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1.  Diurnal Salivary Cortisol, Glycemia and Insulin Resistance: The Multi-Ethnic Study of Atherosclerosis 
Psychoneuroendocrinology  2015;62:327-335.
Hypercortisolism is associated with insulin resistance (IR) and diabetes mellitus (DM); however, to our knowledge prior studies have not examined the association of diurnal cortisol curve features with measures of glycemia or IR in a population-based setting. Using log-transformed salivary cortisol data on 850 ethnically diverse men and women from the Multi-Ethnic Study of Atherosclerosis, we investigated the cross-sectional association of cortisol curve features with (1) glycemia in those with and without DM and (2) IR, in non-diabetic subjects. The log-transformed salivary cortisol curve features included wake-up cortisol, cortisol awakening response (CAR), early decline slope (30 minutes to 2 hours post-awakening), late decline slope (2 hours post-awakening to bedtime), overall decline slope (0 minutes to bedtime, excluding 30 minute cortisol), bedtime cortisol and total area under the curve (AUC). Overall, following multivariable adjustment, among those with diabetes mellitus (DM), early decline slope, overall decline slope, bedtime cortisol, and AUC were significantly and positively associated with a 5.4% (95% CI: 1.3, 9.7), 54.7% (95% CI: 12.4, 112.9), 4.0% (95% CI: 1.6, 6.4), and 6.8% (95% CI: 3.3, 10.4) higher HbA1c per 1 unit increase in log cortisol feature, respectively. Cortisol curve features were not associated with HbA1c among non-diabetic participants; however, wake-up cortisol and AUC were associated with a 8.2% lower (95% CI: −13.3, −2.7) and 7.9% lower (95% CI: −14.6, −0.6) log HOMA-IR, respectively. This was attenuated by adjustment for waist circumference. Among participants with DM, cortisol curve parameters suggestive of higher hypothalamic-pituitary-adrenal (HPA) axis activity and dysfunction were associated with higher HbA1c. In non-diabetic participants, greater HPA activity was paradoxically associated with lower insulin resistance.
PMCID: PMC4637243  PMID: 26356041
Cortisol; Glycemia; Insulin Resistance; Type 2 Diabetes Mellitus; hypothalamic-pituitary-adrenal axis
2.  Structure of Decorin Binding Protein B from Borrelia burgdorferi and Its Interactions with Glycosaminoglycans 
Biochimica et biophysica acta  2015;1854(12):1823-1832.
Decorin-binding proteins (DBPs), DBPA and DBPB, are surface lipoproteins on Borrelia burgdorferi, causative agent of Lyme disease. DBPs bind to the connective tissue proteoglycan decorin and facilitate tissue colonization by the bacterium. Although structural and biochemical properties of DBPA are well understood, little is known about DBPB. In current work, we determined the solution structure of DBPB from strain B31 of B. burgdorferi and characterized its interactions with glycosaminoglycans (GAGs). Our structure shows DBPB adopts the same topology as DBPA, but possesses a much shorter terminal helix, resulting in a longer unstructured C-terminal tail, which is also rich in basic amino acids. Characterization of DBPB-GAG interactions reveals that, despite similar GAG affinities of DBPA and DBPB, the primary GAG-binding sites in DBPB are different from DBPA. In particular, our results indicate lysines in the C-terminus of DBPB are vital to DBPB’s ability to bind GAGs whereas C-terminal tail for DBPA from strain B31 only plays a minor role in facilitating GAG bindings. Furthermore, the traditional GAG-binding pocket important to DBPA-GAG interactions is only secondary to DBPB’s GAG-binding ability.
Graphical abstract
PMCID: PMC4548840  PMID: 26275806
Lyme disease; glycosaminoglycan; adhesin; NMR; decorin
3.  Different Sutures in the Surgical Treatment of Acute Closed Achilles Tendon Rupture 
The Indian Journal of Surgery  2014;77(Suppl 3):936-940.
The aim was to compare the postoperative efficacy of the PDS II and Ethibond W4843 sutures in fresh, closed Achilles tendon rupture. With methods of random grouping (level of evidence II b), a total of 128 patients with fresh Achilles tendon rupture were operated on with PDS II or Ethibond W4843 suture. Postoperative objective examination and the American Orthopaedic Foot & Ankle Society (AOFAS) scoring system were used for the evaluation. Group A underwent 12–39 months of follow-up, for an average of 22 months. Group B underwent 12–37 months of follow-up, for an average of 23 months. The postoperative AOFAS score of group A within 3 months was 93 ± 9.6 points. One case exhibited re-rupture, five cases exhibited incision infection, one case manifested deep infection, and seven cases exhibited Achilles tendon adhesion. The postoperative AOFAS score of group B within 3 months was 97 ± 7.8 points. Eleven cases had incision infection, and 13 cases manifested Achilles tendon adhesion. Minimal differences were observed in the incision infection, re-rupture rate, and Achilles tendon adhesion in the study of the PDS II and Ethibond W4843 sutures. But, based on the AOFAS score and pain score, the Ethibond suture performed better.
PMCID: PMC4775679  PMID: 27011486
Surgical treatment; Ethibond suture; Achilles tendon rupture
4.  PEP-19 modulates calcium binding to calmodulin by electrostatic steering 
Nature Communications  2016;7:13583.
PEP-19 is a small protein that increases the rates of Ca2+ binding to the C-domain of calmodulin (CaM) by an unknown mechanism. Although an IQ motif promotes binding to CaM, an acidic sequence in PEP-19 is required to modulate Ca2+ binding and to sensitize HeLa cells to ATP-induced Ca2+ release. Here, we report the NMR solution structure of a complex between PEP-19 and the C-domain of apo CaM. The acidic sequence of PEP-19 associates between helices E and F of CaM via hydrophobic interactions. This allows the acidic side chains in PEP-19 to extend toward the solvent and form a negatively charged surface that resembles a catcher's mitt near Ca2+ binding loop III of CaM. The topology and gradients of negative electrostatic surface potential support a mechanism by which PEP-19 increases the rate of Ca2+ binding to the C-domain of CaM by ‘catching' and electrostatically steering Ca2+ to site III.
The protein PEP-19 increases the rates of calcium binding to calmodulin. Here, the authors report the structure of PEP-19 bound to the C-terminal domain of calmodulin, and are able to propose a mechanism for the observed increased calcium association rate.
PMCID: PMC5122967  PMID: 27876793
5.  Nonsequential double ionization with mid-infrared laser fields 
Scientific Reports  2016;6:37413.
Using a full-dimensional Monte Carlo classical ensemble method, we present a theoretical study of atomic nonsequential double ionization (NSDI) with mid-infrared laser fields, and compare with results from near-infrared laser fields. Unlike single-electron strong-field processes, double ionization shows complex and unexpected interplays between the returning electron and its parent ion core. As a result of these interplays, NSDI for mid-IR fields is dominated by second-returning electron trajectories, instead of first-returning trajectories for near-IR fields. Some complex NSDI channels commonly happen with near-IR fields, such as the recollision-excitation-with-subsequent-ionization (RESI) channel, are virtually shut down by mid-IR fields. Besides, the final energies of the two electrons can be extremely unequal, leading to novel e-e momentum correlation spectra that can be measured experimentally.
PMCID: PMC5114651  PMID: 27857182
6.  Quantum dot-like excitonic behavior in individual single walled-carbon nanotubes 
Scientific Reports  2016;6:37167.
Semiconducting single-walled carbon nanotubes are one-dimensional materials with great prospects for applications such as optoelectronic and quantum information devices. Yet, their optical performance is hindered by low fluorescent yield. Highly mobile excitons interacting with quenching sites are attributed to be one of the main non-radiative decay mechanisms that shortens the exciton lifetime. In this paper we report on time-integrated photoluminescence measurements on individual polymer wrapped semiconducting carbon nanotubes. An ultra narrow linewidth we observed demonstrates intrinsic exciton dynamics. Furthermore, we identify a state filling effect in individual carbon nanotubes at cryogenic temperatures as previously observed in quantum dots. We propose that each of the CNTs is segmented into a chain of zero-dimensional states confined by a varying local potential along the CNT, determined by local environmental factors such as the amount of polymer wrapping. Spectral diffusion is also observed, which is consistent with the tunneling of excitons between these confined states.
PMCID: PMC5111057  PMID: 27849046
7.  Complete response of extramedullary relapse in breast of acute T lymphoblastic leukemia after bone marrow transplantation to chemoradiotherapy: a case report and literature review 
BMC Cancer  2016;16:875.
Relapse of acute lymphoblastic leukemia (ALL) occurring in the breast after allografting is extremely rare, with only 22 reported cases in the literature thus far. Further, the lack of a systemic analysis provides little information about this entity. We present a case of isolated extramedullary relapse from acute T lymphoblastic leukemia (ATLL) after allogeneic hematopoietic stem cell transplantation (HSCT).
Case presentation
A 32-year-old Chinese woman diagnosed with ATLL with myeloid antigen expression received HSCT from her human leukocyte antigen (HLA)-matched sister and presented with two lesions in her right breast 6 months later. Pathology investigation revealed breast relapse, with complete remission on the basis of bone marrow findings. Combined modality treatment including chemotherapy and local radiotherapy helped achieve complete remission with mild side effects.
The findings from this case indicate that the breast is a potentially involved extramedullary site of relapse for ALL patients after HSCT. In the case of a newly developed breast lump in such patients, clinicians consider local relapse even if the bone marrow findings indicate remission. Combined modality treatment will contribute to better local control and improve prognosis.
PMCID: PMC5103363  PMID: 27829385
Radiotherapy; Extramedullary relapse; Breast; Acute lymphoblastic leukemia; Transplantation; Case report
8.  Phosphorylation of the Nuclear Receptor Co-repressor 1 by Protein Kinase B (PKB/Akt) Switches its Co-repressor Targets in the Liver 
Hepatology (Baltimore, Md.)  2015;62(5):1606-1618.
The nuclear receptor corepressor 1 (NCoR1) is a transcriptional co-regulator that has wide-ranging effects on gene expression patterns. In the liver, NCoR1 represses lipid synthesis in the fasting state, whereas it inhibits the activation of PPARα upon feeding, thereby blunting ketogenesis. Here, we show that insulin via the activation of PKB/Akt induces the phosphorylation of NCoR1 on serine 1460, which selectively favors its interaction with PPARα and ERRα over LXRα. Phosphorylation of NCoR1 on S1460 selectively derepresses LXRα target genes, resulting in increased lipogenesis, while at the same time it inhibits PPARα and ERRα targets, thereby attenuating oxidative metabolism in the liver. The phosphorylation-gated differential recruitment of NCoR1 to different nuclear receptors explains the apparent paradox that liver-specific deletion of NCoR1 concurrently induces both lipogenesis and oxidative metabolism, due to a global derepression of LXRα, PPARα and ERRα activity. This phosphorylation-mediated recruitment switch of NCoR1 between nuclear receptor subsets hence provides a mechanism by which corepressors can selectively modulate liver energy metabolism during the fasting-feeding transition.
PMCID: PMC4618256  PMID: 25998209
Lipogenesis; Ketogenesis; Oxidative Phosphorylation; Insulin Resistance; Fatty Liver
9.  Aqueous two-phase system (ATPS): an overview and advances in its applications 
Aqueous two-phase system (ATPS) is a liquid-liquid fractionation technique and has gained an interest because of great potential for the extraction, separation, purification and enrichment of proteins, membranes, viruses, enzymes, nucleic acids and other biomolecules both in industry and academia. Although, the partition behavior involved in the method is complex and difficult to predict. Current research shows that it has also been successfully used in the detection of veterinary drug residues in food, separation of precious metals, sewage treatment and a variety of other purposes. The ATPS is able to give high recovery yield and is easily to scale up. It is also very economic and environment friendly method. The aim of this review is to overview the basics of ATPS, optimization and its applications.
PMCID: PMC5084470  PMID: 27807400
Aqueous two-phase system (ATPS); Biomolecule separation; Solvent extraction; Veterinary drug residues
10.  Antibiotic use and abuse: A threat to mitochondria and chloroplasts with impact on research, health, and environment 
Bioessays  2015;37(10):1045-1053.
Recently, several studies have demonstrated that tetracyclines, the antibiotics most intensively used in livestock and that are also widely applied in biomedical research, interrupt mitochondrial proteostasis and physiology in animals ranging from round worms, fruit flies, and mice to human cell lines. Importantly, plant chloroplasts, like their mitochondria, are also under certain conditions vulnerable to these and other antibiotics that are leached into our environment. Together these endosymbiotic organelles are not only essential for cellular and organismal homeostasis stricto sensu, but also have an important role to play in the sustainability of our ecosystem as they maintain the delicate balance between autotrophs and heterotrophs, which fix and utilize energy, respectively. Therefore, stricter policies on antibiotic usage are absolutely required as their use in research confounds experimental outcomes, and their uncontrolled applications in medicine and agriculture pose a significant threat to a balanced ecosystem and the well‐being of these endosymbionts that are essential to sustain health.
Also watch the Video Abstract.
PMCID: PMC4698130  PMID: 26347282
antibiotics; chloroplasts; doxycycline; environmental pollution; mitochondria; mitochondrial unfolded protein response; tetracycline
11.  Formal nomenclature and description of cryptic species of the Encyrtus sasakii complex (Hymenoptera: Encyrtidae) 
Scientific Reports  2016;6:34372.
With the recent development of molecular approaches to species delimitation, a growing number of cryptic species have been discovered in what had previously been thought to be single morpho-species. Molecular methods, such as DNA barcoding, have greatly enhanced our knowledge of taxonomy, but taxonomy remains incomplete and needs a formal species nomenclature and description to facilitate its use in other scientific fields. A previous study using DNA barcoding, geometric morphometrics and mating tests revealed at least two cryptic species in the Encyrtus sasakii complex. (Hymenoptera: Encyrtidae). To describe these two new species formally (Encyrtus eulecaniumiae sp. nov. and Encyrtus rhodococcusiae sp. nov.), a detailed morphometric study of Encyrtus spp. was performed in addition to the molecular analysis and evaluation of biological data. Morphometric analyses, a multivariate ratio analysis (MRA) and a geometric morphometric analysis (GMA) revealed a great number of differences between the species, but reliable characteristics were not observed for diagnosing the cryptic species. We thus diagnosed these three Encyrtus species on the basis of the characteristics that resulted from genetic markers (mitochondrial cytochrome c oxidase subunit I and nuclear 28S rRNA) and biological data. A formal nomenclature and description of cryptic species was provided on the basis of an integrated taxonomy.
PMCID: PMC5048151  PMID: 27698441
12.  The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2 
DNA and Cell Biology  2015;34(10):610-617.
In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells both in vitro and in vivo. We demonstrated that OSI-027 inhibited survival and growth of both primary and transformed (PANC-1 and MIA PaCa-2 lines) human pancreatic cancer cells. Meanwhile, OSI-027 induced caspase-dependent apoptotic death of the pancreatic cancer cells. On the other hand, caspase inhibitors alleviated cytotoxicity by OSI-027. At the molecular level, OSI-027 treatment blocked mTORC1 and mTORC2 activation simultaneously, without affecting ERK–mitogen-activated protein kinase activation. Importantly, OSI-027 activated cytoprotective autophagy in the above cancer cells. Whereas pharmacological blockage of autophagy or siRNA knockdown of Beclin-1 significantly enhanced the OSI-027-induced activity against pancreatic cancer cells. Specifically, a relatively low dose of OSI-027 sensitized gemcitabine-induced pancreatic cancer cell death in vitro. Further, administration of OSI-027 or together with gemcitabine dramatically inhibited PANC-1 xenograft growth in severe combined immunodeficiency mice, leading to significant mice survival improvement. In summary, the preclinical results of this study suggest that targeting mTORC1/2 synchronously by OSI-027 could be further investigated as a valuable treatment for pancreatic cancer.
PMCID: PMC4593879  PMID: 26284306
13.  Antibiotic use and abuse: A threat to mitochondria and chloroplasts with impact on research, health and environment 
Recently, several studies have demonstrated that tetracyclines, the antibiotics most intensively used in livestock and that are also widely applied in biomedical research, interrupt mitochondrial proteostasis and physiology in animals ranging from round worms, fruit flies and mice to human cell lines. Importantly, plant chloroplasts, like their mitochondria, are also under certain conditions vulnerable to these and other antibiotics that are leached into our environment. Together these endosymbiotic organelles are not only essential for cellular and organismal homeostasis stricto sensu, but also have an important role to play in the sustainability of our ecosystem as they maintain the delicate balance between autotrophs and heterotrophs, which fix and utilize energy, respectively. Therefore, stricter policies on antibiotic usage are absolutely required as their use in research confounds experimental outcomes, and their uncontrolled applications in medicine and agriculture pose a significant threat to a balanced ecosystem and the wellbeing of these endosymbionts that are essential to sustain health.
PMCID: PMC4698130  PMID: 26347282
antibiotics; chloroplasts; doxycycline; environmental pollution; mitochondria; mitochondrial unfolded protein response; tetracycline
14.  Electrical stimulation promotes regeneration of injured oculomotor nerves in dogs 
Neural Regeneration Research  2016;11(10):1666-1669.
Functional recovery after oculomotor nerve injury is very poor. Electrical stimulation has been shown to promote regeneration of injured nerves. We hypothesized that electrical stimulation would improve the functional recovery of injured oculomotor nerves. Oculomotor nerve injury models were created by crushing the right oculomotor nerves of adult dogs. Stimulating electrodes were positioned in both proximal and distal locations of the lesion, and non-continuous rectangular, biphasic current pulses (0.7 V, 5 Hz) were administered 1 hour daily for 2 consecutive weeks. Analysis of the results showed that electrophysiological and morphological recovery of the injured oculomotor nerve was enhanced, indicating that electrical stimulation improved neural regeneration. Thus, this therapy has the potential to promote the recovery of oculomotor nerve dysfunction.
PMCID: PMC5116848  PMID: 27904500
nerve regeneration; oculomotor nerve; electrical stimulation; dog; nerve injury; model; cranial nerve; peripheral nerve
15.  Macrophage Foam Cell–Derived Extracellular Vesicles Promote Vascular Smooth Muscle Cell Migration and Adhesion 
A new mechanism for intercellular communication has recently emerged that involves intercellular transfer of extracellular vesicles (EVs). Several studies have indicated that EVs may play a potential role in cell‐to‐cell communication between macrophage foam cells and vascular smooth muscle cells (VSMCs) in atherosclerotic lesion.
Methods and Results
This study involved the comparison of circulating EVs from atherosclerotic patients and control participants. The results showed that the circulation of the patients contained more leukocyte‐derived EVs and that these EVs promoted more VSMC adhesion and migration than those of healthy participants. We then established a macrophage foam cell model and characterized the EVs from the macrophages. We used flow cytometric analyses and cell migration and adhesion assays and determined that the foam cells generated more EVs than the normal macrophages and that the foam cell–derived EVs were capable of promoting increased levels of VSMC migration and adhesion. Furthermore, we performed a proteomic analysis of the EVs. The data showed that the foam cell–derived EVs may promote VSMC adhesion and migration by regulating the actin cytoskeleton and focal adhesion pathways. In addition, Western blotting revealed that foam cell–derived EVs could promote the phosphorylation of ERK and Akt in VSMCs in a time‐dependent manner. We also found that foam cell–derived EVs could enter the VSMCs and transfer integrins to the surface of these cells.
The data in our present study provide the first evidence that EVs from foam cells could promote VSMC migration and adhesion, which may be mediated by the integration of EVs into VSMCs and the subsequent downstream activation of ERK and Akt.
PMCID: PMC5121506  PMID: 27792649
atherosclerosis; exosomes; microparticles; microvesicles; proteomics; Atherosclerosis; Vascular Disease
16.  Transgenic Mice Expressing MCP-1 by the Urothelium Demonstrate Bladder Hypersensitivity, Pelvic Pain and Voiding Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study 
PLoS ONE  2016;11(9):e0163829.
Monocyte chemoattractant protein-1 (MCP-1) is one of the key chemokines that play important roles in diverse inflammatory and chronic pain conditions. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and voiding dysfunction. To facilitate IC/BPS research, we used transgenic technology to develop a novel urothelial MCP-1 secretion mouse model (URO-MCP-1). A transgene consisting of the uroplakin II gene promoter and the mouse MCP-1 coding sequence with a secretory element was constructed and microinjected. URO-MCP-1 mice were found to express MCP-1 mRNA in the bladder epithelium and MCP-1 protein in the urine, and developed bladder inflammation 24 hours after intravesical administration of a single sub-noxious dose of lipopolysaccharide (LPS). The inflamed bladders of URO-MCP-1 mice exhibited elevated mRNAs for interleukin (IL)-1ß, IL-6, substance P precursor, and nerve growth factor as well as increased macrophage infiltration. In parallel with these phenotypic changes, URO-MCP-1 mice manifested significant functional changes at days 1 and 3 after cystitis induction. These functional changes included pelvic pain as measured by von Frey filament stimulation and voiding dysfunction (increased urinary frequency, reduced average volume voided per micturition, and reduced maximum volume voided per micturition) as measured by micturition cages. Micturition changes remained evident at day 7 after cystitis induction, although these changes were not statistically significant. Control wild-type C57BL/6 mice manifested no clear changes in histological, biochemical and behavioral features after similar cystitis induction with LPS. Taken together, our results indicate that URO-MCP-1 mice are hypersensitive to bladder irritants such as LPS and develop pelvic pain and voiding dysfunction upon cystitis induction, providing a novel model for IC/BPS research.
PMCID: PMC5042429  PMID: 27684718
17.  Inhibition of osteopontin reduce the cardiac myofibrosis in dilated cardiomyopathy via focal adhesion kinase mediated signaling pathway 
Background: Osteopontin (OPN) is a pleiotropic cytokine, which has been shown to a close relationship with cardiac fibrosis. Overexpression of OPN in cardiomyocytes induces dilated cardiomyopathy (DCM). This research is to study whether inhibition of OPN could reduce myocardial remodelling in DCM, and if this process is focal adhesion kinase (FAK) dependent, which is recently found an important signal molecule in fibrosis. Method: Eight-week-old cTnTR141W transgenic mouse of DCM were injected with OPN-shRNA in left ventricular free wall, which could inhibit the OPN expression. Six weeks later, echocardiographic examinations were performed to test left ventricle function and heart tissues were harvested to test the quality of FAK by western blot and severity of fibrosis by masson staining. Human cardiac fibroblast was administrated with OPN, and FAK inhibition by PP2 was treated 2 h before OPN was given. Expression of α-SMA and collagen-I were tested by western blot and real-time PCR assay. Results: OPN-shRNA group has a relatively high ejection fraction (EF), fractional shortening (FS), LV free wall thickness and a less sever cardiac fibrosis. In vitro, OPN could increase collagen-I and α-SMA expression, and this process can be inhibited by FAK inhibitor. Conclusion: Inhibition of OPN could reduce the LV remodeling and dysfunction in DCM mice, which may attribute to the suppression of collagen-I secretion in fibroblast through a FAK/Akt dependent pathway.
PMCID: PMC5040665  PMID: 27725847
Osteopontin (OPN); focal adhesion kinase (FAK); cardiac fibrosis; dilated cardiomyopathy (DCM); fibroblast
18.  Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients 
Cardiovascular Diabetology  2016;15(1):132.
Angiopoietin-like protein 3 (ANGPTL3) is a major lipoprotein regulator and shows positive correlation with high-density lipoprotein-cholesterol (HDL-c) in population studies and ANGPTL3 mutated subjects. However, no study has looked its correlation with HDL components nor with HDL function in patients with type 2 diabetes mellitus (T2DM).
We studied 298 non-diabetic subjects and 300 T2DM patients who were randomly recruited in the tertiary referral centre. Plasma levels of ANGPTL3 were quantified by ELISA. Plasma samples were fractionated to obtain HDLs. HDL components including apolipoprotein A-I (apoA-I), triglyceride, serum amyloid A (SAA), phospholipid and Sphingosine-1-phosphate were measured. HDLs were isolated from female controls and T2DM patients by ultracentrifugation to assess cholesterol efflux against HDLs. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, body mass index and lipid lowering drugs were performed in male or female non-diabetic participants or diabetic patients, respectively.
We demonstrated that plasma level of ANGPTL3 was lower in female T2DM patients than female controls although no difference of ANGPTL3 levels was detected between male controls and T2DM patients. After adjusting for confounding factors, one SD increase of ANGPTL3 (164.6 ng/ml) associated with increase of 2.57 mg/dL cholesterol and 1.14 μg/mL apoA-I but decrease of 47.07 μg/L of SAA in HDL particles of non-diabetic females (p < 0.05 for cholesterol and SAA; p < 0.0001 for apoA-I). By contrast, 1-SD increase of ANGPTL3 (159.9 ng/ml) associated with increase of 1.69 mg/dl cholesterol and 1.25 μg/mL apoA-I but decrease of 11.70 μg/L of SAA in HDL particles of female diabetic patients (p < 0.05 for cholesterol; p < 0.0001 for apoA-I; p = 0.676 for SAA). Moreover, one SD increase of ANGPTL3 associated with increase of 2.11 % cholesterol efflux against HDLs in non-diabetic females (p = 0.071) but decrease of 1.46 % in female T2DM patients (p = 0.13) after adjusting for confounding factors.
ANGPTL3 is specifically correlated with HDL-c, apoA-I, SAA and HDL function in female non-diabetic participants. The decrease of ANGPTL3 level in female T2DM patients might contribute to its weak association to HDL components and function. ANGPTL3 could be considered as a novel therapeutic target for HDL metabolism for treating diabetes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0450-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5020513  PMID: 27620179
Angiopoietin-like protein; High-density lipoproteins; Diabetes; Apolipoproteins; Serum amyloid A; Cholesterol efflux
19.  Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice 
Hepatology (Baltimore, Md.)  2015;63(4):1190-1204.
With no approved pharmacological treatment, nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in Western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here, we show that a high‐fat high‐sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic nicotinamide adenine dinucleotide (NAD+) levels driving reductions in hepatic mitochondrial content, function, and adenosine triphosphate (ATP) levels, in conjunction with robust increases in hepatic weight, lipid content, and peroxidation in C57BL/6J mice. To assess the effect of NAD+ repletion on the development of steatosis in mice, nicotinamide riboside, a precursor of NAD+ biosynthesis, was added to the HFHS diet, either as a preventive strategy or as a therapeutic intervention. We demonstrate that NR prevents and reverts NAFLD by inducing a sirtuin (SIRT)1‐ and SIRT3‐dependent mitochondrial unfolded protein response, triggering an adaptive mitohormetic pathway to increase hepatic β‐oxidation and mitochondrial complex content and activity. The cell‐autonomous beneficial component of NR treatment was revealed in liver‐specific Sirt1 knockout mice (Sirt1hep−/−), whereas apolipoprotein E‐deficient mice (Apoe −/−) challenged with a high‐fat high‐cholesterol diet affirmed the use of NR in other independent models of NAFLD. Conclusion: Our data warrant the future evaluation of NAD+ boosting strategies to manage the development or progression of NAFLD. (Hepatology 2016;63:1190–1204)
PMCID: PMC4805450  PMID: 26404765
20.  Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research 
Cell reports  2015;S2211-1247(15)00180-1 10.1016/j.celrep.2015.02.034.
In recent years, tetracyclines, such as doxycycline, have become broadly used to control gene expression by virtue of the Tet-On/Tet-Off systems. The wide range of direct effects of tetracycline use has, however, not been fully appreciated. We show here that these antibiotics induce a mitonuclear protein imbalance through their effects on mitochondrial translation, an effect that likely reflects the evolutionary relationship between mitochondria and proteobacteria. Tetracyclines, Even at low concentrations, tetracyclines induce mitochondrial proteotoxic stress, leading to changes in nuclear gene expression and altered mitochondrial dynamics and function in commonly used cell types, as well as worms, flies, mice, and plants. Since tetracyclines are so widely applied in research, scientists should be aware of their potentially confounding effects on experimental results. Furthermore, these results caution against extensive use of tetracyclines in livestock due to potential downstream impacts on the environment and human health.
PMCID: PMC4565776  PMID: 25772356
21.  Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina 
The Journal of Neuroscience  2016;36(9):2827-2842.
Microglia, the principal resident immune cell of the CNS, exert significant influence on neurons during development and in pathological situations. However, if and how microglia contribute to normal neuronal function in the mature uninjured CNS is not well understood. We used the model of the adult mouse retina, a part of the CNS amenable to structural and functional analysis, to investigate the constitutive role of microglia by depleting microglia from the retina in a sustained manner using genetic methods. We discovered that microglia are not acutely required for the maintenance of adult retinal architecture, the survival of retinal neurons, or the laminar organization of their dendritic and axonal compartments. However, sustained microglial depletion results in the degeneration of photoreceptor synapses in the outer plexiform layer, leading to a progressive functional deterioration in retinal light responses. Our results demonstrate that microglia are constitutively required for the maintenance of synaptic structure in the adult retina and for synaptic transmission underlying normal visual function. Our findings on constitutive microglial function are relevant in understanding microglial contributions to pathology and in the consideration of therapeutic interventions that reduce or perturb constitutive microglial function.
SIGNIFICANCE STATEMENT Microglia, the principal resident immune cell population in the CNS, has been implicated in diseases in the brain and retina. However, how they contribute to the everyday function of the CNS is unclear. Using the model of the adult mouse retina, we examined the constitutive role of microglia by depleting microglia from the retina. We found that in the absence of microglia, retinal neurons did not undergo overt cell death or become structurally disorganized in their processes. However, connections between neurons called synapses begin to break down, leading to a decreased ability of the retina to transmit light responses. Our results indicate that retinal microglia contribute constitutively to the maintenance of synapses underlying healthy vision.
PMCID: PMC4879218  PMID: 26937019
degeneration; electroretinogram; glia; microglia; retina; synapse
22.  Phyllanthus emblica Fruit Extract Activates Spindle Assembly Checkpoint, Prevents Mitotic Aberrations and Genomic Instability in Human Colon Epithelial NCM460 Cells 
The fruit of Phyllanthus emblica Linn. (PE) has been widely consumed as a functional food and folk medicine in Southeast Asia due to its remarkable nutritional and pharmacological effects. Previous research showed PE delays mitotic progress and increases genomic instability (GIN) in human colorectal cancer cells. This study aimed to investigate the similar effects of PE by the biomarkers related to spindle assembly checkpoint (SAC), mitotic aberrations and GIN in human NCM460 normal colon epithelial cells. Cells were treated with PE and harvested differently according to the biomarkers observed. Frequencies of micronuclei (MN), nucleoplasmic bridge (NPB) and nuclear bud (NB) in cytokinesis-block micronucleus assay were used as indicators of GIN. Mitotic aberrations were assessed by the biomarkers of chromosome misalignment, multipolar division, chromosome lagging and chromatin bridge. SAC activity was determined by anaphase-to- metaphase ratio (AMR) and the expression of core SAC gene budding uninhibited by benzimidazoles related 1 (BubR1). Compared with the control, PE-treated cells showed (1) decreased incidences of MN, NPB and NB (p < 0.01); (2) decreased frequencies of all mitotic aberration biomarkers (p < 0.01); and (3) decreased AMR (p < 0.01) and increased BubR1 expression (p < 0.001). The results revealed PE has the potential to protect human normal colon epithelial cells from mitotic and genomic damages partially by enhancing the function of SAC.
PMCID: PMC5037716  PMID: 27598149
Phyllanthus emblica; mitotic aberrations; genomic instability; spindle assembly checkpoint; BubR1
23.  Functional Role and Mechanism of microRNA-28b in Atrial Myocyte in a Persistent Atrial Fibrillation Rat Model 
Persistent atrial fibrillation has been indicated to be related with microRNA-28b. However, the exact role of microRNA-28b in persistent atrial fibrillation needs to be further elucidated. Therefore, this study aimed to establish a rat model of persistent atrial fibrillation to investigate the level of microRNA-28b in atrial myocytes and to explore the molecular mechanism involved.
A persistent atrial fibrillation model was established in rats by using chronic rapid atrial pacing induction. The size of the heart was measured by ultrasonic method. The expression of microRNA-28b in left atrial myocytes was quantified by RT-PCR. Cardiomyocytes were isolated and cultured to detect cell proliferation and apoptosis by MTT and flow cytometry, respectively. The specific inhibitor of ERK signaling pathway, PD98059, was used to further illustrate the role of ERK signaling pathway in the modulation of cardiomyocytes in persistent atrial fibrillation.
MicroRNA-28b was up-regulated in the experimental rat model with persistent atrial fibrillation. The proliferation of cardiomyocytes was significantly inhibited with potentiated apoptosis. Blockage of the ERK pathway suppressed the microRNA-28b expression and inhibited cell apoptosis.
microRNA-28b-induced growth inhibition and cell apoptosis of atrial myocytes was observed in the rat model with persistent atrial fibrillation, via activation of the ERK signaling pathway.
PMCID: PMC5008747  PMID: 27574952
Atrial Natriuretic Factor; Cellulose 1,4-beta-Cellobiosidase; Central Nervous System Vascular Malformations; Mitogen-Activated Protein Kinase 3
24.  OGS2: genome re-annotation of the jewel wasp Nasonia vitripennis 
BMC Genomics  2016;17(1):678.
Nasonia vitripennis is an emerging insect model system with haplodiploid genetics. It holds a key position within the insect phylogeny for comparative, evolutionary and behavioral genetic studies. The draft genomes for N. vitripennis and two sibling species were published in 2010, yet a considerable amount of transcriptiome data have since been produced thereby enabling improvements to the original (OGS1.2) annotated gene set. We describe and apply the EvidentialGene method used to produce an updated gene set (OGS2). We also carry out comparative analyses showcasing the usefulness of the revised annotated gene set.
The revised annotation (OGS2) now consists of 24,388 genes with supporting evidence, compared to 18,850 for OGS1.2. Improvements include the nearly complete annotation of untranslated regions (UTR) for 97 % of the genes compared to 28 % of genes for OGS1.2. The fraction of RNA-Seq validated introns also grow from 85 to 98 % in this latest gene set. The EST and RNA-Seq expression data provide support for several non-protein coding loci and 7712 alternative transcripts for 4146 genes. Notably, we report 180 alternative transcripts for the gene lola.
Nasonia now has among the most complete insect gene set; only 27 conserved single copy orthologs in arthropods are missing from OGS2. Its genome also contains 2.1-fold more duplicated genes and 1.4-fold more single copy genes than the Drosophila melanogaster genome. The Nasonia gene count is larger than those of other sequenced hymenopteran species, owing both to improvements in the genome annotation and to unique genes in the wasp lineage.
We identify 1008 genes and 171 gene families that deviate significantly from other hymenopterans in their rates of protein evolution and duplication history, respectively. We also provide an analysis of alternative splicing that reveals that genes with no annotated isoforms are characterized by shorter transcripts, fewer introns, faster protein evolution and higher probabilities of duplication than genes having alternative transcripts.
Genome-wide expression data greatly improves the annotation of the N. vitripennis genome, by increasing the gene count, reducing the number of missing genes and providing more comprehensive data on splicing and gene structure. The improved gene set identifies lineage-specific genomic features tied to Nasonia’s biology, as well as numerous novel genes.
OGS2 and its associated search tools are available at, and waspAtlas:
The EvidentialGene pipeline is available at
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-2886-9) contains supplementary material, which is available to authorized users.
PMCID: PMC5000498  PMID: 27561358
Genome annotation; Hymenoptera; Parasitoid wasp; Transcriptome; Alternative gene splicing; Gene duplication; Histones; Protein evolution
25.  Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis 
Epigenetics  2015;10(10):958-969.
Epigenetic changes, such as DNA methylation, have been hypothesized to provide a link between the social environment and disease development. The purpose of this study was to examine associations between life course measures of socioeconomic status (SES) and DNA methylation (DNAm) in 18 genes related to stress reactivity and inflammation using a multi-level modeling approach that treats DNAm measurements as repeat measures within an individual. DNAm and gene expression were assessed in purified monocytes for a random subsample of 1,264 non-Hispanic white, African-American, and Hispanic participants aged 55–94 from the Multi-Ethnic Study of Atherosclerosis (MESA). After correction for multiple testing, we found that low childhood SES was associated with DNAm in 3 stress-related genes (AVP, FKBP5, OXTR) and 2 inflammation-related genes (CCL1, CD1D), low adult SES was associated with DNAm in one stress-related gene (AVP) and 5 inflammation-related genes (CD1D, F8, KLRG1, NLRP12, TLR3), and social mobility was associated with DNAm in 3 stress-related genes (AVP, FKBP5, OXTR) and 7 inflammation-related genes (CCL1, CD1D, F8, KLRG1, NLRP12, PYDC1, TLR3). In general, low SES was associated with increased DNAm. Expression data was available for 7 genes that showed a significant relationship between SES and DNAm. In 5 of these 7 genes (CD1D, F8, FKBP5, KLRG1, NLRP12), DNAm was associated with gene expression for at least one transcript, providing evidence of the potential functional consequences of alterations in DNAm related to SES. The results of this study reflect the biological complexity of epigenetic data and underscore the need for multi-disciplinary approaches to study how DNAm may contribute to the social patterning of disease.
PMCID: PMC4844216  PMID: 26295359
DNA methylation; gene expression; inflammation; socioeconomic status; stress reactivity

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