucose
18.  Early versus delayed laparoscopic common bile duct exploration for common bile duct stone-related nonsevere acute cholangitis 
Scientific Reports  2015;5:11748.
It is undetermined when and how laparoscopic common bile duct exploration (LCBDE) should be used in patients with common bile duct (CBD) stone-related nonsevere acute cholangitis. We aimed to evaluate the effect of LCBDE on the clinical outcome of those patients within (early) or beyond (delayed) 72 hours of emergent admission. Surgery-related complications, length of hospital stay (LOS), and total cost, as well as demographic and clinical parameters were compared between the two groups. Finally, 3 and 5 patients in early and delayed LCBDE group, respectively, had retained stones, which were removed by choledochoscopy before T-tube was removed. Each group had 3 patients who developed biliary leak, which was conservatively cured by the drainage. Shorter LOS and less total cost were observed in early group compared to the late one (13.34 ± 4.48 vs. 18.32 ± 9.13, p < 0.05; 17712 ± 5446.63 vs. 21776 ± 7230.41 ¥RMB, p < 0.05). Improvement of cholangitis was achieved in all patients with LCBDE. None of the patients developed stricture of the CBD after LCBDE. To conclude, both early and delayed LCBDE are safe and effective for the treatment of CBD stone-related nonsevere acute cholangitis during emergent admissions. Early LCBDE may be superior to delayed procedure due to the shorter LOS and less cost.
doi:10.1038/srep11748
PMCID: PMC4485235  PMID: 26123122
19.  Group velocity mismatch-absent nonlinear frequency conversions for mid-infrared femtosecond pulses generation 
Scientific Reports  2015;5:10887.
A novel group velocity mismatch (GVM) absent scheme for nonlinear optical parametric procedure in mid-infrared was developed with type-I quasi phase matching by use of an off-digital nonlinear optical coefficient d31. This was achieved by matching of the group velocities of the pump and the signal waves, while the phase velocities were quasi phase matched. The system employs MgO-doped periodically poled LiNbO3 as the nonlinear medium. Desired group-velocity dispersion would be obtained via appropriately temperature regulation. To demonstrate its potential applications in ultrafast mid-infrared pulses generation, aiming at a typical mid-infrared wavelength of ~3.2 μm, design examples of two basic nonlinear frequency conversion procedures are studied for both the narrow-band seeding mid-IR optical parametric amplification (OPA) and the synchronously pumped femtosecond optical parametric oscillation (SPOPO). Compared with the conventional scheme of type-0 QPM, the quantum-efficiency can be more than doubled with nearly unlimited bandwidth. The proposed GVM- absent phase matching design may provide a promising route to efficient and broadband sub-100 fs mid-infrared ultrafast pulses generation without group-velocity walk-off.
doi:10.1038/srep10887
PMCID: PMC4477408  PMID: 26099837
20.  Overexpression of a bifunctional enzyme, CrtS, enhances astaxanthin synthesis through two pathways in Phaffia rhodozyma 
Background
A moderate-temperature, astaxanthin-overproducing mutant strain (termed MK19) of Phaffia rhodozyma was generated in our laboratory. The intracellular astaxanthin content of MK19 was 17-fold higher than that of wild-type. The TLC profile of MK19 showed a band for an unknown carotenoid pigment between those of β-carotene and astaxanthin. In the present study, we attempted to identify the unknown pigment and to enhance astaxanthin synthesis in MK19 by overexpression of the crtS gene that encodes astaxanthin synthase (CrtS).
Results
A crtS-overexpressing strain was constructed without antibiotic marker. A recombinant plasmid with lower copy numbers was shown to be stable in MK19. In the positive recombinant strain (termed CSR19), maximal astaxanthin yield was 33.5% higher than MK19, and the proportion of astaxanthin as a percentage of total carotenoids was 84%. The unknown carotenoid was identified as 3-hydroxy-3′,4′-didehydro-β,Ψ-carotene-4-one (HDCO) by HPLC, mass spectrometry, and NMR spectroscopy. CrtS was found to be a bifunctional enzyme that helped convert HDCO to astaxanthin. Enhancement of crtS transcriptional level increased transcription levels of related genes (crtE, crtYB, crtI) in the astaxanthin synthesis pathway. A scheme of carotenoid biosynthesis in P. rhodozyma involving alternative bicyclic and monocyclic pathways is proposed.
Conclusions
CrtS overexpression leads to up-regulation of synthesis-related genes and increased astaxanthin production. The transformant CSR19 is a stable, secure strain suitable for feed additive production. The present findings help clarify the regulatory mechanisms that underlie metabolic fluxes in P. rhodozyma carotenoid biosynthesis pathways.
Electronic supplementary material
The online version of this article (doi:10.1186/s12934-015-0279-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12934-015-0279-4
PMCID: PMC4470029  PMID: 26081576
Phaffia rhodozyma; Astaxanthin; HDCO; Astaxanthin synthase (CrtS); Overexpression
21.  Anaerolineaceae and Methanosaeta turned to be the dominant microorganisms in alkanes-dependent methanogenic culture after long-term of incubation 
AMB Express  2015;5:37.
The methanogenic alkanes-degrading enrichment culture which had been incubated for over 1,300 days amended with n-alkanes (C15–C20) was investigated through clone libraries of bacteria, archaea and assA, mcrA functional genes. These enrichment cultures were obtained from oily sludge after an initial incubation of the oily sludge without any carbon source and then an enrichment transfer with n-alkanes (C15–C20) for acclimation. Activation of alkanes, methane precursor generation and methanogenic pathways are considered as three pivotal stages for the continuous methanogenesis from degradation of alkanes. The presence of functional genes encoding the alkylsuccinate synthase α-subunit indicated that fumarate addition is most likely the one of initial activation step for degradation of n-alkanes. Degradation intermediates of n-alkanes were octadecanoate, hexadecanoate, butyrate, isobutyrate, acetate and propionate, which could provide the appropriate substrates for acetate formation. Both methyl coenzyme M reductase gene and 16S rRNA gene analysis showed that microorganisms of Methanoseata were the most dominant methanogens, capable of using acetate as the electron donor to produce methane. Bacterial clone libraries showed organisms of Anaerolineaceae (within the phylum of Chloroflexi) were predominant (45.5%), indicating syntrophically cooperation with Methanosaeta archaea was likely involved in the process of methanogenic degradation of alkanes. Alkanes may initially be activated via fumarate addition and degraded to fatty acids, then converted to acetate, which was further converted to methane and carbon dioxide by methanogens.
Electronic supplementary material
The online version of this article (doi:10.1186/s13568-015-0117-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13568-015-0117-4
PMCID: PMC4469597  PMID: 26080793
Alkanes degradation; Anaerolineaceae; Methanosaeta; 16S rRNA gene; Methanogenesis; Microbial community
22.  Species-Specific Effects on Throughfall Kinetic Energy in Subtropical Forest Plantations Are Related to Leaf Traits and Tree Architecture 
PLoS ONE  2015;10(6):e0128084.
Soil erosion is a key threat to many ecosystems, especially in subtropical China where high erosion rates occur. While the mechanisms that induce soil erosion on agricultural land are well understood, soil erosion processes in forests have rarely been studied. Throughfall kinetic energy (TKE) is influenced in manifold ways and often determined by the tree’s leaf and architectural traits. We investigated the role of species identity in mono-specific stands on TKE by asking to what extent TKE is species-specific and which leaf and architectural traits account for variation in TKE. We measured TKE of 11 different tree species planted in monocultures in a biodiversity-ecosystem-functioning experiment in subtropical China, using sand-filled splash cups during five natural rainfall events in summer 2013. In addition, 14 leaf and tree architectural traits were measured and linked to TKE. Our results showed that TKE was highly species-specific. Highest TKE was found below Choerospondias axillaris and Sapindus saponaria, while Schima superba showed lowest TKE. These species-specific effects were mediated by leaf habit, leaf area (LA), leaf pinnation, leaf margin, stem diameter at ground level (GD), crown base height (CBH), tree height, number of branches and leaf area index (LAI) as biotic factors and throughfall as abiotic factor. Among these, leaf habit, tree height and LA showed the highest effect sizes on TKE and can be considered as major drivers of TKE. TKE was positively influenced by LA, GD, CBH, tree height, LAI, and throughfall amount while it was negatively influenced by the number of branches. TKE was lower in evergreen, simple leaved and dentate leaved than in deciduous, pinnated or entire leaved species. Our results clearly showed that soil erosion in forest plantations can be mitigated by the appropriate choice of tree species.
doi:10.1371/journal.pone.0128084
PMCID: PMC4469422  PMID: 26079260
23.  Genome-wide single-nucleotide polymorphism analysis revealed SUFU suppression of acute graft-versus-host disease through downregulation of HLA-DR expression in recipient dendritic cells 
Scientific Reports  2015;5:11098.
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). To identify recipient risk factors, a genome-wide study was performed including 481,820 single-nucleotide polymorphisms (SNPs). Two GVHD susceptibility loci (rs17114803 and rs17114808) within the SUFU gene were identified in the discovery cohort (p = 2.85 × 10−5). The incidence of acute GVHD among patients homozygous for CC at SUFU rs17114808 was 69%, which was significantly higher than the 8% rate observed in CT heterozygous patients (p = 0.0002). In an independent validation cohort of 100 patients, 50% of the patients with the CC genotype developed GVHD compared to 8% of the patients with either CT or TT genotype (p = 0.01). In comparison to CC dendritic cells, those from CT expressed higher levels of SUFU mRNA and protein, had lower levels of surface HLA-DR, and induced less allogeneic mixed leukocyte response (MLR). Ectopic expression of SUFU in THP-1 derived DCs reduced HLA-DR expression and suppressed MLR, whereas silencing of SUFU enhanced HLA-DR expression and increased MLR. Thus our findings provide novel evidence that recipient SUFU germline polymorphism is associated with acute GVHD and is a novel molecular target for GVHD prevention and treatment.
doi:10.1038/srep11098
PMCID: PMC4464079  PMID: 26067905
24.  Effect of resveratrol on Treg/Th17 signaling and ulcerative colitis treatment in mice 
AIM: To determine the therapeutic efficacy of resveratrol on ulcerative colitis (UC) and its underlying mechanisms.
METHODS: The mouse UC model was developed using 5% dextran sulfate sodium. Mice were randomly divided into four groups: normal control, UC model group, resveratrol low-dose group (RLD; 50 mg/kg per day), and resveratrol high-dose group (RHD; 100 mg/kg per day).
RESULTS: The results showed that RLD regulates Treg/Th17 balance mainly through reducing the number of Th17 cells, whereas RHD regulates Treg/Th17 balance through both downregulating the number of Th17 cells and upregulating the number of Treg cells. Resveratrol can also regulate the level of plasma and intestinal mucosal cytokines including interleukin (IL)-10, transforming growth factor-β1, IL-6, and IL-17. The expressions of hypoxia inducible factor (HIF)-1α, mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 were significantly decreased in the intestinal tissues of mice treated with resveratrol.
CONCLUSION: The therapeutic efficacy of resveratrol in UC is dose dependent and closely associated with the regulation of Treg/Th17 balance and the HIF-1α/mTOR signaling pathway.
doi:10.3748/wjg.v21.i21.6572
PMCID: PMC4458767  PMID: 26074695
Hypoxia inducible factor-α; Mammalian target of rapamycin; Resveratrol; Th17 cells; Treg cells; Ulcerative colitis
25.  Diorcinol D Exerts Fungicidal Action against Candida albicans through Cytoplasm Membrane Destruction and ROS Accumulation 
PLoS ONE  2015;10(6):e0128693.
Candida albicans, which is the most common human fungal pathogen, causes high mortality among immunocompromised patients. Antifungal drug resistance becomes a major challenge for the management of Candida infection. Diorcinol D (DD), a diphenyl ether derivative isolated from an endolichenic fungus, exerted fungicidal action against Candida species. In this study, we investigated the possible mechanism of its antifungal activity. The change of membrane dynamics and permeability suggested that the cell membrane was disrupted by the treatment of DD. This was further supported by the evidences of intracellular glycerol accumulation, alteration of cell ultrastructure, and down-regulation of genes involved in cell membrane synthesis. In addition, the treatment of C. albicans with DD resulted in the elevation of reactive oxygen species (ROS), which caused the dysfunction of mitochondria. These altogether suggested that DD exerted its antifungal activity through cytoplasmic membrane destruction and ROS accumulation. This finding is helpful to uncover the underlying mechanisms for the diphenyl ether derivatives and provides a potential application in fighting clinical fungal infections.
doi:10.1371/journal.pone.0128693
PMCID: PMC4457822  PMID: 26047493

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