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1.  Cumulative mtDNA damage and mutations contribute to the progressive loss of RGCs in a rat model of glaucoma 
Neurobiology of disease  2014;74:167-179.
Glaucoma is a chronic neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Mitochondrial DNA (mtDNA) alterations have been documented as a key component of many neurodegenerative disorders. However, whether mtDNA alterations contribute to the progressive loss of RGCs and the mechanism whereby this phenomenon could occur are poorly understood. We investigated mtDNA alterations in RGCs using a rat model of chronic intraocular hypertension and explored the mechanisms underlying progressive RGC loss. We demonstrate that the mtDNA damage and mutations triggered by intraocular pressure (IOP) elevation are initiating, crucial events in a cascade leading to progressive RGC loss. Damage to and mutation of mtDNA, mitochondrial dysfunction, reduced levels of mtDNA repair/replication enzymes, and elevated reactive oxygen species form a positive feedback loop that produces irreversible mtDNA damage and mutation and contributes to progressive RGC loss, which occurs even after a return to normal IOP. Furthermore, we demonstrate that mtDNA damage and mutations increase the vulnerability of RGCs to elevated IOP and glutamate levels, which are among the most common glaucoma insults. This study suggests that therapeutic approaches that target mtDNA maintenance and repair and that promote energy production may prevent the progressive death of RGCs.
doi:10.1016/j.nbd.2014.11.014
PMCID: PMC4523228  PMID: 25478814
retinal ganglion cell; glaucoma; mitochondrial DNA; mutation
2.  Clinical outcomes among women with mucinous adenocarcinoma of the ovary 
Background/Aims
Patterns of metastasis and clinical behavior of mucinous ovarian cancers are poorly understood because of their rarity.
Methods
A retrospective review of records of women identified with pure mucinous invasive ovarian/tubal/peritoneal cancer 1992–2012 at one institution. Survival differences were compared using Kaplan-Meier methods with log-rank tests.
Results
Among 42 women with mucinous adenocarcinomas the median age was 55 years (range 33–83 years). Most cancers were well differentiated (n = 26, 68%) and stage I/II (n = 31, 74%). One of 27 women with sampled nodes had nodal metastasis; one additional woman recurred in a pelvic node. Most had no visible residual tumor after initial surgery, but of 10 women with stage III/IV cancer and documented residual, 8 had >2cm residual. Except for one woman alive with disease at last follow-up, all who recurred died of disease. Five-year survival was 83% for stage I/II cases but 29% among stage III/IV cases. Stage was a strong predictor of survival (hazard ratio of death among women with stage III/IV cancer 7.73, 95% C.I. 2.33–25.66, P<0.001 vs women with stage I/II cancer).
Conclusion
Mucinous ovarian cancers have a distinct biology, such that lymphadenectomy for staging is unnecessary and metastatic cancers have poor prognosis.
doi:10.1159/000441791
PMCID: PMC4874917  PMID: 26583769
ovarian cancer; mucinous adenocarcinoma; survival analysis
3.  Understanding the Interactions between Porphyrin-Containing Photosensitizers and Polymer-Coated Nanoparticles in Model Biological Environments 
Non-covalent incorporation of hydrophobic drugs into polymeric systems is a commonly-used strategy for drug delivery because non-covalent interactions minimize modification of the drug molecules whose efficacy is retained upon release. The behaviors of the drug-polymer delivery system in the biological environments it encounters will affect the efficacy of treatment. In this report, we have investigated the interaction between a hydrophobic drug and its encapsulating polymer in model biological environment using a photosensitizer encapsulated in a polymer-coated nanoparticle system. The photosensitizer, 3-(1′-hexyloxyethyl)-3-devinylpyropheophorbide-a (HPPH), was non-covalently incorporated to the poly(ethylene glycol) (PEG) layer coated on Au nanocages (AuNCs) to yield AuNC-HPPH complexes. The non-covalent binding was characterized by Scatchard analysis, fluorescence lifetime, and Raman experiments. The dissociation constant (Kd) between PEG and HPPH was found to be ~35 μM with a maximum loading of ~2.5 × 105 HPPHs/AuNC. The release was studied in serum mimetic environment and in vesicles that model human cell membranes. The rate of protein-mediated drug release decreased when using a negatively-charged or cross-linked terminus of the surface-modified PEG. Furthermore, the photothermal effect of AuNCs can initiate burst release, and thus allow control of the release kinetics, demonstrating on-demand drug release. This study provides insights regarding the actions and release kinetics of non-covalent drug delivery systems in biological environments.
Graphical abstract
doi:10.1016/j.jcis.2015.09.037
PMCID: PMC4980129  PMID: 26402781
gold nanostructure; drug delivery; PEG coating; controlled release
4.  Complete Genome Sequence of the Industrial Bacterium Ketogulonicigenium vulgare SKV 
Genome Announcements  2016;4(6):e01426-16.
Ketogulonicigenium vulgare has been widely used in vitamin C two-step fermentation, which converts l-sorbose to 2-keto-l-gluonic acid. Here, the complete genome of K. vulgare SKV, which performs better fermentation production than K. vulgare Hbe602, is deciphered to understand the key differences in metabolism between K. vulgare strains SKV and Hbe602.
doi:10.1128/genomeA.01426-16
PMCID: PMC5180388  PMID: 28007860
5.  The use of aminoglycoside derivatives to study the mechanism of aminoglycoside 6′-N-acetyltransferase and the role of 6′-NH2 in antibacterial activity 
Bioorganic & medicinal chemistry  2007;15(8):2944-2951.
Aminoglycoside antibiotics act by binding to 16S rRNA. Resistance to these antibiotics occurs via drug modifications by enzymes such as aminoglycoside 6′-N-acetyltransferases (AAC(6′)s). We report here the regioselective and efficient synthesis of N-6′-acylated aminoglycosides and their use as probes to study AAC(6′)-Ii and aminoglycoside-RNA complexes. Our results emphasize the central role of N-6′ nucleophilicity for transformation by AAC(6′)-Ii and the importance of hydrogen bonding between 6′-NH2 and 16S rRNA for antibacterial activity.
doi:10.1016/j.bmc.2007.02.009
PMCID: PMC5173354  PMID: 17317190 CAMSID: cams6381
antibiotic; A-site; neamine; regioselective; resistance
6.  Fast Dissemination of New HIV-1 CRF02/A1 Recombinants in Pakistan 
PLoS ONE  2016;11(12):e0167839.
A number of HIV-1 subtypes are identified in Pakistan by characterization of partial viral gene sequences. Little is known whether new recombinants are generated and how they disseminate since whole genome sequences for these viruses have not been characterized. Near full-length genome (NFLG) sequences were obtained by amplifying two overlapping half genomes or next generation sequencing from 34 HIV-1-infected individuals in Pakistan. Phylogenetic tree analysis showed that the newly characterized sequences were 16 subtype As, one subtype C, and 17 A/G recombinants. Further analysis showed that all 16 subtype A1 sequences (47%), together with the vast majority of sequences from Pakistan from other studies, formed a tight subcluster (A1a) within the subtype A1 clade, suggesting that they were derived from a single introduction. More in-depth analysis of 17 A/G NFLG sequences showed that five shared similar recombination breakpoints as in CRF02 (15%) but were phylogenetically distinct from the prototype CRF02 by forming a tight subcluster (CRF02a) while 12 (38%) were new recombinants between CRF02a and A1a or a divergent A1b viruses. Unique recombination patterns among the majority of the newly characterized recombinants indicated ongoing recombination. Interestingly, recombination breakpoints in these CRF02/A1 recombinants were similar to those in prototype CRF02 viruses, indicating that recombination at these sites more likely generate variable recombinant viruses. The dominance and fast dissemination of new CRF02a/A1 recombinants over prototype CRF02 suggest that these recombinant have more adapted and may become major epidemic strains in Pakistan.
doi:10.1371/journal.pone.0167839
PMCID: PMC5156399  PMID: 27973597
7.  Discussion on software aging management of nuclear power plant safety digital control system 
SpringerPlus  2016;5(1):2092.
Managing the aging of digital control systems ensures that nuclear power plant systems are in adequate safety margins during their life cycles. Software is a core component in the execution of control logic and differs between digital and analog control systems. The hardware aging management for the digital control system is similar to that for the analog system, which has matured over decades of study. However, software aging management is still in the exploratory stage. Software aging evaluation is critical given the higher reliability and safety requirements of nuclear power plants. To ensure effective inputs for reliability assessment, this paper provides the required software aging information during the life cycle. Moreover, the software aging management scheme for safety digital control system is proposed on the basis of collected aging information.
doi:10.1186/s40064-016-3780-2
PMCID: PMC5153394  PMID: 28028490
Safety digital control system; Software aging factors; Software aging management
8.  Use of bedaquiline and delamanid in diabetes patients: clinical and pharmacological considerations 
Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo® (bedaquiline) and Deltyba® (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients. Possible alterations in the pharmacokinetics of these novel drugs induced by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy in diabetes patients, and possible drug–drug interactions with hypoglycemic agents, are of special interest, since the efficacy of bedaquiline and delamanid is concentration dependent. Moreover, it is of fundamental importance to avoid possible additive or synergistic effects of adverse drug reactions in this already vulnerable patient group. We reviewed clinical particularities related to the use of bedaquiline and delamanid in patients with type 1 and 2 diabetes mellitus (DM), as well as pharmacological aspects of the concurrent use of these agents with oral and injectable hypoglycemic agents. Bedaquiline shares liver metabolic pathways with several oral hypoglycemic agents, whereas delamanid may compete with several oral hypoglycemic agents and insulin analogs at protein-binding sites. Special concern exists regarding the use of bedaquiline and delamanid in diabetes patients aged >65 years and patients with severe renal or hepatic impairment or electrolyte disturbances. Concurrent use of bedaquiline and delamanid with insulin analogs, and other hypoglycemic agents that prolong the heart rate-corrected QT interval, such as sulfonylureas and glinides, may enhance this adverse reaction. Hepatic-related adverse reactions may develop more frequently when these drugs are combined with thiazolidinediones and acarbose. Data from Phase III and postmarketing studies are needed to elucidate the effect of DM and hypoglycemic agents on bedaquiline and delamanid effects in MDR-TB patients.
doi:10.2147/DDDT.S121630
PMCID: PMC5153280  PMID: 27994440
bedaquiline; delamanid; oral hypoglycemic agents; insulin analogs; pharmacokinetics
9.  Palladium-Catalyzed Benzylic C–H Arylation of Azaarylmethylamines 
Organic letters  2015;17(23):5788-5791.
A direct C–H functionalization approach to produce aryl(azaaryl)methylamines from azaarylmethylamines without directing groups is described. Under conditions where the azaarylmethylamines’ C–H is reversibly deprotonated, a Pd(OAc)2/NIXANTPHOS-based catalyst couples the resulting carbanions with various aryl halides to provide aryl(azaaryl)methylamines. This umpolung strategy directly provides tertiary amines without protecting or activating groups.
doi:10.1021/acs.orglett.5b02898
PMCID: PMC4880366  PMID: 26576005
10.  Risk Factors and Treatment for Hemorrhage after Pancreaticoduodenectomy: A Case Series of 423 Patients 
BioMed Research International  2016;2016:2815693.
The study aimed to investigate the risk factors of postpancreatectomy hemorrhage (PPH) after pancreaticoduodenectomy (PD). A retrospective analysis of 423 patients who underwent PD between January 2008 and January 2014 was conducted. The overall incidence and all-cause mortality of PPH were 9.9% (42/423) and 2.1% (9/423), respectively. Independent risk factors of early PPH were revascularization (odds ratio (OR) = 6.786; 95% confidence interval (95% CI): 1.785–25.792; P = 0.005), history of abdominal surgery (OR = 5.009; 95% CI: 1.968–12.749; P = 0.001), and preoperative albumin levels (OR = 4.863; 95% CI: 1.962–12.005; P = 0.001). Independent risk factors of late PPH included postoperative pancreatic leakage (OR = 4.696; 95% CI: 1.605–13.740; P = 0.005), postoperative biliary fistula (OR = 6.096; 95% CI: 1.575–23.598; P = 0.009), postoperative abdominal infection (OR = 4.605; 95% CI: 1.108–19.144; P = 0.036), revascularization (OR = 9.943; 95% CI: 1.900–52.042; P = 0.007), history of abdominal surgery (OR = 8.790; 95% CI: 2.779–27.806; P < 0.001), and preoperative albumin levels (OR = 5.563; 95% CI: 1.845–16.776; P = 0.002).
doi:10.1155/2016/2815693
PMCID: PMC5128684  PMID: 27975049
11.  Region-based diffuse optical tomography with registered atlas: in vivo acquisition of mouse optical properties 
Biomedical Optics Express  2016;7(12):5066-5080.
The reconstruction quality in the model-based optical tomography modalities can greatly benefit from a priori information of accurate tissue optical properties, which are difficult to be obtained in vivo with a conventional diffuse optical tomography (DOT) system alone. One of the solutions is to apply a priori anatomical structures obtained with anatomical imaging systems such as X-ray computed tomography (XCT) to constrain the reconstruction process of DOT. However, since X-ray offers low soft-tissue contrast, segmentation of abdominal organs from sole XCT images can be problematic. In order to overcome the challenges, the current study proposes a novel method of recovering a priori organ-oriented tissue optical properties, where anatomical structures of an in vivo mouse are approximately obtained by registering a standard anatomical atlas, i.e., the Digimouse, to the target XCT volume with the non-rigid image registration, and, in turn, employed to guide DOT for extracting the optical properties of inner organs. Simulative investigations have validated the methodological availability of such atlas-registration-based DOT strategy in revealing both a priori anatomical structures and optical properties. Further experiments have demonstrated the feasibility of the proposed method for acquiring the organ-oriented tissue optical properties of in vivo mice, making it as an efficient way of the reconstruction enhancement.
doi:10.1364/BOE.7.005066
PMCID: PMC5175552  PMID: 28018725
(110.2960) Image analysis; (170.3010) Image reconstruction techniques; (170.6960) Tomography; (170.3880) Medical and biological imaging
12.  Reliability of digital reactor protection system based on extenics 
SpringerPlus  2016;5(1):1953.
After the Fukushima nuclear accident, safety of nuclear power plants (NPPs) is widespread concerned. The reliability of reactor protection system (RPS) is directly related to the safety of NPPs, however, it is difficult to accurately evaluate the reliability of digital RPS. The method is based on estimating probability has some uncertainties, which can not reflect the reliability status of RPS dynamically and support the maintenance and troubleshooting. In this paper, the reliability quantitative analysis method based on extenics is proposed for the digital RPS (safety–critical), by which the relationship between the reliability and response time of RPS is constructed. The reliability of the RPS for CPR1000 NPP is modeled and analyzed by the proposed method as an example. The results show that the proposed method is capable to estimate the RPS reliability effectively and provide support to maintenance and troubleshooting of digital RPS system.
doi:10.1186/s40064-016-3618-y
PMCID: PMC5104704  PMID: 27882285
RPS; Response time; Extenics; Reliability
13.  Sevoflurane postconditioning attenuates cardiomyocyte hypoxia/reoxygenation injury via restoring mitochondrial morphology 
PeerJ  2016;4:e2659.
Background
Anesthetic postconditioning is a cellular protective approach whereby exposure to a volatile anesthetic renders a tissue more resistant to subsequent ischemic/reperfusion event. Sevoflurane postconditioning (SPostC) has been shown to exert cardioprotection against ischemia/reperfusion injury, but the underlying mechanism is unclear. We hypothesized that SPostC protects cardiomyocytes against hypoxia/reoxygenation (H/R) injury by maintaining/restoring mitochondrial morphological integrity, a critical determinant of cell fate.
Methods
Primary cultures of neonatal rat cardiomyocytes (NCMs) were subjected to H/R injury (3 h of hypoxia followed by 3 h reoxygenation). Intervention with SPostC (2.4% sevoflurane) was administered for 15 min upon the onset of reoxygenation. Cell viability, Lactate dehydrogenase (LDH) level, cell death, mitochondrial morphology, mitochondrial membrane potential and mitochondrial permeability transition pore (mPTP) opening were assessed after intervention. Mitochondrial fusion and fission regulating proteins (Drp1, Fis1, Mfn1, Mfn2 and Opa1) were assessed by immunofluorescence staining and western blotting was performed to determine the level of protein expression.
Results
Cardiomyocyte H/R injury resulted in significant increases in LDH release and cell death that were concomitant with reduced cell viability and reduced mitochondrial interconnectivity (mean area/perimeter ratio) and mitochondrial elongation, and with reduced mitochondrial membrane potential and increased mPTP opening. All the above changes were significantly attenuated by SPostC. Furthermore, H/R resulted in significant reductions in mitochondrial fusion proteins Mfn1, Mfn2 and Opa1 and significant enhancement of fission proteins Drp1 and Fis1. SPostC significantly enhanced Mfn2 and Opa1 and reduced Drp1, without significant impact on Mfn1 and Fis1.
Conclusions
Sevoflurane postconditioning attenuates cardiomyocytes hypoxia/reoxygenation injury (HRI) by restoring mitochondrial fusion/fission balance and morphology.
doi:10.7717/peerj.2659
PMCID: PMC5101611  PMID: 27833818
Sevoflurane postconditioning; Mitochondria; Hypoxia/reoxygenation; Mitochondrial fusion and fission; Cardiomyocyte
14.  Bivariate correlation coefficients in family-type clustered studies 
We propose a unified approach based on a bivariate linear mixed effects model to estimate three types of bivariate correlation coefficients (BCCs), as well as the associated variances between two quantitative variables in cross-sectional data from a family-type clustered design. These BCCs are defined at different levels of experimental units including clusters (e.g., families) and subjects within clusters and assess different aspects on the relationships between two variables. We study likelihood-based inferences for these BCCs, and provide easy implementation using standard software SAS. Unlike several existing BCC estimators in the literature on clustered data, our approach can seamlessly handle two major analytic challenges arising from a family-type clustered design: (1) many families may consist of only one single subject; (2) one of the paired measurements may be missing for some subjects. Hence, our approach maximizes the use of data from all subjects (even those missing one of the two variables to be correlated) from all families, regardless of family size. We also conduct extensive simulations to show that our estimators are superior to existing estimators in handling missing data or/and imbalanced family sizes and the proposed Wald test maintains good size and power for hypothesis testing. Finally, we analyze a real-world Alzheimer’s disease dataset from a family clustered study to investigate the BCCs across different modalities of disease markers including cognitive tests, cerebrospinal fluid biomarkers, and neuroimaging biomarkers.
doi:10.1002/bimj.201400131
PMCID: PMC4741284  PMID: 26360805
Bivariate correlation; Bivariate linear mixed effects model; Missing data; Power; Random effect; Size; Wald test
15.  Discovery of putative capsaicin biosynthetic genes by RNA-Seq and digital gene expression analysis of pepper 
Scientific Reports  2016;6:34121.
The Indian pepper ‘Guijiangwang’ (Capsicum frutescens L.), one of the world’s hottest chili peppers, is rich in capsaicinoids. The accumulation of the alkaloid capsaicin and its analogs in the epidermal cells of the placenta contribute to the pungency of Capsicum fruits. To identify putative genes involved in capsaicin biosynthesis, RNA-Seq was used to analyze the pepper’s expression profiles over five developmental stages. Five cDNA libraries were constructed from the total RNA of placental tissue and sequenced using an Illumina HiSeq 2000. More than 19 million clean reads were obtained from each library, and greater than 50% of the reads were assignable to reference genes. Digital gene expression (DGE) profile analysis using Solexa sequencing was performed at five fruit developmental stages and resulted in the identification of 135 genes of known function; their expression patterns were compared to the capsaicin accumulation pattern. Ten genes of known function were identified as most likely to be involved in regulating capsaicin synthesis. Additionally, 20 new candidate genes were identified related to capsaicin synthesis. We use a combination of RNA-Seq and DGE analyses to contribute to the understanding of the biosynthetic regulatory mechanism(s) of secondary metabolites in a nonmodel plant and to identify candidate enzyme-encoding genes.
doi:10.1038/srep34121
PMCID: PMC5069471  PMID: 27756914
16.  The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells 
Rejuvenation Research  2015;18(5):413-421.
Abstract
Our previous study suggests that ginger root extract can reverse behavioral dysfunction and prevent Alzheimer's disease (AD)-like symptoms induced by the amyloid-β protein (Aβ) in a rat model. 6-Gingerol is the major gingerol in ginger rhizomes, but its effect on the treatment of AD remains unclear. In this study, we aimed to determine if 6-gingerol had a protective effect on Aβ1–42-induced damage and apoptotic death in rat pheochromocytoma cells (PC12 cells) and to investigate the underlying mechanisms by which 6-gingerol may exert its neuroprotective effects. Our results indicated that pre-treatment with 6-gingerol significantly increased cell viability and reduced cell apoptosis in Aβ1–42-treated cells. Moreover, 6-gingerol pretreatment markedly reduced the level of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), the production of nitric oxide (NO), and the leakage of lactate dehydrogenase (LDH) and increased superoxide dismutase (SOD) activity compared with the Aβ1–42 treatment group. In addition, 6-gingerol pretreatment also significantly enhanced the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3β (p-GSK-3β). Overall, these results indicate that 6-gingerol exhibited protective effects on apoptosis induced by Aβ1–42 in cultured PC12 cells by reducing oxidative stress and inflammatory responses, suppressing the activation of GSK-3β and enhancing the activation of Akt, thereby exerting neuroprotective effects. Therefore, 6-gingerol may be useful in the prevention and/or treatment of AD.
doi:10.1089/rej.2014.1657
PMCID: PMC4620533  PMID: 25811848
17.  Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome 
Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD) and facilitate a graft-versus-leukemia effect by enhancing the effect of T-regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplant started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10 and 15 mg/m2/day x 5 days every 6 weeks, for maximum 8 cycles. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which ≤25% of people experience dose limiting toxicities (DLT) during the 1st cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose-levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3/4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose-level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients have died due to: relapse (n=4), infectious complications (n=3) and GVHD (n=2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; one patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in post-allotransplant setting. Although MTD was not reached, the dose of 10 mg/m2 for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m2, where most hematological toxicities occurred.
doi:10.1016/j.bbmt.2015.05.026
PMCID: PMC4568135  PMID: 26055299
decitabine; stem cell transplantation; maintenance; myelodysplastic syndrome; acute leukemia
18.  Sulforaphane Prevents Testicular Damage in Kunming Mice Exposed to Cadmium via Activation of Nrf2/ARE Signaling Pathways 
Sulforaphane (SFN) is a natural and highly effective antioxidant. Studies suggest that SFN protects cells and tissues against cadmium (Cd) toxicity. This study investigated the protective effect of SFN against oxidative damage in the testes of Kunming mice exposed to cadmium, and explored the possible molecular mechanisms involved. Cadmium greatly reduced the serum testosterone levels in mice, reduced sperm motility, total sperm count, and increased the sperm deformity rate. Cadmium also reduces superoxide dismutase (T-SOD) and glutathione (GSH) levels and increases malondialdehyde (MDA) concentrations. SFN intervention improved sperm quality, serum testosterone, and antioxidant levels. Both mRNA and protein expression of mouse testicular nuclear factor-erythroid 2-related factor 2 (Nrf2) was reduced in cadmium-treated group. Furthermore, the downstream genes of Nrf2, glutathione peroxidase (GSH-Px), γ-glutamyl cysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) were also decreased in cadmium-treated group. SFN intervention increases the expression of these genes. Sulforaphane prevents cadmium-induced testicular damage, probably via activation of Nrf2/ARE signaling.
doi:10.3390/ijms17101703
PMCID: PMC5085735  PMID: 27727176
sulforaphane; cadmium; oxidative damage; Nrf2/ARE pathway; testes; mice
19.  Comparative Study between Robotic Total Thyroidectomy with Central Lymph Node Dissection via Bilateral Axillo-breast Approach and Conventional Open Procedure for Papillary Thyroid Microcarcinoma 
Chinese Medical Journal  2016;129(18):2160-2166.
Background:
A large proportion of the patients with papillary thyroid microcarcinoma are young women. Therefore, minimally invasive endoscopic thyroidectomy with central neck dissection (CND) emerged and showed well-accepted results with improved cosmetic outcome, accelerated healing, and comforting the patients. This study aimed to evaluate the safety and effectiveness of robotic total thyroidectomy with CND via bilateral axillo-breast approach (BABA), compared with conventional open procedure in papillary thyroid microcarcinoma.
Methods:
One-hundred patients with papillary thyroid microcarcinoma from March 2014 to January 2015 in Jinan Military General Hospital of People's Liberation Army (PLA) were randomly assigned to robotic group or conventional open approach group (n = 50 in each group). The total operative time, estimated intraoperative blood loss, numbers of lymph node removed, visual analog scale (VAS), postoperative hospital stay time, complications, and numerical scoring system (NSS, used to assess cosmetic effect) were analyzed.
Results:
The robotic total thyroidectomy with CND via BABA was successfully performed in robotic group. There were no conversion from the robotic surgeries to open or endoscopic surgery. The subclinical central lymph node metastasis rate was 35%. The mean operative time of the robotic group was longer than that of the conventional open approach group (118.8 ± 16.5 min vs. 90.7 ± 10.3 min, P < 0.05). The study showed significant differences between the two groups in terms of the VASs (2.1 ± 1.0 vs. 3.8 ± 1.2, P < 0.05) and NSS (8.9 ± 0.8 vs. 4.8 ± 1.7, P < 0.05). The differences between the two groups in the estimated intraoperative blood loss, postoperative hospital stay time, numbers of lymph node removed, postoperative thyroglobulin levels, and complications were not statistically significant (all P > 0.05). Neither iatrogenic implantation nor metastasis occurred in punctured porous channel or chest wall in both groups. Postoperative cosmetic results were very satisfactory in the robotic group.
Conclusions:
Robotic total thyroidectomy with CND via BABA is safe and effective for Chinese patients with papillary thyroid microcarcinoma who worry about the neck scars.
doi:10.4103/0366-6999.189911
PMCID: PMC5022334  PMID: 27625085
Bilateral Axillo-breast Approach; da Vinci Si Surgical System; Papillary Thyroid Microcarcinoma; Robotic Central Lymph Node Dissection; Robotic Total Thyroidectomy
20.  The evidence of porcine hemagglutinating encephalomyelitis virus induced nonsuppurative encephalitis as the cause of death in piglets 
PeerJ  2016;4:e2443.
An acute outbreak of porcine hemagglutinating encephalomyelitis virus (PHEV) infection in piglets, characterized with neurological symptoms, vomiting, diarrhea, and wasting, occurred in China. Coronavirus-like particles were observed in the homogenized tissue suspensions of the brain of dead piglets by electron microscopy, and a wild PHEV strain was isolated, characterized, and designated as PHEV-CC14. Histopathologic examinations of the dead piglets showed characteristics of non-suppurative encephalitis, and some neurons in the cerebral cortex were degenerated and necrotic, and neuronophagia. Similarly, mice inoculated with PHEV-CC14 were found to have central nervous system (CNS) dysfunction, with symptoms of depression, arched waists, standing and vellicating front claws. Furthmore, PHEV-positive labeling of neurons in cortices of dead piglets and infected mice supported the viral infections of the nervous system. Then, the major structural genes of PHEV-CC14 were sequenced and phylogenetically analyzed, and the strain shared 95%–99.2% nt identity with the other PHEV strains available in GenBank. Phylogenetic analysis clearly proved that the wild strain clustered into a subclass with a HEV-JT06 strain. These findings suggested that the virus had a strong tropism for CNS, in this way, inducing nonsuppurative encephalitis as the cause of death in piglets. Simultaneously, the predicted risk of widespread transmission showed a certain variation among the PHEV strains currently circulating around the world. Above all, the information presented in this study can not only provide good reference for the experimental diagnosis of PHEV infection for pig breeding, but also promote its new effective vaccine development.
doi:10.7717/peerj.2443
PMCID: PMC5028786  PMID: 27672502
Porcine hemagglutinating encephalomyelitis virus; Nonsuppurative encephalitis; Vomiting; Neurological symptoms; Phylogenetic analysis; Viral isolation; Coronavirus
21.  Expression and clinicopathological significance of the lncRNA HOXA11-AS in colorectal cancer 
Oncology Letters  2016;12(5):4155-4160.
HOXA11 antisense RNA (HOXA11-AS) is a long non-coding RNA (lncRNA) that is important in determining cancer progression. HOXA11-AS was recently identified as a novel biomarker in lung cancer progression. However, its role in colorectal cancer (CRC) remains poorly understood. The present study aimed to analyze lncRNA HOXA11-AS expression in CRC and investigate a possible association between HOXA11-AS and clinicopathological factors. HOXA11-AS expression was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 84 CRC tissues and adjacent non-cancerous tissues, in addition to 3 CRC cell lines and 1 human normal colorectal cell line. The results demonstrated that HOXA11-AS expression was decreased in the CRC tissues and cell lines compared with that of the controls (P<0.05). Clinicopathological analysis indicated that low HOXA11-AS expression was significantly correlated with tumor size, advanced tumor-node-metastasis stage, lymph node metastasis and carcinoembryonic antigen level of patients with CRC (P<0.05). Furthermore, the areas under the curve (AUC) were 0.613 and 0.628 for HOXA11-AS, indicating that the lncRNA is able to distinguish CRC tissue from non-cancerous tissue, and CRC tissue with lymph node metastasis from CRC without lymph node metastasis. Therefore, HOXA11-AS may function as a potential biomarker and target for novel therapeutic strategies to treat CRC.
doi:10.3892/ol.2016.5129
PMCID: PMC5104251  PMID: 27895785
biomarker; colorectal cancer; HOXA11-AS; long non-coding RNA
22.  Narrow Groove and Restricted Anchors of MHC Class I Molecule BF2*0401 Plus Peptide Transporter Restriction can Explain Disease Susceptibility of B4 Chickens 
The major histocompatibility complex (MHC) has genetic associations with many diseases, often due to differences in presentation of antigenic peptides by polymorphic MHC molecules to T lymphocytes of the immune system. In chickens, only a single classical class I molecule in each MHC haplotype is expressed well due to co-evolution with the polymorphic transporters associated with antigen presentation (TAPs), which means that resistance and susceptibility to infectious pathogens are particularly easy to observe. Previously, structures of chicken MHC class I molecule BF2*2101 from B21 haplotype showed an unusually large peptide-binding groove that accommodates a broad spectrum of peptides to present as epitopes to cytotoxic T lymphocytes (CTL), explaining the MHC-determined resistance of B21 chickens to Marek's disease. Here, we report the crystal structure of BF2*0401 from the B4 (also known as B13) haplotype, showing a highly positively-charged surface hitherto unobserved in other MHC molecules, as well as a remarkably narrow groove due to the allele-specific residues with bulky side chains. Together, these properties limit the number of epitope peptides that can bind this class I molecule. However, peptide-binding assays show that in vitro BF2*0401 can bind a wider variety of peptides than are found on the surface of B4 cells. Thus, a combination of the specificities of the polymorphic TAP transporter and the MHC results in a very limited set of BF2*0401 peptides with negatively charged anchors to be presented to T lymphocytes.
doi:10.4049/jimmunol.1200885
PMCID: PMC5018395  PMID: 23041567
disease; susceptibility/chicken; MHC; BF2*0401/crystal; structure/peptide-binding; groove/TAP
23.  Strain-specific V3 and CD4 binding site autologous HIV-1 neutralizing antibodies select neutralization-resistant viruses 
Cell host & microbe  2015;18(3):354-362.
Summary
The third variable (V3) loop and the CD4 binding site (CD4bs) of the HIV-1 envelope are frequently targeted by neutralizing antibodies (nAbs) in infected individuals. In chronic infection, HIV-1 escape mutants repopulate the plasma, and V3 and CD4bs nAbs emerge that can neutralize heterologous tier 1 easy-to-neutralize, but not tier 2 difficult-to-neutralize HIV-1 isolates. However, neutralization sensitivity of autologous plasma viruses to this type of nAb response has not been studied. We describe the development and evolution in vivo of antibodies distinguished by their target specificity for V3and CD4bs epitopes on autologous tier 2 viruses but not on heterologous tier 2 viruses. A surprisingly high fraction of autologous circulating viruses was sensitive to these antibodies. These findings demonstrate a role for V3 and CD4bs antibodies in constraining the native envelope trimer in vivo to a neutralization-resistant phenotype, explaining why HIV-1 transmission generally occurs by tier 2 neutralization-resistant viruses.
doi:10.1016/j.chom.2015.08.006
PMCID: PMC4567706  PMID: 26355218
24.  Observation on therapeutic efficacy of rt-PA intravenous thrombolysis combined with compound anisodine injection on central retinal artery occlusion 
The aim of the present study was to observe the clinical efficacy and safety of recombinant tissue plasminogen activator (rt-PA) combined with compound anisodine in treating central retinal artery occlusion (CRAO). Forty-eight patients diagnosed with CRAO were randomly divided into a treatment group (24 cases) and a control group (24 cases). For the control group, nitroglycerin, 654-2, methazolamide, puerarin and compound anisodine were used for the treatment, along with oxygen, massage and other conventional treatments. Besides conventional therapy, the treatment group was also given intravenous rt-PA thrombolysis. Visual acuity, fundus oculi, visual field changes were taken as indicators for efficacy evaluation. It was found that the total effective rate of the control group was 70.83%, while that for the treatment group was 91.67%, and the comparative difference between the two groups was of statistical significance (p<0.05). The visual field defect of the control group after treatment was approximately 74.26±12.91%, and the visual field defect of the treatment group after treatment approximately 35.08±16.33%; thus, the comparative difference was statistically significant (p<0.01). The comparative difference of the original contents of fibrous protein in blood in the treatment group before and after treatment was statistically significant (p<0.01). In conclusion, the result show that intravenous thrombolysis with rt-PA combined with compound anisodine is safe and effective in treating CRAO, which can significantly improve the prognosis of patients.
doi:10.3892/etm.2016.3681
PMCID: PMC5038466  PMID: 27698763
recombinant tissue plasminogen activator; compound anisodine; intravenous thrombolysis; acute central retinal artery occlusion
25.  GSK-3β phosphorylation of cytoplasmic dynein reduces Ndel1 binding to intermediate chains and alters dynein motility 
Traffic (Copenhagen, Denmark)  2015;16(9):941-961.
Glycogen synthase kinase 3 (GSK-3) has been linked to regulation of kinesin-dependent axonal transport in squid and flies, and to indirect regulation of cytoplasmic dynein. We have now found evidence for direct regulation of dynein by mammalian GSK-3β in both neurons and non-neuronal cells. GSK-3β coprecipitates with and phosphorylates mammalian dynein. Phosphorylation of dynein intermediate chain (IC) reduces its interaction with Ndel1, a protein that contributes to dynein force generation. Two conserved residues, S87/T88 in IC-1B and S88/T89 in IC-2C, have been identified as GSK-3 targets by both mass spectrometry and site-directed mutagenesis. These sites are within a Ndel1-binding domain, and mutation of both sites alters the interaction of IC’s with Ndel1. Dynein motility is stimulated by 1) pharmacological and genetic inhibition of GSK-3β; 2) an insulin-sensitizing agent (rosiglitazone); 3) manipulating an insulin response pathway that leads to GSK-3β inactivation. Thus our study connects a well-characterized insulin-signaling pathway directly to dynein stimulation via GSK-3 inhibition.
doi:10.1111/tra.12304
PMCID: PMC4543430  PMID: 26010407
Cytoplasmic dynein; Insulin; axon transport; Ndel1/Nde1; centrosome; retrograde transport

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