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1.  Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy 
Journal of Medicinal Chemistry  2014;57(16):7016-7030.
Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
doi:10.1021/jm500694p
PMCID: PMC4148150  PMID: 25079952
2.  The effectiveness and safety of plum-blossom needle therapy for Tourette syndrome: study protocol for a randomized controlled trial 
Trials  2015;16:320.
Background
Previous studies have indicated that acupuncture can alleviate the symptoms of Tourette syndrome (TS), but the evidence is insufficient. So far, there have been no reports on plum-blossom needle therapy for TS. Here we present a protocol for a randomized controlled trial using plum-blossom needle therapy to treat TS.
Methods/design
Sixty patients will be randomly allocated into either the plum-blossom needle therapy group or the habit reversal training (HRT) group. All patients in each group will be given 12 weeks of treatment, with follow-up at the 24th week. The primary outcome measure will be the mean change from baseline in the total tic score on the Yale Global Tic Severity Scale (YGTSS) at the 12th week. Secondary outcome measures will include the scores on the TS Clinical Global Impression Scale (CGI) and the mean changes from baseline in the YGTSS score and the Children and Adolescents’ Quality of Life Scale (CAQOL) at other time points. Safety will also be evaluated.
Discussion
This trial will evaluate the effectiveness and safety of plum-blossom needle therapy for TS compared with HRT. A limitation of this trial is that patients and acupuncturists cannot be blinded.
Trial registration
ClinicalTrials.gov Identifier: NCT02403258 (Date of registration: March 31, 2015).
doi:10.1186/s13063-015-0873-0
PMCID: PMC4517654  PMID: 26220439
Acupuncture; Plum-blossom needle; Tourette syndrome; Randomized controlled trial
3.  Demonstration of polarization-insensitive spatial light modulation using a single polarization-sensitive spatial light modulator 
Scientific Reports  2015;5:9959.
We present a simple configuration incorporating a single polarization-sensitive phase-only liquid crystal spatial light modulator (LC-SLM) to facilitate polarization-insensitive spatial light modulation. The polarization-insensitive configuration is formed by a polarization beam splitter (PBS), a polarization-sensitive phase-only LC-SLM, a half-wave plate (HWP), and a mirror in a loop structure. We experimentally demonstrate polarization-insensitive spatial light modulations for incident linearly polarized beams with different polarization states and polarization-multiplexed beams. Polarization-insensitive spatial light modulations generating orbital angular momentum (OAM) beams are demonstrated in the experiment. The designed polarization-insensitive configuration may find promising applications in spatial light modulations accommodating diverse incident polarizations.
doi:10.1038/srep09959
PMCID: PMC4491842  PMID: 26146032
4.  Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brain 
eLife  null;4:e07860.
The maternal and paternal genomes play different roles in mammalian brains as a result of genomic imprinting, an epigenetic regulation leading to differential expression of the parental alleles of some genes. Here we investigate genomic imprinting in the cerebellum using a newly developed Bayesian statistical model that provides unprecedented transcript-level resolution. We uncover 160 imprinted transcripts, including 41 novel and independently validated imprinted genes. Strikingly, many genes exhibit parentally biased—rather than monoallelic—expression, with different magnitudes according to age, organ, and brain region. Developmental changes in parental bias and overall gene expression are strongly correlated, suggesting combined roles in regulating gene dosage. Finally, brain-specific deletion of the paternal, but not maternal, allele of the paternally-biased Bcl-x, (Bcl2l1) results in loss of specific neuron types, supporting the functional significance of parental biases. These findings reveal the remarkable complexity of genomic imprinting, with important implications for understanding the normal and diseased brain.
DOI: http://dx.doi.org/10.7554/eLife.07860.001
eLife digest
Most cells in the human body contain two copies of each chromosome—one that was inherited from the individual's mother and one from the father—and therefore contain two copies of every gene. While both copies are usually used equally and simultaneously to produce proteins, in a minority of cases the gene from one parent is silenced in a process known as genomic imprinting. This is generally achieved via the addition of chemical marks onto the DNA, which prevent the molecular machinery that activates genes from accessing the genetic material.
Previous efforts to map imprinting in the brain throughout the mouse genome have yielded inconsistent results, due in part to the large number of factors that can affect gene expression. Perez, Rubinstein, Fernandez et al. have now addressed this issue by applying a combined approach, which includes developing a powerful statistical model that takes into account variation in age, sex, and mouse strain and extensively validating each imprinted gene candidate using an independent experimental technique.
Perez, Rubinstein, Fernandez et al. analyzed genomic imprinting initially in a part of the brain called the cerebellum in both young and adult mice. This analysis confirmed the occurrence of imprinting in 74 genes identified in previous studies, and revealed imprinting for the first time in a further 41 genes. The degree of imprinting varied between genes. In some genes only one copy was expressed and the other was completely silenced whereas others only deviated from the two copies being expressed equally. For individual genes, imprinting varied with age, tending to be more pronounced in young animals than in adults. It also varied between brain regions and typically genes were imprinted more in the brain compared to elsewhere in the body.
Mapping the activities of the imprinted genes revealed that many are involved in regulating the process of controlled cell death, or ‘apoptosis’. For one particular test gene, selectively deleting either the maternal or paternal copy had different effects on the mice, thereby confirming that imprinting can affect brain development and activity. With this in mind, the potential impact of imprinting should also be considered when evaluating the effects of inherited mutations on human health.
DOI: http://dx.doi.org/10.7554/eLife.07860.002
doi:10.7554/eLife.07860
PMCID: PMC4512258  PMID: 26140685
genomic imprinting; molecular neuroscience; cerebellum; RNA-seq; apoptosis; Bcl-x; mouse
5.  Expansion of biological pathways based on evolutionary inference 
Cell  2014;158(1):213-225.
Summary
Availability of diverse genomes makes it possible to predict gene function based on shared evolutionary history. This approach can be challenging, however, for pathways whose components do not exhibit a shared history, but rather, consist of distinct “evolutionary modules.” We introduce a computational algorithm, CLIME (clustering by inferred models of evolution), which inputs a eukaryotic species tree, homology matrix, and pathway (gene set) of interest. CLIME partitions the gene set into disjoint evolutionary modules, simultaneously learning the number of modules and a tree-based evolutionary history that defines each module. CLIME then expands each module by scanning the genome for new components that likely arose under the inferred evolutionary model. Application of CLIME to ∼1000 annotated human pathways, organelles and proteomes of yeast, red algae, and malaria, reveals unanticipated evolutionary modularity and novel, co-evolving components. CLIME is freely available and should become increasingly powerful with the growing wealth of eukaryotic genomes.
doi:10.1016/j.cell.2014.05.034
PMCID: PMC4171950  PMID: 24995987
6.  Human prion protein sequence elements impede cross-species chronic wasting disease transmission 
The Journal of Clinical Investigation  2015;125(4):1485-1496.
Chronic wasting disease (CWD) is a fatal prion disease of North American deer and elk and poses an unclear risk for transmission to humans. Human exposure to CWD occurs through hunting activities and consumption of venison from prion-infected animals. Although the amino acid residues of the prion protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based structural studies suggest that the β2-α2 loop (residues 165–175) may impact species barriers. Here we sought to define PrP sequence determinants that affect CWD transmission to humans. We engineered transgenic mice that express human PrP with four amino acid substitutions that result in expression of PrP with a β2-α2 loop (residues 165–175) that exactly matches that of elk PrP. Compared with transgenic mice expressing unaltered human PrP, mice expressing the human-elk chimeric PrP were highly susceptible to elk and deer CWD prions but were concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A systematic in vitro survey of amino acid differences between humans and cervids identified two additional residues that impacted CWD conversion of human PrP. This work identifies amino acids that constitute a substantial structural barrier for CWD transmission to humans and helps illuminate the molecular requirements for cross-species prion transmission.
doi:10.1172/JCI79408
PMCID: PMC4396485  PMID: 25705888
Infectious disease; Neuroscience
7.  Chemokine Signaling Pathway Involved in CCL2 Expression in Patients with Rheumatoid Arthritis 
Yonsei Medical Journal  2015;56(4):1134-1142.
Purpose
Rheumatoid arthritis (RA) is an inflammatory joint disorder, the progression of which leads to the destruction of cartilage and bone. Chemokines are involved in RA pathogenesis. In this study, we investigated the chemokine signaling pathway associated with CCL2 in peripheral blood (PB) and synovial tissues (ST) of RA patients based on our previous work about chemokine signaling pathway involved in the activation of CCL2 production in collagen-induced arthritis rat ST.
Materials and Methods
Total RNA was isolated from PB leukocytes and synovium of the knee joint in both RA patients and control populations. Real-time polymerase chain reaction was used to determine CCL4, CCR5, c-Jun, c-Fos, and CCL2 expressions. Serum level of CCL2 was assessed by enzyme-linked immunosorbent assay, and the production of CCL2 in ST was analyzed immunohistochemically.
Results
The expressions of CCL4, CCR5, c-Jun, c-Fos, and CCL2 messenger RNA in RA patients were significantly higher than those in healthy controls, both in ST and on PB leukocyte. Serum CCL2 levels were elevated in RA patients. Histological examination of rheumatoid joints revealed extensive CCL2 expression in RA ST.
Conclusion
CCL2, CCL4, c-Jun, c-Fos, and CCR5 may play an important role in the recruitment of PB leukocytes into the RA joints. These data provide evidence that the chemokine signaling pathway is involved in CCL2 expression in RA patient tissues, which may contribute to chronic inflammation associated with RA. Targeting this signaling pathway may provide a novel therapeutic avenue in RA.
doi:10.3349/ymj.2015.56.4.1134
PMCID: PMC4479845  PMID: 26069140
CCL2; leukocytes; rheumatoid; arthritis; synovial membrane
8.  Liver lobe-based magnetic resonance diffusion-weighted imaging using multiple b values in patients with hepatitis B-related liver cirrhosis: association with the liver disease severity according to the Child-Pugh class 
Clinics  2015;70(7):486-492.
OBJECTIVE:
To determine the associations of liver lobe-based magnetic resonance diffusion-weighted imaging findings using multiple b values with the presence and Child-Pugh class of cirrhosis in patients with hepatitis B.
METHODS:
Seventy-four cirrhotic patients with hepatitis B and 25 healthy volunteers underwent diffusion-weighted imaging using b values of 0, 500, 800 and 1000 sec/mm2. The apparent diffusion coefficients of individual liver lobes for b(0,500), b(0,800) and b(0,1000) were derived from the signal intensity averaged across images obtained using b values of 0 and 500 sec/mm2, 0 and 800 sec/mm2, or 0 and 1000 sec/mm2, respectively, and were statistically analyzed to evaluate cirrhosis.
RESULTS:
The apparent diffusion coefficients for b(0,500), b(0,800) and b(0,1000) inversely correlated with the Child-Pugh class in the left lateral liver lobe, the left medial liver lobe, the right liver lobe and the caudate lobe (r=–0.35 to –0.60, all p<0.05), except for the apparent diffusion coefficient for b(0,1000) in the left medial liver lobe (r=–0.17, p>0.05). Among these parameters, the apparent diffusion coefficient for b(0,500) in the left lateral liver lobe best differentiated normal from cirrhotic liver, with an area under the receiver operating characteristic curve of 0.989. The apparent diffusion coefficient for b(0,800) in the right liver lobe best distinguished Child-Pugh class A from B–C and A–B from C, with areas under the receiver operating characteristic curve of 0.732 and 0.747, respectively.
CONCLUSION:
Liver lobe-based apparent diffusion coefficients for b(0,500) and b(0,800) appear to be associated with the presence and Child-Pugh class of liver cirrhosis.
doi:10.6061/clinics/2015(07)05
PMCID: PMC4496756  PMID: 26222818
Diffusion Magnetic Resonance Imaging; Liver Cirrhosis; Hepatitis B; Chronic
9.  Robot assisted navigated drilling for percutaneous pedicle screw placement: A preliminary animal study 
Indian Journal of Orthopaedics  2015;49(4):452-457.
Background:
There is much more radiation exposure to the surgeons during minimally invasive pedicle screws placement. In order to ease the surgeon's hand-eye coordination and to reduce the iatrogenic radiation injury to the surgeons, a robot assisted percutaneous pedicle screw placement is useful. This study assesses the feasibility and clinical value of robot assisted navigated drilling for pedicle screw placement and the results thus achieved formed the basis for the development of a new robot for pedicle screw fixation surgery.
Materials and Methods:
Preoperative computed tomography (CT) of eight bovine lumbar spines (L1–L5) in axial plane were captured for each vertebra, the entry points and trajectories of the screws were preoperatively planned. On the basis of preoperative CT scans and intraoperative fluoroscopy, we aligned the robot drill to the desired entry point and trajectory, as dictated by the surgeon's preoperative plan. Eight bovine lumbar spines were inserted 80 K-wires using the spine robot system. The time for system registration and pedicle drilling, fluoroscopy times were measured and recorded. Postoperative CT scans were used to assess the position of the K-wires.
Results:
Assisted by spine robot system, the average time for system registration was (343.4 ± 18.4) s, the average time for procedure of drilling one pedicle screw trajectory was (89.5 ± 6.1) s, times of fluoroscopy for drilling one pedicle screw were (2.9 ± 0.8) times. Overall, 12 (15.0%) of the 80 K-wires violated the pedicle wall. Four screws (5.0%) were medial to the pedicle and 8 (10.5%) were lateral. The number of K-wires wholly within the pedicle were 68 (85%).
Conclusions:
The preliminary study supports the view that computer assisted pedicle screw fixation using spinal robot is feasible and the robot can decrease the intraoperative fluoroscopy time during the minimally invasive pedicle screw fixation surgery. As spine robotic surgery is still in its infancy, further research in this field is worthwhile especially the accuracy of spine robot system should be improved.
doi:10.4103/0019-5413.159670
PMCID: PMC4510801
Computer assisted orthopedic surgery; pedicle screw; robot; spine; lumbar spine; Computer assisted surgery; bone screws; spine; robotics; minimally invasive surgical procedures
10.  Correction: Surface Vulnerability of Cerebral Cortex to Major Depressive Disorder 
PLoS ONE  2015;10(6):e0128947.
doi:10.1371/journal.pone.0128947
PMCID: PMC4488314  PMID: 26121359
11.  Understanding spatial organizations of chromosomes via statistical analysis of Hi-C data 
Quantitative biology  2013;1(2):156-174.
Understanding how chromosomes fold provides insights into the transcription regulation, hence, the functional state of the cell. Using the next generation sequencing technology, the recently developed Hi-C approach enables a global view of spatial chromatin organization in the nucleus, which substantially expands our knowledge about genome organization and function. However, due to multiple layers of biases, noises and uncertainties buried in the protocol of Hi-C experiments, analyzing and interpreting Hi-C data poses great challenges, and requires novel statistical methods to be developed. This article provides an overview of recent Hi-C studies and their impacts on biomedical research, describes major challenges in statistical analysis of Hi-C data, and discusses some perspectives for future research.
doi:10.1007/s40484-013-0016-0
PMCID: PMC4483177  PMID: 26124977
12.  Acrylamide toxic effects on mouse oocyte quality and fertility in vivo 
Scientific Reports  2015;5:11562.
Acrylamide is an industrial chemical that has attracted considerable attention due to its presumed carcinogenic, neurotoxic, and cytotoxic effects. In this study we investigated possible acrylamide reproductive toxic effects in female mice. Mice were fed an acrylamide-containing diet for 6 weeks. Our results showed the following effects of an acrylamide-containing diet. (1) Ovary weights were reduced in acrylamide-treated mice and oocyte developmental competence was also reduced, as shown by reduced GVBD and polar body extrusion rates. (2) Acrylamide feeding resulted in aberrant oocyte cytoskeletons, as shown by an increased abnormal spindle rate and confirmed by disrupted γ-tubulin and p-MAPK localization. (3) Acrylamide feeding resulted in oxidative stress and oocyte early stage apoptosis, as shown by increased ROS levels and p-MAPK expression. (4) Fluorescence intensity analysis showed that DNA methylation levels were reduced in acrylamide-treated oocytes and histone methylation levels were also altered, as H3K9me2, H3K9me3, H3K4me2, and H3K27me3 levels were reduced after acrylamide treatment. (5) After acrylamide feeding, the litter sizes of acrylamide-treated mice were significantly smaller compared to thus of control mice. Thus, our results indicated that acrylamide might affect oocyte quality through its effects on cytoskeletal integrity, ROS generation, apoptosis induction, and epigenetic modifications.
doi:10.1038/srep11562
PMCID: PMC4479821  PMID: 26108138
13.  Let-7 miRNAs Modulate the Activation of NF-κB by Targeting TNFAIP3 and Are Involved in the Pathogenesis of Lupus Nephritis 
PLoS ONE  2015;10(6):e0121256.
TNFAIP3 is a ubiquitin-editing enzyme that negatively regulates multiple NF-κB signaling pathways and dysregulation of TNFAIP3 is related to systemic lupus erythematosus (SLE). Although there exists evidence indicating that microRNAs (miRNAs) modulate the expression of TNFAIP3, whether and how miRNAs regulate TNFAIP3 and contribute to lupus nephritis (LN) is still not well understood. In this study, we screened eleven selected miRNAs that potentially regulated TNFAIP3 expression by dual luciferase assay and found that Let-7 miRNAs repressed TNFAIP3 expression by targeting the 3′UTR of TNFAIP3 mRNA. Overexpression of Let-7 miRNAs led to increased phosphorylation and sustained degradation of IκBα and enhanced phosphorylation of p65 following TNFα stimulation and promoted SeV-induced production of cytokines in HEK293T cells. In addition, the expression of Let-7 miRNAs was significantly up-regulated, and TNFAIP3 level was remarkably down-regulated in samples from LN patients compared control samples. Our findings have uncovered Let-7-TNFAIP3-NF-κB pathway that is involved in LN and thus provided a potential target for therapeutic intervention.
doi:10.1371/journal.pone.0121256
PMCID: PMC4482407  PMID: 26110642
14.  Visual Perception of Procedural Textures: Identifying Perceptual Dimensions and Predicting Generation Models 
PLoS ONE  2015;10(6):e0130335.
Procedural models are widely used in computer graphics for generating realistic, natural-looking textures. However, these mathematical models are not perceptually meaningful, whereas the users, such as artists and designers, would prefer to make descriptions using intuitive and perceptual characteristics like "repetitive," "directional," "structured," and so on. To make up for this gap, we investigated the perceptual dimensions of textures generated by a collection of procedural models. Two psychophysical experiments were conducted: free-grouping and rating. We applied Hierarchical Cluster Analysis (HCA) and Singular Value Decomposition (SVD) to discover the perceptual features used by the observers in grouping similar textures. The results suggested that existing dimensions in literature cannot accommodate random textures. We therefore utilized isometric feature mapping (Isomap) to establish a three-dimensional perceptual texture space which better explains the features used by humans in texture similarity judgment. Finally, we proposed computational models to map perceptual features to the perceptual texture space, which can suggest a procedural model to produce textures according to user-defined perceptual scales.
doi:10.1371/journal.pone.0130335
PMCID: PMC4481328  PMID: 26106895
15.  Effect of Repeated Electroacupuncture Intervention on Hippocampal ERK and p38MAPK Signaling in Neuropathic Pain Rats 
Results of our past studies showed that hippocampal muscarinic acetylcholine receptor (mAChR)-1 mRNA and differentially expressed proteins participating in MAPK signaling were involved in electroacupuncture (EA) induced cumulative analgesia in neuropathic pain rats, but the underlying intracellular mechanism remains unknown. The present study was designed to observe the effect of EA stimulation (EAS) on hippocampal extracellular signal-regulated kinases (ERK) and p38 MAPK signaling in rats with chronic constrictive injury (CCI) of the sciatic nerve, so as to reveal its related intracellular targets in pain relief. After CCI, the thermal pain thresholds of the affected hind were significantly decreased compared with the control group (P < 0.05). Following one and two weeks' EAS of ST 36-GB34, the pain thresholds were significantly upregulated (P < 0.05), and the effect of EA2W was remarkably superior to that of EA2D and EA1W (P < 0.05). Correspondingly, CCI-induced decreased expression levels of Ras, c-Raf, ERK1 and p-ERK1/2 proteins, and p38 MAPK mRNA and p-p38MAPK protein in the hippocampus tissues were reversed by EA2W (P < 0.05). The above mentioned results indicated that EA2W induced cumulative analgesic effect may be closely associated with its function in removing neuropathic pain induced suppression of intracellular ERK and p38MAPK signaling in the hippocampus.
doi:10.1155/2015/641286
PMCID: PMC4487344  PMID: 26161123
16.  A Novel AT-Rich DNA Recognition Mechanism for Bacterial Xenogeneic Silencer MvaT 
PLoS Pathogens  2015;11(6):e1004967.
Bacterial xenogeneic silencing proteins selectively bind to and silence expression from many AT rich regions of the chromosome. They serve as master regulators of horizontally acquired DNA, including a large number of virulence genes. To date, three distinct families of xenogeneic silencers have been identified: H-NS of Proteobacteria, Lsr2 of the Actinomycetes, and MvaT of Pseudomonas sp. Although H-NS and Lsr2 family proteins are structurally different, they all recognize the AT-rich DNA minor groove through a common AT-hook-like motif, which is absent in the MvaT family. Thus, the DNA binding mechanism of MvaT has not been determined. Here, we report the characteristics of DNA sequences targeted by MvaT with protein binding microarrays, which indicates that MvaT prefers binding flexible DNA sequences with multiple TpA steps. We demonstrate that there are clear differences in sequence preferences between MvaT and the other two xenogeneic silencer families. We also determined the structure of the DNA-binding domain of MvaT in complex with a high affinity DNA dodecamer using solution NMR. This is the first experimental structure of a xenogeneic silencer in complex with DNA, which reveals that MvaT recognizes the AT-rich DNA both through base readout by an “AT-pincer” motif inserted into the minor groove and through shape readout by multiple lysine side chains interacting with the DNA sugar-phosphate backbone. Mutations of key MvaT residues for DNA binding confirm their importance with both in vitro and in vivo assays. This novel DNA binding mode enables MvaT to better tolerate GC-base pair interruptions in the binding site and less prefer A tract DNA when compared to H-NS and Lsr2. Comparison of MvaT with other bacterial xenogeneic silencers provides a clear picture that nature has evolved unique solutions for different bacterial genera to distinguish foreign from self DNA.
Author Summary
During evolution, the bacteria frequently acquire new genes through horizontal transfer, in order to adapt new environments. However, foreign DNA sequences acquired are more likely to decrease rather than increase the fitness of the recipient bacteria. Therefore, many bacterial genera have evolved unique proteins to selectively repress the transcription of foreign genes. The opportunistic pathogen Pseudomonas aeruginosa is the principal cause of the morbidity and mortality in cystic fibrosis patients and is among the major causes of nosocomial infections. As a xenogeneic silencer, the MvaT protein of P. aeruginosa is a master regulator of horizontally acquired genes including many critical for drug resistance and virulence. Here, we have characterized the DNA sequences preferentially targeted by MvaT, and identified differences in sequence preferences between MvaT and other xenogeneic silencers. The high resolution structure of the DNA-binding domain of MvaT in complex with a high affinity DNA target reveals a novel AT-rich DNA minor groove recognition mechanism, which perfectly explains the characteristic of MvaT’s DNA sequence preferences. Comparison between MvaT and other bacterial xenogeneic silencers demonstrates how unique solutions have been employed by different bacterial genera in distinguishing foreign DNA from DNA of their own genome.
doi:10.1371/journal.ppat.1004967
PMCID: PMC4466236  PMID: 26068099
17.  Sch9 regulates intracellular protein ubiquitination by controlling stress responses 
Redox Biology  2015;5:290-300.
Protein ubiquitination and the subsequent degradation are important means by which aberrant proteins are removed from cells, a key requirement for long-term survival. In this study, we found that the overall level of ubiquitinated proteins dramatically decreased as yeast cell grew from log to stationary phase. Deletion of SCH9, a gene encoding a key protein kinase for longevity control, decreased the level of ubiquitinated proteins in log phase and this effect could be reversed by restoring Sch9 function. We demonstrate here that the decrease of ubiquitinated proteins in sch9Δ cells in log phase is not caused by changes in ubiquitin expression, proteasome activity, or autophagy, but by enhanced expression of stress response factors and a decreased level of oxidative stress. Our results revealed for the first time how Sch9 regulates the level of ubiquitinated proteins and provides new insight into how Sch9 controls longevity.
doi:10.1016/j.redox.2015.06.002
PMCID: PMC4477112  PMID: 26087116
SCH9; Yeast; Ubiquitination; Oxidation; Hydrogen peroxide
18.  Association between Interleukin-1β Gene −511C>T/+3954C>T Polymorphisms and Aggressive Periodontitis Susceptibility: Evidence from a Meta-Analysis 
Background
Interleukin-1β (IL-1β) is an important inflammatory cytokine. The associations between IL-1β gene −511C>T/+3954C>T polymorphisms and aggressive periodontitis (AgP) susceptibility have been conflicting. We therefore conducted a meta-analysis to investigate the association of IL-1β genetic polymorphisms with susceptibility to AgP.
Material/Methods
PubMed and Embase electronic databases were searched for relevant studies. Odds ratios (ORs) with 95% confidence interval (CIs) were used to assess the association between IL-1β polymorphisms and AgP risk. Heterogeneity, publication bias, and sensitivity analysis were performed to guarantee the statistical power.
Results
Twenty published studies involving 965 patients and 1234 control subjects were included. No significant association between IL-1β polymorphisms and AgP was found. For −511C>T (T vs. C: OR=0.966, 95%CI=0.696–1.341, P=0.869; CT vs. CC: OR=0.936, 95%CI=0.761–1.151; TT vs. CC: OR=0.892, 95%CI=0.464–1.715, P=0.719; CT+TT vs. CC: OR=1.026, 95%CI=0.795–1.323; TT vs. CC+CT: OR=0.864, 95%CI=0.436–1.713). For +3954C>T (T vs. C: OR=1.069, 95%CI=0.901–1.268; CT vs. CC: OR=0.921, 95%CI=0.699–1.212; TT vs. CC: OR=1.064, 95%CI=0.747–1.515; CT+TT vs. CC: OR=0.990, 95%CI=0.764–1.283; TT vs. CC+CT: OR=1.229, 95%CI=0.919–1.643). Subgroup analyses were conducted with HWE, ethnicity, and study design, and no significant association was detected.
Conclusions
These results demonstrate that IL-1β −511C>T and +3954C>T polymorphisms are not the risk factors for developing AgP.
doi:10.12659/MSM.894402
PMCID: PMC4467605  PMID: 26038188
Aggressive Periodontitis; Interleukin-1; Polymorphism, Single Nucleotide
19.  The Risk of Atrial Fibrillation in Patients with Rheumatoid Arthritis 
Annals of the rheumatic diseases  2013;73(6):1091-1095.
Background
Prior research suggests an important role of systemic inflammation in pathogenesis of atrial fibrillation (AF). It is well-known that rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder, increases the risk of cardiovascular disease (CVD), but little evidence exists whether the risk of AF is increased in RA.
Methods
Using data from a large US commercial insurance plan, we examined the incidence rate (IR) of hospitalization for AF in patients with RA compared to non-RA. RA patients were identified with ≥ 2 separate visits coded for RA and ≥ 1 disease-modifying anti-rheumatic drug dispensing. The IR of AF in RA patients was also compared to those with osteoarthritis, a chronic non-inflammatory condition.
Results
There were 20,852 RA and 104,260 non-RA patients, matched on age, sex and index date. The mean follow-up was 2 years. The IR per 1,000 person-years of AF was 4.0 (95% CI, 3.4–4.7) in RA and 2.8 (95% CI, 2.6–3.0) in non-RA patients. The incidence rate ratio for AF was 1.4 (95% CI, 1.2–1.7) in RA compared to non-RA patients. In a multivariable Cox model adjusting for a number of risk factors such as diabetes, CVD, medications and health care utilization, the risk of AF was no longer increased in RA (hazard ratio 1.1, 95% CI: 0.9–1.4) compared to non-RA patients. There was also no difference in the AF risk between RA and osteoarthritis patients.
Conclusion
Our results show no increased risk of AF associated with RA, after adjusting for various comorbidities, medications and health care use.
doi:10.1136/annrheumdis-2013-203343
PMCID: PMC3884023  PMID: 23606703
atrial fibrillation; inflammation; rheumatoid arthritis; cohort study
20.  The c-ring ion-binding site of the ATP synthase from Bacillus pseudofirmus OF4 is adapted to alkaliphilic lifestyle 
Molecular microbiology  2014;92(5):973-984.
Summary
In the c-ring rotor of ATP synthases ions are shuttled across the membrane during ATP synthesis by a unique rotary mechanism. We investigated characteristics of the c-ring from the alkaliphile Bacillus pseudofirmus OF4 with respect to evolutionary adaptations to operate with protons at high environmental pH. The X-ray structures of the wild-type c13 ring at pH 9.0 and a ‘neutralophile-like’ mutant (P51A) at pH 4.4, at 2.4 and 2.8 Å resolution, respectively, reveal a dependency of the conformation and protonation state of the proton-binding glutamate (E54) on environmental hydrophobicity. Faster labeling kinetics with the inhibitor dicyclohexylcarbodiimide (DCCD) demonstrate a greater flexibility of E54 in the mutant due to reduced water occupancy within the H+-binding site. A second ‘neutralophile-like’ mutant (V21N) shows reduced growth at high pH, which is explained by restricted conformational freedom of the mutant's E54 carboxylate. The study directly connects subtle structural adaptations of the c-ring ion-binding site to in vivo effects of alkaliphile cell physiology.
doi:10.1111/mmi.12605
PMCID: PMC4064006  PMID: 24707994
F1Fo-ATP-synthase; rotary ATPase; membrane protein complex; X-ray structure; bioenergetics; extremophiles; alkaliphiles
21.  Spatially heterogeneous corneal mechanical responses before and after riboflavin–ultraviolet-A crosslinking 
PURPOSE
To determine the heterogeneous through-thickness strains in the cornea at physiologic intraocular pressures before and after corneal collagen crosslinking (CXL) using noninvasive ultrasound.
SETTING
Department of Biomedical Engineering, Ohio State University, Columbus, Ohio, USA.
DESIGN
Experimental study.
METHODS
Sixteen paired canine corneoscleral shells were divided into 2 groups. The CXL group completed a standard CXL protocol using riboflavin–ultraviolet-A (UVA) irradiation. The control group was given an identical treatment except UVA irradiation. Ultrasound scans (at 55 MHz) of the cornea were obtained before and after treatment as the corneoscleral shell was inflated from 5 mm Hg to 45 mm Hg to calculate the distributive through-thickness strains in the cornea. The mean radial and tangential strains of the whole cornea layer, as well as those of the anterior, middle, and posterior thirds of the cornea, were compared before and after treatment in the control group and CXL group using linear mixed models with repeated measures.
RESULTS
Significant reductions in tangential and radial strains occurred in the CXL group (P=.003 and P=.0025, respectively) but not the control group (P=.08 and P=.63, respectively). The anterior third had the smallest strains in all pretreated corneas (P<.001) and posttreated corneas (CXL group, P=.023; control group, P=.01).
CONCLUSIONS
Ultrasound speckle tracking showed heterogeneous strain distributions through the cornea and confirmed that CXL results in a stiffer corneal response (ie, smaller strains during physiologic loadings). This technique may provide a clinical tool to quantify the biomechanical effects of CXL.
Financial Disclosure
No author has a financial or proprietary interest in any material or method mentioned.
doi:10.1016/j.jcrs.2013.09.022
PMCID: PMC4096125  PMID: 24751145
22.  Functional Evaluation of ES–Somatic Cell Hybrids In Vitro and In Vivo 
Cellular Reprogramming  2014;16(3):167-174.
Abstract
Embryonic stem cells (ESCs) have previously been reported to reprogram somatic cells following fusion. The resulting ES–somatic cell hybrids have been shown to adopt the transcriptional profile of ESCs, suggesting that the pluripotent program is dominant. ES–somatic cell hybrids have most characteristics of pluripotent cells in vitro; however, it remains unclear whether the somatic genome is an active partner in the hybrid cells or simply retained predominately as silent cargo. Furthermore, the functional properties of ES–somatic cell hybrids in vivo have been limited to studies on their contribution to teratomas and developing embryos/chimeras. The extent of their pluripotency remains largely unclear. Here we determined that the somatic genome is actively transcribed by generating ES–somatic cell hybrids using Rag2-deficient ESCs fused to autologous wild-type somatic cells. Rag2 expression was detected during in vitro differentiation, suggesting that the somatic genome follows the correct temporal cues during differentiation. Furthermore, ES–somatic cell hybrids maintain their tetraploid state following 4 weeks of differentiation in vivo and are immune tolerated when transferred into matched individuals. The ES–somatic cell hybrids can efficiently differentiate into hematopoietic precursors in both myeloid and lymphoid lineages in vitro, suggesting that the somatic genome is actively transcribed following cell fusion based reprogramming. However, the ES–somatic cell hybrids showed an altered hematopoietic potential following in vitro differentiation and were unable to show hematopoietic engraftment in a mouse model.
doi:10.1089/cell.2013.0079
PMCID: PMC4030652  PMID: 24787484
23.  Ecological roles of dominant and rare prokaryotes in acid mine drainage revealed by metagenomics and metatranscriptomics 
The ISME Journal  2014;9(6):1280-1294.
High-throughput sequencing is expanding our knowledge of microbial diversity in the environment. Still, understanding the metabolic potentials and ecological roles of rare and uncultured microbes in natural communities remains a major challenge. To this end, we applied a ‘divide and conquer' strategy that partitioned a massive metagenomic data set (>100 Gbp) into subsets based on K-mer frequency in sequence assembly to a low-diversity acid mine drainage (AMD) microbial community and, by integrating with an additional metatranscriptomic assembly, successfully obtained 11 draft genomes most of which represent yet uncultured and/or rare taxa (relative abundance <1%). We report the first genome of a naturally occurring Ferrovum population (relative abundance >90%) and its metabolic potentials and gene expression profile, providing initial molecular insights into the ecological role of these lesser known, but potentially important, microorganisms in the AMD environment. Gene transcriptional analysis of the active taxa revealed major metabolic capabilities executed in situ, including carbon- and nitrogen-related metabolisms associated with syntrophic interactions, iron and sulfur oxidation, which are key in energy conservation and AMD generation, and the mechanisms of adaptation and response to the environmental stresses (heavy metals, low pH and oxidative stress). Remarkably, nitrogen fixation and sulfur oxidation were performed by the rare taxa, indicating their critical roles in the overall functioning and assembly of the AMD community. Our study demonstrates the potential of the ‘divide and conquer' strategy in high-throughput sequencing data assembly for genome reconstruction and functional partitioning analysis of both dominant and rare species in natural microbial assemblages.
doi:10.1038/ismej.2014.212
PMCID: PMC4438317  PMID: 25361395
24.  The Serum Profile of Hypercytokinemia Factors Identified in H7N9-Infected Patients can Predict Fatal Outcomes 
Scientific Reports  2015;5:10942.
The novel avian origin influenza A (H7N9) virus has caused severe diseases in humans in eastern China since the spring of 2013. Fatal outcomes of H7N9 infections are often attributed to the severe pneumonia and acute respiratory distress syndrome (ARDS). There is urgent need to discover biomarkers predicting the progression of disease and fatal outcome of potentially lethal flu infections, based on sound statistical analysis. We discovered that 34 of the 48 cytokines and chemokines examined in this study were significantly elevated in the plasma samples from patients infected with H7N9. We report for the first time that the levels of MIF, SCF, MCP-1, HGF, and SCGF-β are highly positively linked to disease severity and the profile of mediators MIF, SCF, MCP-1, HGF, SCGF-β, IP-10, IL-18, and IFN-γ is an independent outcome predictor.
doi:10.1038/srep10942
PMCID: PMC4450576  PMID: 26028236
25.  A Comparison of Postoperative Early Enteral Nutrition with Delayed Enteral Nutrition in Patients with Esophageal Cancer 
Nutrients  2015;7(6):4308-4317.
We examined esophageal cancer patients who received enteral nutrition (EN) to evaluate the validity of early EN compared to delayed EN, and to determine the appropriate time to start EN. A total of 208 esophagectomy patients who received EN postoperatively were divided into three groups (Group 1, 2 and 3) based on whether they received EN within 48 h, 48 h–72 h or more than 72 h, respectively. The postoperative complications, length of hospital stay (LOH), days for first fecal passage, cost of hospitalization, and the difference in serum albumin values between pre-operation and post-operation were all recorded. The statistical analyses were performed using the t-test, the Mann-Whitney U test and the chi square test. Statistical significance was defined as p < 0.05. Group 1 had the lowest thoracic drainage volume, the earliest first fecal passage, and the lowest LOH and hospitalization expenses of the three groups. The incidence of pneumonia was by far the highest in Group 3 (p = 0.019). Finally, all the postoperative outcomes of nutritional conditions were the worst by a significant margin in Group 3. It is therefore safe and valid to start early enteral nutrition within 48 h for postoperative esophageal cancer patients.
doi:10.3390/nu7064308
PMCID: PMC4488785  PMID: 26043031
early enteral nutrition; delayed enteral nutrition; esophageal cancer; postoperative complication

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