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1.  ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway 
Journal of Virology  2016;90(15):6832-6845.
ABSTRACT
Interferons (IFNs) restrict various kinds of viral infection via induction of hundreds of IFN-stimulated genes (ISGs), while the functions of the majority of ISGs are broadly unclear. Here, we show that a high-IFN-inducible gene, ISG12a (also known as IFI27), exhibits a nonapoptotic antiviral effect on hepatitis C virus (HCV) infection. Viral NS5A protein is targeted specifically by ISG12a, which mediates NS5A degradation via a ubiquitination-dependent proteasomal pathway. K374R mutation in NS5A domain III abrogates ISG12a-induced ubiquitination and degradation of NS5A. S-phase kinase-associated protein 2 (SKP2) is identified as an ubiquitin E3 ligase for NS5A. ISG12a functions as a crucial adaptor that promotes SKP2 to interact with and degrade viral protein. Moreover, the antiviral effect of ISG12a is dependent on the E3 ligase activity of SKP2. These findings uncover an intriguing mechanism by which ISG12a restricts viral infection and provide clues for understanding the actions of innate immunity.
IMPORTANCE Upon virus invasion, IFNs induce numerous ISGs to control viral spread, while the functions of the majority of ISGs are broadly unclear. The present study shows a novel antiviral mechanism of ISGs and elucidated that ISG12a recruits an E3 ligase, SKP2, for ubiquitination and degradation of viral protein and restricts viral infection. These findings provide important insights into exploring the working principles of innate immunity.
doi:10.1128/JVI.00352-16
PMCID: PMC4944290  PMID: 27194766
2.  The Emerging Duck Flavivirus Is Not Pathogenic for Primates and Is Highly Sensitive to Mammalian Interferon Antiviral Signaling 
Journal of Virology  2016;90(14):6538-6548.
ABSTRACT
Flaviviruses pose a significant threat to both animals and humans. Recently, a novel flavivirus, duck Tembusu virus (DTMUV), was identified to be the causative agent of a serious duck viral disease in Asia. Its rapid spread, expanding host range, and uncertain transmission routes have raised substantial concerns regarding its potential threats to nonavian hosts, including humans. Here, we demonstrate that DTMUV is not pathogenic for nonhuman primates and is highly sensitive to mammal type I interferon (IFN) signaling. In vitro assays demonstrated that DTMUV infected and replicated efficiently in various mammalian cell lines. Further tests in mice demonstrated high neurovirulence and the age-dependent neuroinvasiveness of the virus. In particular, the inoculation of DTMUV into rhesus monkeys did not result in either viremia or apparent clinical symptoms, although DTMUV-specific humoral immune responses were detected. Furthermore, we revealed that although avian IFN failed to inhibit DTMUV in avian cells, DTMUV was more sensitive to the antiviral effects of type I interferon than other known human-pathogenic flaviviruses. Knockout of the type I IFN receptor in mice caused apparent viremia, viscerotropic disease, and mortality, indicating a vital role of IFN signaling in protection against DTMUV infection. Collectively, we provide direct experimental evidence that this novel avian-origin DTMUV possesses a limited capability to establish infection in immunocompetent primates due to its decreased antagonistic activity in the mammal IFN system. Furthermore, our findings highlight the potential risk of DTMUV infection in immunocompromised individuals and warrant studies on the cross-species transmission and pathogenesis of this novel flavivirus.
IMPORTANCE Mosquito-borne flaviviruses comprise a large group of pathogenic and nonpathogenic members. The pathogenic flaviviruses include dengue, West Nile, and Japanese encephalitis viruses, and the nonpathogenic flaviviruses normally persist in a natural cycle and rarely cause disease in humans. A novel flavivirus, DTMUV (also known as duck egg drop syndrome flavivirus [DEDSV]) was identified in 2012 in ducks and then rapidly spread to several Asian countries. This new flavivirus was then shown to infect multiple avian species, resulting in neurological symptoms with unknown routes of transmission. There is public concern regarding its potential transmission from birds to humans and other nonavian hosts. Our present study shows that the mammalian IFN system can efficiently eliminate DTMUV infection and that the emergence of severe DTMUV-associated disease in mammals, especially humans, is unlikely. Currently, DTMUV infection mostly affects avian species.
doi:10.1128/JVI.00197-16
PMCID: PMC4936123  PMID: 27147750
3.  STAT3 Undergoes Acetylation-dependent Mitochondrial Translocation to Regulate Pyruvate Metabolism 
Scientific Reports  2016;6:39517.
Cytoplasmic STAT3, after activation by growth factors, translocates to different subcellular compartments, including nuclei and mitochondria, where it carries out different biological functions. However, the precise mechanism by which STAT3 undergoes mitochondrial translocation and subsequently regulates the tricarboxylic acid (TCA) cycle-electron transport chain (ETC) remains poorly understood. Here, we clarify this process by visualizing STAT3 acetylation in starved cells after serum reintroduction or insulin stimulation. CBP-acetylated STAT3 undergoes mitochondrial translocation in response to serum introduction or insulin stimulation. In mitochondria, STAT3 associates with the pyruvate dehydrogenase complex E1 (PDC-E1) and subsequently accelerates the conversion of pyruvate to acetyl-CoA, elevates the mitochondrial membrane potential, and promotes ATP synthesis. SIRT5 deacetylates STAT3, thereby inhibiting its function in mitochondrial pyruvate metabolism. In the A549 lung cancer cell line, constitutively acetylated STAT3 localizes to mitochondria, where it maintains the mitochondrial membrane potential and ATP synthesis in an active state.
doi:10.1038/srep39517
PMCID: PMC5177931  PMID: 28004755
4.  The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1 
Redox Biology  2016;11:297-311.
Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.
doi:10.1016/j.redox.2016.12.022
PMCID: PMC5196243  PMID: 28033563
Mitoq; Diabetic kidney disease; Mitophagy; Tubular
5.  An insoluble frontotemporal lobar degeneration-associated TDP-43 C-terminal fragment causes neurodegeneration and hippocampus pathology in transgenic mice 
Human Molecular Genetics  2015;24(25):7241-7254.
Frontotemporal dementia (FTD) causes progressive personality, behavior and/or language disturbances and represents the second most common form of dementia under the age of 65. Over half of all FTD cases are classified pathologically as frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein of 43 kDa (TDP-43) pathology (FTLD-TDP). In FTLD-TDP brains, TDP-43 is phosphorylated, C-terminally cleaved, lost from the nucleus and accumulates in the cytoplasm and processes of neurons and glia. However, the contribution of TDP-43 C-terminal fragments (CTFs) to pathogenesis remains poorly understood. Here, we developed transgenic (Tg) mice with forebrain Camk2a-controlled doxycycline-suppressible expression of a TDP-43 CTF (amino acids 208–414, designated 208 TDP-43 CTF), previously identified in FTLD-TDP brains. In these 208 TDP-43 Tg mice, detergent-insoluble 208 TDP-43 CTF was present in a diffuse punctate pattern in neuronal cytoplasm and dendrites without forming large cytoplasmic inclusions. Remarkably, the hippocampus showed progressive neuron loss and astrogliosis in the dentate gyrus (DG). This was accompanied by phosphorylated TDP-43 in the CA1 subfield, and ubiquitin and mitochondria accumulations in the stratum lacunosum moleculare (SLM) layer, without loss of endogenous nuclear TDP-43. Importantly, 208 TDP-43 CTF and phosphorylated TDP-43 were rapidly cleared when CTF expression was suppressed in aged Tg mice, which ameliorated neuron loss in the DG despite persistence of ubiquitin accumulation in the SLM. Our results demonstrate that Camk2a-directed 208 TDP-43 CTF overexpression is sufficient to cause hippocampal pathology and neurodegeneration in vivo, suggesting an active role for TDP-43 CTFs in the pathogenesis of FTLD-TDP and related TDP-43 proteinopathies.
doi:10.1093/hmg/ddv424
PMCID: PMC5007600  PMID: 26476406
6.  Adipocyte-derived PAMM suppresses macrophage inflammation by inhibiting MAPK signalling 
The Biochemical journal  2015;472(3):309-318.
Macrophages within adipose tissue play a key role in mediating inflammatory responses in adipose tissue that are associated with obesity-related metabolic complications. In an effort to identify novel proteins secreted from adipocytes that may negatively regulate macrophage inflammation, we found that peroxiredoxin (PRX)-like 2 activated in M-CSF stimulated monocytes (PAMM), a CXXC-type PRX-like 2 domain-containing redox regulatory protein, is a novel secreted protein with potent anti-inflammatory properties. PAMM is secreted from mature human adipocytes but not preadipocytes. Overexpression of PAMM significantly attenuated lipopolysaccharide (LPS)-induced macrophage inflammation. Incubation of macrophages with adipocyte-conditional medium treated with anti-PAMM antibody significantly enhanced LPS-induced interleukin-12 (IL-12) expression in Raw264.7 cells. In addition, incubation of Raw264.7 cells with purified PAMM protein had a similar anti-inflammatory effect. Moreover, forced expression of PAMM in Raw264.7 cells resulted in decreased LPS-induced ERK1/2, p38 and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting that PAMM exerted the anti-inflammatory function probably by suppressing the mitogen-activated protein kinase (MAPK) signalling pathway. Mutations in the CXXC motif of PAMM that suppressed its anti-redox activity were still able to suppress production of inflammatory cytokines in LPS-stimulated macrophages, suggesting that PAMM’s anti-inflammatory properties may be independent of its antioxidant properties. Finally, PAMM was highly expressed in both white (WAT) and brown adipose tissues (BAT) and further increased in obesity status. Our results suggest that adipocyte-derived PAMM may suppress macrophage activation by inhibiting MAPK signalling pathway.
doi:10.1042/BJ20150019
PMCID: PMC4754088  PMID: 26438880
adipocyte; anti-inflammation; macrophage; peroxiredoxin-like 2 activated in M-CSF-stimulated monocytes (PAMM); redox; secreted protein
7.  Intramuscular nerve distribution patterns of anterior forearm muscles in children: a guide for botulinum toxin injection 
Botulinum toxin (BoNT) can relieve muscle spasticity by blocking axon terminals acetylcholine release at the motor endplate (MEP) and is the safest and most effective agent for the treatment of muscle spasticity in children with cerebral palsy. In order to achieve maximum effect with minimum effective dose of BoNT, one needs to choose an injection site as near to the MEP zone as possible. This requires a detailed understanding about the nerve terminal distributions within the muscles targeted for BoNT injection. This study focuses on BoNT treatment in children with muscle spasms caused by cerebral palsy. Considering the differences between children and adults in anatomy, we used child cadavers and measured both the nerve entry points and nerve terminal sense zones in three deep muscles of the anterior forearm: flexor digitorum profundus (FDP), flexor pollicis longus (FPL), and pronator quadratus (PQ). We measured the nerve entry points by using the forearm midline as a reference and demonstrated intramuscular nerve terminal dense zones by using a modified Sihler’s nerve staining technique. The locations of the nerve entry points and that of the nerve terminal dense zones in the muscles were compared. We found that all nerve entry points are away from the corresponding intramuscular nerve terminal dense zones. Simply selecting nerve entry points as the sites for BoNT injection may not be an optimal choice for best effects in blocking muscle spasm. We propose that the location of the nerve terminal dense zones in each individual muscle should be used as the optimal target sites for BoNT injection when treating muscle spasms in children with cerebral palsy.
PMCID: PMC5209499  PMID: 28078019
Anterior forearm muscles; intramuscular nerve; botulinum toxin injection; cerebral palsy; muscle spasms
8.  Tunneling induced absorption with competing Nonlinearities 
Scientific Reports  2016;6:38251.
We investigate tunneling induced nonlinear absorption phenomena in a coupled quantum-dot system. Resonant tunneling causes constructive interference in the nonlinear absorption that leads to an increase of more than an order of magnitude over the maximum absorption in a coupled quantum dot system without tunneling. Resonant tunneling also leads to a narrowing of the linewidth of the absorption peak to a sublinewidth level. Analytical expressions show that the enhanced nonlinear absorption is largely due to the fifth-order nonlinear term. Competition between third- and fifth-order nonlinearities leads to an anomalous dispersion of the total susceptibility.
doi:10.1038/srep38251
PMCID: PMC5153664  PMID: 27958303
9.  Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis 
JCI Insight  null;1(20):e90558.
Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing (scRNA-seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in IPF. Individual IPF cells frequently coexpressed alveolar type 1 (AT1), AT2, and conducting airway selective markers, demonstrating “indeterminate” states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-β, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. The present study provides a rich data source to further explore lung health and disease.
doi:10.1172/jci.insight.90558
PMCID: PMC5135277  PMID: 27942595
10.  iTRAQ-Based Quantitative Proteomic Comparison of Early- and Late-Passage Human Dermal Papilla Cell Secretome in Relation to Inducing Hair Follicle Regeneration 
PLoS ONE  2016;11(12):e0167474.
Alopecia is an exceedingly prevalent problem that lacks effective therapy. Recently, research has focused on early-passage dermal papilla cells (DPCs), which have hair inducing activity both in vivo and in vitro. Our previous study indicated that factors secreted from early-passage DPCs contribute to hair follicle (HF) regeneration. To identify which factors are responsible for HF regeneration and why late-passage DPCs lose this potential, we collected 48-h-culture medium (CM) from both of passage 3 and 9 DPCs, and subcutaneously injected the DPC-CM into NU/NU mice. Passage 3 DPC-CM induced HF regeneration, based on the emergence of a white hair coat, but passage 9 DPC-CM did not. In order to identify the key factors responsible for hair induction, CM from passage 3 and 9 DPCs was analyzed by iTRAQ-based quantitative proteomic technology. We identified 1360 proteins, of which 213 proteins were differentially expressed between CM from early-passage vs. late-passage DPCs, including SDF1, MMP3, biglycan and LTBP1. Further analysis indicated that the differentially-expressed proteins regulated the Wnt, TGF-β and BMP signaling pathways, which directly and indirectly participate in HF morphogenesis and regeneration. Subsequently, we selected 19 proteins for further verification by multiple reaction monitoring (MRM) between the two types of CM. These results indicate DPC-secreted proteins play important roles in HF regeneration, with SDF1, MMP3, biglycan, and LTBP1 being potential key inductive factors secreted by dermal papilla cells in the regeneration of hair follicles.
doi:10.1371/journal.pone.0167474
PMCID: PMC5132394  PMID: 27907131
11.  Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43 
Acta neuropathologica  2015;130(5):643-660.
Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (ΔNLS) under the control of the neurofilament heavy chain promoter. Expression of hTDP-43ΔNLS in these ‘regu-latable NLS’ (rNLS) mice resulted in the accumulation of insoluble, phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor neuron loss, and progressive motor impairments leading to death. Notably, suppression of hTDP-43ΔNLS expression by return of Dox to rNLS mice after disease onset caused a dramatic decrease in phosphorylated TDP-43 pathology, an increase in nuclear mTDP-43 to control levels, and the prevention of further motor neuron loss. rNLS mice back on Dox also showed a significant increase in muscle innervation, a rescue of motor impairments, and a dramatic extension of lifespan. Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP. Importantly, even after neurodegeneration and onset of motor dysfunction, removal of cytoplasmic TDP-43 and the concomitant return of nuclear TDP-43 led to neuron preservation, muscle re-innervation and functional recovery.
doi:10.1007/s00401-015-1460-x
PMCID: PMC5127391  PMID: 26197969
Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia (FTD); Frontotemporal lobar degeneration (FTLD); TDP-43; Neurodegeneration; Motor neuron; Spinal cord; Mouse model
12.  Enabling the democratization of the genomics revolution with a fully integrated web-based bioinformatics platform 
Nucleic Acids Research  2016;45(1):67-80.
Continued advancements in sequencing technologies have fueled the development of new sequencing applications and promise to flood current databases with raw data. A number of factors prevent the seamless and easy use of these data, including the breadth of project goals, the wide array of tools that individually perform fractions of any given analysis, the large number of associated software/hardware dependencies, and the detailed expertise required to perform these analyses. To address these issues, we have developed an intuitive web-based environment with a wide assortment of integrated and cutting-edge bioinformatics tools in pre-configured workflows. These workflows, coupled with the ease of use of the environment, provide even novice next-generation sequencing users with the ability to perform many complex analyses with only a few mouse clicks and, within the context of the same environment, to visualize and further interrogate their results. This bioinformatics platform is an initial attempt at Empowering the Development of Genomics Expertise (EDGE) in a wide range of applications for microbial research.
doi:10.1093/nar/gkw1027
PMCID: PMC5224473  PMID: 27899609
13.  Fluorescence- and magnetic-activated cell sorting strategies to separate spermatozoa involving plural contributors from biological mixtures for human identification 
Scientific Reports  2016;6:36515.
No effective method has been developed to distinguish sperm cells originating from different men in multi-suspect sexual assault cases. Here we combined MACS and FACS to isolate single donor sperm cells from forensic mixture samples including female vaginal epithelial cells and sperm cells from multiple contributors. Sperms from vaginal swab were isolated by MACS using FITC-conjugated A kinase anchor protein 3 (AKAP3) antibody; target individual sperm cells involving two or three donors were separated by FACS using FITC-labeled blood group A/B antigen antibody. This procedure was further tested in two mock multi-suspect sexual assault samples and one practical casework sample. Our results showed that complete single donor STR profiles could be successfully obtained from sperm/epithelial cell and sperm mixtures from two contributors. For unbalanced sperm/epithelial cells and sperm cells mixtures, sensitivity results revealed that target cells could be detected at as low as 1:32 and 1:8 mixed ratios, respectively. Although highly relies on cell number and blood types or secretor status of the individuals, this procedure would still be useful tools for forensic DNA analysis of multi-suspect sexual assault cases by the combined use of FACS and MACS based on sperm-specific AKAP3 antigen and human blood type antigen.
doi:10.1038/srep36515
PMCID: PMC5114643  PMID: 27857155
14.  Extended Course and Increased Dose of Initial Chemotherapy for Extranodal Nasal Type Natural Killer/T (NK/T)-Cell Lymphoma in Patients <60 Years Old: A Single-Center Retrospective Cohort Study 
Background
Extranodal NK/T-cell lymphoma (ENKTL) of the nasal type is highly invasive and relatively resistant to chemotherapy. This study aimed to assess the efficacy and safety of an extended chemotherapy regimen with increased dose intensity.
Material/Methods
This was a retrospective cohort study of 69 patients <60 years old with an ECOG score 0–2 treated for ENKTL at the Second Affiliated Hospital of Xi’an Jiaotong University between January 2004 and December 2013. The outcomes were compared between patients who received >8 courses of high-intensity chemotherapy (n=37) vs. 6–8 courses (n=18) and <6 courses (n=14) of conventional chemotherapy. Regimens included improved CHOP, CHOP-E, EPOCH, MAED, MMED, SMILE, and Hyper-CVAD with an increased dose intensity in the >8 courses group.
Results
The mean follow-up was 52 months (8 to 82 months). Remission rate did not differ significantly when compared among the 3 groups after 3 courses of chemotherapy (83.8%, 77.8%, and 78.6%, respectively, overall P=0.834), but the 5-year overall survival (OS) differed significantly (63.5%, 45.1%, and 22.9%, respectively, overall P=0.030), as did progression-free survival (PFS) (59.1%, 36.0%, and 15.1%, respectively, overall P=0.020), disease-free survival (DFS) (54.1%, 35.5%, and 12.9%, respectively, overall P=0.022), and total relapse rate throughout follow-up (37.04%, 50.0%, and 88.89%, respectively, overall P=0.027). There were no differences in adverse effects among the 3 groups.
Conclusions
These results suggest improved OS, PFS, DFS, and relapse rate in young patients with ENKTL receiving >8 courses of high-intensity chemotherapy.
doi:10.12659/MSM.897650
PMCID: PMC5117239  PMID: 27843135
Drug Therapy; Lymphoma, Extranodal NK-T-Cell; Survival
15.  Non-invasive metabolomic profiling of embryo culture media and morphology grading to predict implantation outcome in frozen-thawed embryo transfer cycles 
Purpose
Assessment of embryo viability is a crucial component of in vitro fertilization and currently relies largely on embryo morphology and cleavage rate. Because morphological assessment remains highly subjective, it can be unreliable in predicting embryo viability. This study investigated the metabolomic profiling of embryo culture media using near-infrared (NIR) spectroscopy for predicting the implantation potential of human embryos in frozen-thawed embryo transfer (FET) cycles.
Methods
Spent embryo culture media was collected on day 4 after thawed embryo transfer (n = 621) and analysed using NIR spectroscopy. Viability scores were calculated using a predictive multivariate algorithm of fresh embryos with known pregnancy outcomes.
Results
The mean viability indices of embryos resulting in clinical pregnancy following FET were significantly higher than those of non-implanted embryos and differed between the 0, 50, and 100 % implantation groups. Notably, the 0 % group index was significantly lower than the 100 % implantation group index (–0.787 ± 0.382 vs. 1.064 ± 0.331, P < 0.01). To predict implantation outcomes, we examined the area under the ROC curve (AUCROC), which was significantly higher for the viability than for the morphology score (0.94 vs. 0.55; P < 0.01); however, the AUCROCs for the composite and viability scores did not differ significantly (0.92 vs. 0.94; P > 0.05).
Conclusions
NIR metabolomic profiling of thawed embryo culture media is independent of morphology and correlates with embryo implantation potential in FET cycles. The viability score alone or in conjunction with morphologic grading is a more objective marker for implantation outcome in FET cycles than morphology alone.
doi:10.1007/s10815-015-0578-z
PMCID: PMC4651941  PMID: 26463877
Near infrared spectroscopy/NIR; Non-invasive embryo selection; Viability score; Morphologic grading; Frozen-thawed embryo transfer/FET
16.  Photoperiod induced obesity in the Brandt's vole (Lasiopodomys brandtii): a model of ‘healthy obesity’? 
Disease Models & Mechanisms  2016;9(11):1357-1366.
ABSTRACT
Brandt's voles have an annual cycle of body weight and adiposity. These changes can be induced in the laboratory by manipulation of photoperiod. In the present study, male captive-bred Brandt's voles aged 35 days were acclimated to a short day (SD) photoperiod (8L:16D) for 70 days. A subgroup of individuals (n=16) were implanted with transmitters to monitor physical activity and body temperature. They were then randomly allocated into long day (LD=16L:8D) (n=19, 8 with transmitters) and SD (n=18, 8 with transmitters) groups for an additional 70 days. We monitored aspects of energy balance, glucose and insulin tolerance (GTT and ITT), body composition and organ fat content after exposure to the different photoperiods. LD voles increased in weight for 35 days and then re-established stability at a higher level. At the end of the experiment LD-exposed voles had greater white adipose tissue mass than SD voles (P=0.003). During weight gain they did not differ in their food intake or digestive efficiency; however, daily energy expenditure was significantly reduced in the LD compared with SD animals (ANCOVA, P<0.05) and there was a trend to reduced resting metabolic rate RMR (P=0.075). Physical activity levels were unchanged. Despite different levels of fat storage, the GTT and ITT responses of SD and LD voles were not significantly different, and these traits were not correlated to body fatness. Hence, the photoperiod-induced obesity was independent on disruptions to glucose homeostasis, indicating a potential adaptive decoupling of these states in evolutionary time. Fat content in both the liver and muscle showed no significant difference between LD and SD animals. How voles overcome the common negative aspects of fat storage might make them a useful model for understanding the phenomenon of ‘healthy obesity’.
Summary: Obesity induced by long-day photoperiod in voles is not accompanied by impaired glucose tolerance or insulin sensitivity and might be a useful model of ‘healthy obesity’.
doi:10.1242/dmm.026070
PMCID: PMC5117229  PMID: 27736740
Brandt's vole; Photoperiod; Healthy obesity; Glucose tolerance; Insulin sensitivity; Lipotoxicity; Adipose tissue expandability
17.  Aquaporin 1 contributes to chondrocyte apoptosis in a rat model of osteoarthritis 
Aquaporins (AQPs) have been found to be associated with a number of diseases. However, the role of AQP-1 in the pathogenesis of osteoarthritis remains unclear. We previously found that AQP-1 expression was upregulated in osteoarthritic cartilage and strongly correlated with caspase-3 expression and activity. The aim of this study was to further investigate the association of AQP-1 expression with chondrocyte apoptosis in a rat model of osteoarthritis, using RNA interference to knock down AQP-1. For this purspose, 72 male Sprague-Dawley rats were randomly assigned to 3 groups as follows: the control group not treated surgically (n=24), the sham-operated group (n=24), and the osteoarthritis group (n=24). Osteoarthritis was induced by amputating the anterior cruciate ligament and medial collateral ligament and partially excising the medial meniscus. Chondrocytes from the rats with osteoarthritis were isolated and cultured. shRNAs were used to knock down AQP-1 expression in the cultured chondrocytes. The expression of AQP-1 and caspase-3 was determined by reverse transcription-quantitative polymerase chain reaction. Caspase-3 activity was measured using a caspase-3 colorimetric assay. The rats in our model of osteoarthritis exhibited severe cartilage damage. The knockdown of AQP-1 decreased caspase-3 expression and activity in the cultured chondrocytes. In addition, the expression of AQP-1 positively correlated with caspase-3 expression and activity. Thus, the findings of our study, suggest that AQP-1 promotes caspase-3 activation and thereby contributes to chondrocyte apoptosis and to the development of osteoarthritis.
doi:10.3892/ijmm.2016.2785
PMCID: PMC5117737  PMID: 27779640
osteoarthritis; aquaporin 1; chondrocyte; apoptosis
18.  Clinicopathological and Prognostic Factors in 106 Prostate Cancer Patients Aged ≤55 Years: A Single-Center Study in China 
Background
Early-onset prostate cancer patients (aged ≤55 years) from Western countries have been well characterized in previous studies. However, the clinicopathological and prognostic characteristics of early-onset Chinese prostate cancer patients have not yet been assessed. This study aimed to examine the clinicopathological and prognostic factors of prostate cancer patients aged ≤55 years in a single Chinese center.
Material/Methods
One hundred six prostate cancer patients aged ≤55 years with complete clinicopathological data who were treated at our hospital between January 2000 and June 2014 were selected for this study. Survival rate was investigated by Kaplan-Meier analysis, and prognostic factors were examined by univariate and multivariate analysis.
Results
The median time from the onset of symptoms to diagnosis was 3.5 months (range, 2–55 months). The median time after endocrine therapy to development of androgen-independent prostate cancer was 10.5 months. A total of 54 patients died (50.9%), of whom 96.2% died from prostate cancer. The 1-, 3-, and 5-year overall survival rates were 88.7%, 66.2%, and 36.0%, respectively. Univariate and multivariate analysis showed that T staging, visceral metastasis, pathological pattern, and Gleason sum were independent prognostic factors in these patients.
Conclusions
Prostate cancer patients aged ≤55 years are often omitted or misdiagnosed in China. Furthermore, the pathology patterns in this age group were mostly complicated with a high degree of malignancy. Late staging, visceral metastasis, pathological pattern, and high Gleason score were independent prognostic factors in these patients. Comprehensive therapy combined with local therapy is an effective treatment strategy.
doi:10.12659/MSM.901040
PMCID: PMC5081234  PMID: 27771734
China; Prognosis; Prostatic Neoplasms
19.  H19 Long Noncoding RNA Regulates Intestinal Epithelial Barrier Function via MicroRNA 675 by Interacting with RNA-Binding Protein HuR 
Molecular and Cellular Biology  2016;36(9):1332-1341.
The disruption of the intestinal epithelial barrier function occurs commonly in various pathologies, but the exact mechanisms responsible are unclear. The H19 long noncoding RNA (lncRNA) regulates the expression of different genes and has been implicated in human genetic disorders and cancer. Here, we report that H19 plays an important role in controlling the intestinal epithelial barrier function by serving as a precursor for microRNA 675 (miR-675). H19 overexpression increased the cellular abundance of miR-675, which in turn destabilized and repressed the translation of mRNAs encoding tight junction protein ZO-1 and adherens junction E-cadherin, resulting in the dysfunction of the epithelial barrier. Increasing the level of the RNA-binding protein HuR in cells overexpressing H19 prevented the stimulation of miR-675 processing from H19, promoted ZO-1 and E-cadherin expression, and restored the epithelial barrier function to a nearly normal level. In contrast, the targeted deletion of HuR in intestinal epithelial cells enhanced miR-675 production in the mucosa and delayed the recovery of the gut barrier function after exposure to mesenteric ischemia/reperfusion. These results indicate that H19 interacts with HuR and regulates the intestinal epithelial barrier function via the H19-encoded miR-675 by altering ZO-1 and E-cadherin expression posttranscriptionally.
doi:10.1128/MCB.01030-15
PMCID: PMC4836219  PMID: 26884465
20.  The rs6771157 C/G polymorphism in SCN10A is associated with the risk of atrial fibrillation in a Chinese Han population 
Scientific Reports  2016;6:35212.
A recent genome wide associated study in European descent population identified the association of Atrial fibrillation (AF) risk with a single nucleotide polymorphism (SNP) in SCN10A. The aim of this study was to evaluate whether SCN10A polymorphisms are associated with AF risk in the Chinese Han population. A total of 2,300 individuals of Chinese Han origin were recruited and three potentially functional SNPs were genotyped. Logistic regression models were utilized to calculate odds ratios (ORs) at a 95% confidence intervals (CIs). Logistic regression analysis in an additive genetic model revealed that one SNP in SCN10A (rs6771157) was associated with an increased risk of AF (adjusted OR = 1.20, 95% CI: 1.06 - 1.36, P = 0.003). Stratification analysis of several main AF risk factors indicated that the risk associations with rs6771157 were not statistically different among different subgroups. In summary, our study suggests the possible involvement of the SCN10A variant in AF development in Chinese Han populations. Further biological function analyses are required to confirm our finding.
doi:10.1038/srep35212
PMCID: PMC5057108  PMID: 27725708
21.  Flare differentially rotates sunspot on Sun's surface 
Nature Communications  2016;7:13104.
Sunspots are concentrations of magnetic field visible on the solar surface (photosphere). It was considered implausible that solar flares, as resulted from magnetic reconnection in the tenuous corona, would cause a direct perturbation of the dense photosphere involving bulk motion. Here we report the sudden flare-induced rotation of a sunspot using the unprecedented spatiotemporal resolution of the 1.6 m New Solar Telescope, supplemented by magnetic data from the Solar Dynamics Observatory. It is clearly observed that the rotation is non-uniform over the sunspot: as the flare ribbon sweeps across, its different portions accelerate (up to ∼50° h−1) at different times corresponding to peaks of flare hard X-ray emission. The rotation may be driven by the surface Lorentz-force change due to the back reaction of coronal magnetic restructuring and is accompanied by a downward Poynting flux. These results have direct consequences for our understanding of energy and momentum transportation in the flare-related phenomena.
Sunspots are concentration of magnetic field visible on the solar surface, which were thought to be unaffected by solar flares that take place in the solar corona. Here the authors report evidence of a flare-induced rotation of a sunspot, showing nonuniform acceleration following the peaks of X-ray emissions.
doi:10.1038/ncomms13104
PMCID: PMC5062561  PMID: 27721463
22.  Multifocal extranodal lymphoma 
Medicine  2016;95(40):e5029.
Abstract
Introduction:
We report an unusual and interesting case of non-Hodgkin lymphoma involving 7 extranodal sites.
In this case, a 43-year-old woman with diffuse large B-cell lymphoma, including stomach, breasts, pancreas, adrenal glands, ovary and bones, was confirmed by biopsy and positron emission tomography/computed tomography scan. The patient achieved a complete response after 2 cycles of chemotherapy with combined rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, but subsequently developed central nervous system involvement.
Conclusion:
This case illustrated the usefulness of positron emission tomography/computed tomography in diagnosis, disease staging, and assessment of response to therapy. Selection of the optimal treatment regimen is challenging and needs further research.
doi:10.1097/MD.0000000000005029
PMCID: PMC5059066  PMID: 27749564
central nervous system involvement; diffuse large B cell lymphoma; multifocal extranodal lymphoma; positron emission tomography/computed tomography
23.  Small dense low-density lipoprotein cholesterol was associated with future cardiovascular events in chronic kidney disease patients 
BMC Nephrology  2016;17:143.
Background
Cardiovascular disease (CVD) is often comorbid with chronic kidney disease (CKD). Small low-density lipoprotein cholesterol (sdLDL-C) has also been found to increase risk for CVD. The goal of the present study was to determine the nature of the relationship between sdLDL-C concentration and CVD in patients with CKD.
Methods
One-hundred and forty-five subjects (113 men and 32 women) with CKD (Stage 3 and Stage 4) participated this retrospective study. The concentration of sdLDL-C was measured in samples from 145 CKD patients between 2010 and 2012 during a four-year follow-up period.
Results
A total of eight fatal cardiovascular events (CVs) and 46 nonfatal CVs were registered in the four-year follow-up period. Multivariate Cox regression analysis showed that sdLDL-C [1.278, 95 % (1.019–1.598)] and sdLDL-C/LDL-C [2.456, 95 % (1.421–15.784)], at final observation, were independent risks of CVs. A Kaplan-Meier survival analysis showed that patients with sdLDL-C >38 mg/dl (logrank: 4.375, P = 0.037), and sdLDL-C/LDL-C ratio >0.3 levels (logrank: 11.94, P = 0.018) were at increased risk for CVs.
Conclusion
The results of this study indicated that for patients suffering CKD, a significant relationship exists between an elevated sdLDL-C concentration and the risk of cardiovascular disease.
doi:10.1186/s12882-016-0358-8
PMCID: PMC5053337  PMID: 27716087
Chronic kidney disease; Cardiovascular diseases; Lipids; sdLDL-C
24.  Edible Safety Assessment of Genetically Modified Rice T1C-1 for Sprague Dawley Rats through Horizontal Gene Transfer, Allergenicity and Intestinal Microbiota 
PLoS ONE  2016;11(10):e0163352.
In this study, assessment of the safety of transgenic rice T1C-1 expressing Cry1C was carried out by: (1) studying horizontal gene transfer (HGT) in Sprague Dawley rats fed transgenic rice for 90 d; (2) examining the effect of Cry1C protein in vitro on digestibility and allergenicity; and (3) studying the changes of intestinal microbiota in rats fed with transgenic rice T1C-1 in acute and subchronic toxicity tests. Sprague Dawley rats were fed a diet containing either 60% GM Bacillus thuringiensis (Bt) rice T1C-1 expressing Cry1C protein, the parental rice Minghui 63, or a basic diet for 90 d. The GM Bt rice T1C-1 showed no evidence of HGT between rats and transgenic rice. Sequence searching of the Cry1C protein showed no homology with known allergens or toxins. Cry1C protein was rapidly degraded in vitro with simulated gastric and intestinal fluids. The expressed Cry1C protein did not induce high levels of specific IgG and IgE antibodies in rats. The intestinal microbiota of rats fed T1C-1 was also analyzed in acute and subchronic toxicity tests by DGGE. Cluster analysis of DGGE profiles revealed significant individual differences in the rats' intestinal microbiota.
doi:10.1371/journal.pone.0163352
PMCID: PMC5051820  PMID: 27706188
25.  Illuminating Anaerobic Microbial Community and Cooccurrence Patterns across a Quality Gradient in Chinese Liquor Fermentation Pit Muds 
Fermentation pit mud, an important reservoir of diverse anaerobic microorganisms, is essential for Chinese strong-aroma liquor production. Pit mud quality, according to its sensory characteristics, can be divided into three grades: degraded, normal, and high quality. However, the relationship between pit mud microbial community and pit mud quality is poorly understood, as are microbial associations within the pit mud ecosystem. Here, microbial communities at these grades were compared using Illumina MiSeq sequencing of the variable region V4 of the 16S rRNA gene. Our results revealed that the pit mud microbial community was correlated with its quality and environmental factors. Species richness, biodiversity, and relative and/or absolute abundances of Clostridia, Clostridium kluyveri, Bacteroidia, and Methanobacteria significantly increased, with corresponding increases in levels of pH, NH4+, and available phosphorus, from degraded to high-quality pit muds, while levels of Lactobacillus, dissolved organic carbon, and lactate significantly decreased, with normal samples in between. Furthermore, 271 pairs of significant and robust correlations (cooccurrence and negative) were identified from 76 genera using network analysis. Thirteen hubs of cooccurrence patterns, mainly under the Clostridia, Bacteroidia, Methanobacteria, and Methanomicrobia, may play important roles in pit mud ecosystem stability, which may be destroyed with rapidly increased levels of lactic acid bacteria (Lactobacillus, Pediococcus, and Streptococcus). This study may help clarify the relationships among microbial community, environmental conditions, and pit mud quality, allow the improvement of pit mud quality by using bioaugmentation and controlling environmental factors, and shed more light on the ecological rules guiding community assembly in pit mud.
doi:10.1128/AEM.03409-15
PMCID: PMC4959489  PMID: 26896127

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