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1.  Structural Insights into the Tumor-Promoting Function of the MTDH-SND1 Complex 
Cell reports  2014;8(6):1704-1713.
SUMMARY
Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1’s roles in breast cancer and for SND1 stability under stress. Our study revealed a unique mode of interaction with SN domains that dictates cancer-promoting activity, and provided structural basis for mechanistic understanding of MTDH-SND1 mediated signaling and for exploring therapeutic targeting of this complex.
doi:10.1016/j.celrep.2014.08.033
PMCID: PMC4309369  PMID: 25242325
2.  Sub-micrometer-precision, three-dimensional (3D) hydrodynamic focusing via “microfluidic drifting” 
Lab on a chip  2013;14(2):415-423.
In this article, we demonstrate single-layered, “microfluidic drifting” based three-dimensional (3D) hydrodynamic focusing devices with particle/cell focal positioning approaching submicron precision along both lateral and vertical directions. By systematically optimizing channel geometries and sample/sheath flow rates, a series of “microfluidic drifting” based 3D hydrodynamic focusing devices with different curvature angles are designed and fabricated. Their performances are then evaluated by confocal microscopy, fast camera imaging, and side-view imaging techniques. Using a device with a curvature angle of 180°, we have achieved a standard deviation of ±0.45 µm in particle focal position and a coefficient of variation (CV) of 2.37% in flow cytometric measurements. To the best of our knowledge, this is the best CV that has been achieved by a microfluidic flow cytometry device. Moreover, the device showed the capability to distinguish 8 peaks when subjected to a stringent 8-peak rainbow calibration test, signifying the ability to perform sensitive, accurate tests similar to commercial flow cytometers. We have further tested and validated our device by detection of HEK-293 cells. With its advantages in simple fabrication (i.e., single-layered device), precise 3D hydrodynamic focusing (i.e., submicrometer precision along both lateral and vertical directions), and high detection resolution (i.e., low CV), our method could serve as an important basis for high-performance, mass-producible microfluidic flow cytometry.
doi:10.1039/c3lc50810b
PMCID: PMC3989543  PMID: 24287742
3.  Superhydrophobic Surface Enhanced Raman Scattering Sensing using Janus Particle Arrays Realized by Site-Specific Electrochemical Growth 
Site-specific electrochemical deposition is used to prepare polystyrene (PS)-Ag Janus particle arrays with superhydrophobic properties. The analyte molecules can be significantly enriched using the superhydrophobic property of the PS-Ag Janus particle array before SERS detections, enabling an extremely sensitive detection of molecules in a highly diluted solution (e.g., femtomolar level). This superhydrophobic surface enhanced Raman scattering sensing concept described here is of critical significance in biosensing and bioanalysis. Most importantly, the site-specific electrochemical growth method we developed here is a versatile approach that can be used to prepare Janus particle arrays with different properties for various applications.
doi:10.1039/C3TC31635A
PMCID: PMC3989947  PMID: 24748991
4.  Theory and experiment on particle trapping and manipulation via optothermally generated bubbles 
Lab on a chip  2013;14(2):384-391.
We present a theoretical analysis and experimental demonstration of particle trapping and manipulation around optothermally generated bubbles. We show that a particle located within 500 μm of a surface bubble can be attracted towards a bubble by the drag force resulting from a convective flow. Once the particle comes in contact with the bubble’s surface, a balance between surface tension forces and pressure forces traps the particle on the bubble surface, allowing the particle to move with the bubble without detaching. The proposed mechanism is confirmed by computational fluid dynamics simulations, force calculations, and experiments. Based on this mechanism, we experimentally demonstrated a novel approach for manipulating microparticles via optothermally generated bubbles. Using this approach, randomly distributed microparticles were effectively collected and carried to predefined locations. Single particles were also manipulated along prescribed trajectories. This bubble-based particle trapping and manipulation technique can be useful in applications such as micro assembly, particle concentration, and high-precision particle separation.
doi:10.1039/c3lc50748c
PMCID: PMC3998756  PMID: 24276624
5.  Centralized isolation of Helicobacter pylori from multiple centers and transport condition influences 
AIM: To evaluate the efficacy of centralized culture and possible influencing factors.
METHODS: From January 2010 to July 2012, 66452 patients with suspected Helicobacter pylori (H. pylori) infection from 26 hospitals in Zhejiang and Jiangsu Provinces in China underwent gastrointestinal endoscopy. Gastric mucosal biopsies were taken from the antrum for culture. These biopsies were transported under natural environmental temperature to the central laboratory in Hangzhou city and divided into three groups based on their transport time: 5, 24 and 48 h. The culture results were reported after 72 h and the positive culture rates were analyzed by a χ2 test. An additional 5736 biopsies from H. pylori-positive patients (5646 rapid urease test-positive and 90 14C-urease breath test-positive) were also cultured for quality control in the central laboratory setting.
RESULTS: The positive culture rate was 31.66% (21036/66452) for the patient samples and 71.72% (4114/5736) for the H. pylori-positive quality control specimens. In the 5 h transport group, the positive culture rate was 30.99% (3865/12471), and 32.84% (14960/45553) in the 24 h transport group. In contrast, the positive culture rate declined significantly in the 48 h transport group (26.25%; P < 0.001). During transportation, the average natural temperature increased from 4.67 to 29.14 °C, while the positive culture rate declined from 36.67% (1462/3987) to 24.12% (1799/7459). When the temperature exceeded 24 °C, the positive culture rate decreased significantly, especially in the 48 h transport group (23.17%).
CONCLUSION: Transportation of specimens within 24 h and below 24 °C is reasonable and acceptable for centralized culture of multicenter H. pylori samples.
doi:10.3748/wjg.v21.i3.944
PMCID: PMC4299348  PMID: 25624729
Centralized isolation; Helicobacter pylori; Influencing factor; Multiple centers; Personalized treatment
6.  Parameter Estimation of Fractional-Order Chaotic Systems by Using Quantum Parallel Particle Swarm Optimization Algorithm 
PLoS ONE  2015;10(1):e0114910.
Parameter estimation for fractional-order chaotic systems is an important issue in fractional-order chaotic control and synchronization and could be essentially formulated as a multidimensional optimization problem. A novel algorithm called quantum parallel particle swarm optimization (QPPSO) is proposed to solve the parameter estimation for fractional-order chaotic systems. The parallel characteristic of quantum computing is used in QPPSO. This characteristic increases the calculation of each generation exponentially. The behavior of particles in quantum space is restrained by the quantum evolution equation, which consists of the current rotation angle, individual optimal quantum rotation angle, and global optimal quantum rotation angle. Numerical simulation based on several typical fractional-order systems and comparisons with some typical existing algorithms show the effectiveness and efficiency of the proposed algorithm.
doi:10.1371/journal.pone.0114910
PMCID: PMC4300217  PMID: 25603158
7.  Detailed investigation of the microbial community in foaming activated sludge reveals novel foam formers 
Scientific Reports  2015;5:7637.
Foaming of activated sludge (AS) causes adverse impacts on wastewater treatment operation and hygiene. In this study, we investigated the microbial communities of foam, foaming AS and non-foaming AS in a sewage treatment plant via deep-sequencing of the taxonomic marker genes 16S rRNA and mycobacterial rpoB and a metagenomic approach. In addition to Actinobacteria, many genera (e.g., Clostridium XI, Arcobacter, Flavobacterium) were more abundant in the foam than in the AS. On the other hand, deep-sequencing of rpoB did not detect any obligate pathogenic mycobacteria in the foam. We found that unknown factors other than the abundance of Gordonia sp. could determine the foaming process, because abundance of the same species was stable before and after a foaming event over six months. More interestingly, although the dominant Gordonia foam former was the closest with G. amarae, it was identified as an undescribed Gordonia species by referring to the 16S rRNA gene, gyrB and, most convincingly, the reconstructed draft genome from metagenomic reads. Our results, based on metagenomics and deep sequencing, reveal that foams are derived from diverse taxa, which expands previous understanding and provides new insight into the underlying complications of the foaming phenomenon in AS.
doi:10.1038/srep07637
PMCID: PMC4284521  PMID: 25560234
8.  Accelerating drug discovery via organs-on-chips 
Lab on a chip  2013;13(24):4697-4710.
Considerable advances have been made in the development of micro-physiological systems that seek to faithfully replicate the complexity and functionality of animal and human physiology in research laboratories. Sometimes referred to as “organs-on-chips”, these systems provide key insights into physiological or pathological processes associated with health maintenance and disease control, and serve as powerful platforms for new drug development and toxicity screening. In this Focus article, we review the state-of-the-art designs and examples for developing multiple “organs-on-chips”, and discuss the potential of this emerging technology to enhance our understanding of human physiology, and to transform and accelerate the drug discovery and pre-clinical testing process. This Focus article highlights some of the recent technological advances in this field, along with the challenges that must be addressed for these technologies to fully realize their potential.
doi:10.1039/c3lc90115g
PMCID: PMC3998760  PMID: 24193241
9.  Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials 
Critical Care  2014;18(6):702.
Introduction
The aim of this study was to examine whether albumin reduced mortality when employed for the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid by meta-analysis.
Methods
We searched for and gathered data from MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. Studies were eligible if they compared the effects of albumin versus crystalloid therapy on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Data including mortality, sample size of the patients with severe sepsis, sample size of the patients with septic shock and resuscitation endpoints were extracted. Data were analyzed by the methods recommended by the Cochrane Collaboration Review Manager 4.2 software.
Results
A total of 5,534 records were identified through the initial search. Five studies compared albumin with crystalloid. In total, 3,658 severe sepsis and 2,180 septic shock patients were included in the meta-analysis. The heterogeneity was determined to be non-significant (P = 0.86, I2 = 0%). Compared with crystalloid, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; P = 0.08). However, the use of albumin for resuscitation significantly decreased 90-day mortality in septic shock patients (OR 0.81; 95% CI, 0.67 to 0.97; P = 0.03). Compared with saline, the use of albumin for resuscitation slightly improved outcome in severe sepsis patients (OR 0.81; 95% CI, 0.64 to 1.08; P = 0.09).
Conclusions
In this meta-analysis, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the 90-day mortality of patients with septic shock decreased significantly.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0702-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0702-y
PMCID: PMC4284920  PMID: 25499187
10.  The metabolite alpha-ketoglutarate extends lifespan by inhibiting the ATP synthase and TOR 
Nature  2014;510(7505):397-401.
Metabolism and ageing are intimately linked. Compared to ad libitum feeding, dietary restriction (DR) or calorie restriction (CR) consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms1,2. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits3,4. Recently, several metabolites have been identified that modulate ageing5,6 with largely undefined molecular mechanisms. Here we show that the tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate (α-KG) extends the lifespan of adult C. elegans. ATP synthase subunit beta is identified as a novel binding protein of α-KG using a small-molecule target identification strategy called DARTS (drug affinity responsive target stability)7. The ATP synthase, also known as Complex V of the mitochondrial electron transport chain (ETC), is the main cellular energy-generating machinery and is highly conserved throughout evolution8,9. Although complete loss of mitochondrial function is detrimental, partial suppression of the ETC has been shown to extend C. elegans lifespan10–13. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit beta and is dependent on the target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased upon starvation and α-KG does not extend the lifespan of DR animals, indicating that α-KG is a key metabolite that mediates longevity by DR. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator, and DR in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.
doi:10.1038/nature13264
PMCID: PMC4263271  PMID: 24828042
11.  Long-Term Effects of the Booster-Enhanced READY-Girls Preconception Counseling Program on Intentions and Behaviors for Family Planning in Teens With Diabetes 
Diabetes Care  2013;36(12):3870-3874.
OBJECTIVE
To examine 12-month effects of a booster-enhanced preconception counseling (PC) program (READY-Girls) on family planning for teen girls with type 1 and type 2 diabetes.
RESEARCH DESIGN AND METHODS
Participants 13–19 years of age (n = 109) were randomized to a standard care control group (CG) or intervention group (IG) that received PC over three consecutive clinic visits. Prepost data were collected at baseline, 3- and 6-month booster sessions, and a 12-month follow-up visit.
RESULTS
Mean age was 15.8 years; 9 (8%) subjects had type 2 diabetes; and 18 (17%) subjects were African American. At baseline, 20% (n = 22 of 109) had been sexually active, and of these, 50% (n = 11) had at least one episode of unprotected sex. Over time, IG participants retained greater PC knowledge (F[6, 541] = 4.05, P = 0.0005) and stronger intentions regarding PC (significant group-by-time effects) especially after boosters. IG participants had greater intentions to discuss PC (F[6, 82.4] = 2.56, P = 0.0254) and BC (F[6, 534] = 3.40, P = 0.0027) with health care providers (HCPs) and seek PC when planning a pregnancy (F[6, 534] = 2.58, P = 0.0180). Although not significant, IG participants, compared with CG, showed a consistent trend toward lower rates of overall sexual activity over time: less sexual debut (35 vs. 41%) and higher rates of abstinence (44 vs. 32%). No pregnancies were reported in either group throughout the study.
CONCLUSIONS
READY-Girls appeared to have long-term sustaining effects on PC knowledge, beliefs, and intentions to initiate discussion with HCPs that could improve reproductive health behaviors and outcomes. Strong boosters and providing PC at each clinic visit could play important roles in sustaining long-term effects.
doi:10.2337/dc13-0355
PMCID: PMC3836127  PMID: 24130343
12.  Variability in Crash and Near-Crash Risk among Novice Teenage Drivers: A Naturalistic Study 
The Journal of pediatrics  2013;163(6):10.1016/j.jpeds.2013.07.025.
Objective
Using video monitoring technologies, we investigated teenage driving risk variation during the first 18 months of independent driving.
Study design
Driving data were collected on 42 teenagers whose vehicles were instrumented with sophisticated video and data recording devices. Surveys on demographic and personality characteristics were administered at baseline. Drivers were classified into three risk groups using a K-mean clustering method based on crash and near-crash (CNC) rate. The change in CNC rates over time was evaluated by mixed-effect Poisson models.
Results
Compared with the first three months after licensure (first quarter), the CNC rate for participants during the third, fourth and fifth quarters decreased significantly to 59%, 62%, and 48%, respectively. Three distinct risk groups were identified with CNC rates of 21.8 (high-risk), 8.3 (moderate-risk), and 2.1 (low-risk) per 10000 kilometers traveled. High- and low-risk drivers showed no significant change in CNC rates throughout the 18-month study period. CNC rates for moderate-risk drivers decreased substantially from 8.8 per 10000 kilometers in the first quarter to 0.8 and 3.2 in the fourth and fifth quarters, respectively. The three groups were not distinguishable with respect to personality characteristics.
Conclusion
Teenage CNC rates varied substantially, with distinct high-, moderate-, and low-risk groups. Risk declined over time only in the moderate-risk group. The high-risk drivers appeared to be insensitive to experience, with CNC rates consistently high throughout the 18-month study period, and the moderate-risk group appeared to learn from experience.
doi:10.1016/j.jpeds.2013.07.025
PMCID: PMC3842416  PMID: 23992677
Naturalistic driving study; driving risk; novice driver; teenage drivers; adolescents; learning; driving experience
13.  Upregulation of ICAM-1 in diabetic rats after transient forebrain ischemia and reperfusion injury 
Background
Hyperglycemia exacerbates brain damage caused by cerebral ischemia. Neuroinflammation may play a role in mediating such enhanced damage. The objectives of this study were to examine the mRNA and protein levels and cell type distribution of ICAM-1 after cerebral ischemia in normo-and diabetic hyperglycemic rats.
Results
Compared to normoglycemic ischemia animals, diabetes aggravated neuronal death, decreased Nissl body staining, and increased ICAM-1 mRNA and protein levels in the frontal cortex. The increased ICAM-1 was located not only in vascular endothelial cells but also in cortical neurons.
Conclusions
Our results suggest that exacerbated neuro-inflammation in the brain may mediate the detrimental effects of diabetes on the ischemic brain.
doi:10.1186/s12950-014-0035-2
PMCID: PMC4226864  PMID: 25389378
Cerebral ischemia; Endothelia; Forebrain ischemia; ICAM-1; Inflammation; Neurodegeneration; Neuron; Stroke
14.  Effects of cyclooxygenase-2 gene silencing on the biological behavior of SKOV3 ovarian cancer cells 
Molecular Medicine Reports  2014;11(1):59-66.
The aim of the present study was to investigate the effects of plasmid-mediated RNA interference targeting of cyclooxygenase-2 (COX-2) on the biological behaviors of SKOV3 human ovarian cancer cells and to analyze the function of COX-2 in carcinogenesis and development of ovarian cancer. A COX-2 small hairpin (sh)RNA sequence was designed and synthesized and pGPU6-COX-2-shRNA plasmids were constructed. The recombinant vector plasmids were stably transfected into SKOV3 cells. The mRNA and protein expression of COX-2 was subsequently analyzed by quantitative polymerase chain reaction and western blot analysis, respectively. MTT and colony formation assays were used to detect the cellular proliferation ability and flow cytometry was performed to detect phase changes in the cell cycle. Finally, a Transwell assay was used to detect cell invasion. The SKOV3 cells, transfected with recombinant vector plasmids, and control cells, were injected into nude mice and the tumor emergence time, volume and weight were measured. The impact of COX-2 gene silencing on the growth of xenograft tumors in nude mice was analyzed. Following transfection of the pGPU6-COX-2-shRNA plasmid, in vitro analyses indicated that the shRNA efficiently suppressed the mRNA and protein expression of COX-2. COX-2 gene silencing significantly inhibited the proliferation and invasion ability of SKOV3 cells, leading to cell cycle arrest in G1. The tumor formation time in the interference group was significantly prolonged, and the tumor volume and weight were significantly decreased, as compared with the control group. Plasmid-mediated shRNA was shown to effectively silence COX-2 expression in SKOV3 ovarian cancer cells. It was identified that COX-2 functioned in regulating proliferation, cell cycle and invasion of ovarian cancer cells. These findings provided a theoretical basis for determining the function of COX-2 in the development of ovarian cancer and suggested that COX-2 may be an effective target for gene therapy and clinical applications.
doi:10.3892/mmr.2014.2732
PMCID: PMC4237092  PMID: 25335121
ovarian cancer; cyclooxygenase-2; RNA interference; proliferation; invasion; gene therapy
15.  Evidence of Carbon Fixation Pathway in a Bacterium from Candidate Phylum SBR1093 Revealed with Genomic Analysis 
PLoS ONE  2014;9(10):e109571.
Autotrophic CO2 fixation is the most important biotransformation process in the biosphere. Research focusing on the diversity and distribution of relevant autotrophs is significant to our comprehension of the biosphere. In this study, a draft genome of a bacterium from candidate phylum SBR1093 was reconstructed with the metagenome of an industrial activated sludge. Based on comparative genomics, this autotrophy may occur via a newly discovered carbon fixation path, the hydroxypropionate-hydroxybutyrate (HPHB) cycle, which was demonstrated in a previous work to be uniquely possessed by some genera from Archaea. This bacterium possesses all of the thirteen enzymes required for the HPHB cycle; these enzymes share 30∼50% identity with those in the autotrophic species of Archaea that undergo the HPHB cycle and 30∼80% identity with the corresponding enzymes of the mixotrophic species within Bradyrhizobiaceae. Thus, this bacterium might have an autotrophic growth mode in certain conditions. A phylogenetic analysis based on the 16S rRNA gene reveals that the phylotypes within candidate phylum SBR1093 are primarily clustered into 5 clades with a shallow branching pattern. This bacterium is clustered with phylotypes from organically contaminated environments, implying a demand for organics in heterotrophic metabolism. Considering the types of regulators, such as FnR, Fur, and ArsR, this bacterium might be a facultative aerobic mixotroph with potential multi-antibiotic and heavy metal resistances. This is the first report on Bacteria that may perform potential carbon fixation via the HPHB cycle, thus may expand our knowledge of the distribution and importance of the HPHB cycle in the biosphere.
doi:10.1371/journal.pone.0109571
PMCID: PMC4195664  PMID: 25310003
16.  Repetitive Transcranial Magnetic Stimulation Promotes Neural Stem Cell Proliferation via the Regulation of MiR-25 in a Rat Model of Focal Cerebral Ischemia 
PLoS ONE  2014;9(10):e109267.
Repetitive transcranial magnetic stimulation (rTMS) has increasingly been studied over the past decade to determine whether it has a therapeutic benefit on focal cerebral ischemia. However, the underlying mechanism of rTMS in this process remains unclear. In the current study, we investigated the effects of rTMS on the proliferation of adult neural stem cells (NSCs) and explored microRNAs (miRNAs) that were affected by rTMS. Our data showed that 10 Hz rTMS significantly increased the proliferation of adult NSCs after focal cerebral ischemia in the subventricular zone (SVZ), and the expression of miR-25 was obviously up-regulated in the ischemic cortex after rTMS. p57, an identified miR-25 target gene that regulates factors linked to NSC proliferation, was also evaluated, and it exhibited down-regulation. To further verify the role of miR-25, rats were injected with a single dose of antagomir-25 and were subjected to focal cerebral ischemia followed by rTMS treatment. The results confirmed that miR-25 could be repressed specifically and could drive the up-regulation of its target gene (p57), which resulted in the inhibition of adult NSC proliferation in the SVZ after rTMS. Thus, our studies strongly indicated that 10 Hz rTMS can promote the proliferation of adult NSCs in the SVZ after focal cerebral ischemia by regulating the miR-25/p57 pathway.
doi:10.1371/journal.pone.0109267
PMCID: PMC4193773  PMID: 25302788
17.  Distracted Driving and Risk of Road Crashes among Novice and Experienced Drivers 
BACKGROUND
Distracted driving attributable to the performance of secondary tasks is a major cause of motor vehicle crashes both among teenagers who are novice drivers and among adults who are experienced drivers.
METHODS
We conducted two studies on the relationship between the performance of secondary tasks, including cell-phone use, and the risk of crashes and near-crashes. To facilitate objective assessment, accelerometers, cameras, global positioning systems, and other sensors were installed in the vehicles of 42 newly licensed drivers (16.3 to 17.0 years of age) and 109 adults with more driving experience.
RESULTS
During the study periods, 167 crashes and near-crashes among novice drivers and 518 crashes and near-crashes among experienced drivers were identified. The risk of a crash or near-crash among novice drivers increased significantly if they were dialing a cell phone (odds ratio, 8.32; 95% confidence interval [CI], 2.83 to 24.42), reaching for a cell phone (odds ratio, 7.05; 95% CI, 2.64 to 18.83), sending or receiving text messages (odds ratio, 3.87; 95% CI, 1.62 to 9.25), reaching for an object other than a cell phone (odds ratio, 8.00; 95% CI, 3.67 to 17.50), looking at a roadside object (odds ratio, 3.90; 95% CI, 1.72 to 8.81), or eating (odds ratio, 2.99; 95% CI, 1.30 to 6.91). Among experienced drivers, dialing a cell phone was associated with a significantly increased risk of a crash or near-crash (odds ratio, 2.49; 95% CI, 1.38 to 4.54); the risk associated with texting or accessing the Internet was not assessed in this population. The prevalence of high-risk attention to secondary tasks increased over time among novice drivers but not among experienced drivers.
CONCLUSIONS
The risk of a crash or near-crash among novice drivers increased with the performance of many secondary tasks, including texting and dialing cell phones. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Highway Traffic Safety Administration.)
doi:10.1056/NEJMsa1204142
PMCID: PMC4183154  PMID: 24382065
18.  Recognition of Protein-coding Genes Based on Z-curve Algorithms 
Current Genomics  2014;15(2):95-103.
Recognition of protein-coding genes, a classical bioinformatics issue, is an absolutely needed step for annotating newly sequenced genomes. The Z-curve algorithm, as one of the most effective methods on this issue, has been successfully applied in annotating or re-annotating many genomes, including those of bacteria, archaea and viruses. Two Z-curve based ab initio gene-finding programs have been developed: ZCURVE (for bacteria and archaea) and ZCURVE_V (for viruses and phages). ZCURVE_C (for 57 bacteria) and Zfisher (for any bacterium) are web servers for re-annotation of bacterial and archaeal genomes. The above four tools can be used for genome annotation or re-annotation, either independently or combined with the other gene-finding programs. In addition to recognizing protein-coding genes and exons, Z-curve algorithms are also effective in recognizing promoters and translation start sites. Here, we summarize the applications of Z-curve algorithms in gene finding and genome annotation.
doi:10.2174/1389202915999140328162724
PMCID: PMC4009845  PMID: 24822027
Genome annotation; Genome re-annotation; Z-curve algorithm; ZCURVE; ZCURVE_V.
19.  Analysis of the Relationship between Genomic GC Content and Patterns of Base Usage, Codon Usage and Amino Acid Usage in Prokaryotes: Similar GC Content Adopts Similar Compositional Frequencies Regardless of the Phylogenetic Lineages 
PLoS ONE  2014;9(9):e107319.
The GC contents of 2670 prokaryotic genomes that belong to diverse phylogenetic lineages were analyzed in this paper. These genomes had GC contents that ranged from 13.5% to 74.9%. We analyzed the distance of base frequencies at the three codon positions, codon frequencies, and amino acid compositions across genomes with respect to the differences in the GC content of these prokaryotic species. We found that although the phylogenetic lineages were remote among some species, a similar genomic GC content forced them to adopt similar base usage patterns at the three codon positions, codon usage patterns, and amino acid usage patterns. Our work demonstrates that in prokaryotic genomes: a) base usage, codon usage, and amino acid usage change with GC content with a linear correlation; b) the distance of each usage has a linear correlation with the GC content difference; and c) GC content is more essential than phylogenetic lineage in determining base usage, codon usage, and amino acid usage. This work is exceptional in that we adopted intuitively graphic methods for all analyses, and we used these analyses to examine as many as 2670 prokaryotes. We hope that this work is helpful for understanding common features in the organization of microbial genomes.
doi:10.1371/journal.pone.0107319
PMCID: PMC4177787  PMID: 25255224
20.  Surface acoustic wave microfluidics 
Lab on a chip  2013;13(18):3626-3649.
The recent introduction of surface acoustic wave (SAW) technology onto lab-on-a-chip platforms has opened a new frontier in microfluidics. The advantages provided by such SAW microfluidics are numerous: simple fabrication, high biocompatibility, fast fluid actuation, versatility, compact and inexpensive devices and accessories, contact-free particle manipulation, and compatibility with other microfluidic components. We believe that these advantages enable SAW microfluidics to play a significant role in a variety of applications in biology, chemistry, engineering, and medicine. In this review article, we discuss the theory underpinning SAWs and their interactions with particles and the contacting fluids in which they are suspended. We then review the SAW-enabled microfluidic devices demonstrated to date, starting with devices that accomplish fluid mixing and transport through the use of travelling SAW; we follow that by reviewing the more recent innovations achieved with standing SAW that enable such actions as particle/cell focusing, sorting, and patterning. Finally, we look forward and appraise where the discipline of SAW microfluidics could go next.
doi:10.1039/c3lc50361e
PMCID: PMC3992948  PMID: 23900527
21.  Regulation of T cell proliferation by JMJD6 and PDGF-BB during chronic hepatitis B infection 
Scientific Reports  2014;4:6359.
T cell functional exhaustion during chronic hepatitis B virus (HBV) infection may contribute to the failed viral clearance; however, the underlying molecular mechanisms remain largely unknown. Here we demonstrate that jumonji domain-containing protein 6 (JMJD6) is a potential regulator of T cell proliferation during chronic HBV infection. The expression of JMJD6 was reduced in T lymphocytes in chronic hepatitis B (CHB) patients, and this reduction in JMJD6 expression was associated with impaired T cell proliferation. Moreover, silencing JMJD6 expression in primary human T cells impaired T cell proliferation. We found that JMJD6 promotes T cell proliferation by suppressing the mRNA expression of CDKN3. Furthermore, we have identified platelet derived growth factor-BB (PDGF-BB) as a regulator of JMJD6 expression. PDGF-BB downregulates JMJD6 expression and inhibits the proliferation of human primary T cells. Importantly, the expression levels of JMJD6 and PDGF-BB in lymphocytes from CHB patients were correlated with the degree of liver damage and the outcome of chronic HBV infection treatment. Our results demonstrate that PDGF-BB and JMJD6 regulate T cell function during chronic HBV infection and may provide insights for the treatment strategies for CHB patients.
doi:10.1038/srep06359
PMCID: PMC4163673  PMID: 25219359
22.  Multipaddled Anterolateral Thigh Chimeric Flap for Reconstruction of Complex Defects in Head and Neck 
PLoS ONE  2014;9(9):e106326.
The anterolateral thigh flap has been the workhouse flap for coverage of soft-tissue defects in head and neck for decades. However, the reconstruction of multiple and complex soft-tissue defects in head and neck with multipaddled anterolateral thigh chimeric flaps is still a challenge for reconstructive surgeries. Here, a clinical series of 12 cases is reported in which multipaddled anterolateral thigh chimeric flaps were used for complex soft-tissue defects with several separately anatomic locations in head and neck. Of the 12 cases, 7 patients presented with trismus were diagnosed as advanced buccal cancer with oral submucous fibrosis, 2 tongue cancer cases were found accompanied with multiple oral mucosa lesions or buccal cancer, and 3 were hypopharyngeal cancer with anterior neck skin invaded. All soft-tissue defects were reconstructed by multipaddled anterolateral thigh chimeric flaps, including 9 tripaddled anterolateral thigh flaps and 3 bipaddled flaps. The mean length of skin paddle was 19.2 (range: 14–23) cm and the mean width was 4.9 (range: 2.5–7) cm. All flaps survived and all donor sites were closed primarily. After a mean follow-up time of 9.1 months, there were no problems with the donor or recipient sites. This study supports that the multipaddled anterolateral thigh chimeric flap is a reliable and good alternative for complex and multiple soft-tissue defects of the head and neck.
doi:10.1371/journal.pone.0106326
PMCID: PMC4152256  PMID: 25180680
23.  Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection 
Cell & Bioscience  2014;4(1):50.
Background
Ductular reactions (DRs) are well documented in many acute and chronic liver disease.The DRs are thought to be the transit amplifying cells deriving from activation of the stem/progenitor cell compartments of the liver. The aim of this study was to examine the presence of proliferative index of DR (PI-DR) and HPC markers’ expression in HCCs after curative hepatectomy, as well as their relationship with clinicopathological features and prognosis.
Results
Tissue microarray with peritumoral and intratumoral tissue samples of 120 HCCs after hepatectomy was analysed for peritumoral expression of proliferating cell nuclear antigen for PI-DR. Peritumoral and intratumoral expression status of HPC markers including EpCAM, OV6, CD133 and c-kit were also examined by immunohistochemistry. TMA analysis of HCCs revealed that peritumoral PI-DR strongly correlated with the degree of inflammation and fibrosis. The peritumoral PI-DR positively correlated with peritumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Moreover, there were highly significant correlations between peritumoral PI-DR and intratumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Further, multivariate analysis showed that peritumoral PI-DR was the independent prognostic factor for overall survival (HR; 3.316, P < 0.001), and peritumoral PI-DR had a better power to predict disease-free survival (HR; 2.618, P < 0.001).
Conclusions
Peritumoral PI-DR, as a valid surrogate for peritumoral and intratumoral expression of HPC markers, could be served as a potential prognostic marker for recurrence and survival in HCC after hepatectomy.
doi:10.1186/2045-3701-4-50
PMCID: PMC4156622  PMID: 25197550
Proliferative index of ductular reaction; Hepatic progenitor cell; Recurrence; Hepatocellular carcinoma
24.  Probing cell-cell communication with microfluidic devices 
Lab on a chip  2013;13(16):3152-3162.
Cell-cell communication plays an essential role in organismal development and functionality, and communication errors can lead to deleterious effects such as degenerative and autoimmune diseases. However, the intercellular communication network is extremely complex in multicellular organisms making isolation of the functional unit and study of basic mechanisms technically challenging. Despite the level of complexity and many challenges facing researchers in this area, recent development in microfluidic technology allows miniaturized and integrated devices to perform intercellular communication experiments on-chip. Microfluidics have many advantages, including the ability to accurately mimic the chemical, mechanical, and physical cellular microenvironment, precise spatial and temporal control, dynamic characterization, high throughput, scalability and reproducibility. In this Focus article, we highlight some of the recent works and advances in the application of microfluidics to the study of mammalian intercellular communication with particular emphasis on cell contact and soluble factor mediated communication. In addition, we provide some insights into the likely direction of the future developments in this field.
doi:10.1039/c3lc90067c
PMCID: PMC3998754  PMID: 23843092
25.  Higher Crash and Near-Crash Rates in Teenaged Drivers With Lower Cortisol Response 
JAMA pediatrics  2014;168(6):517-522.
IMPORTANCE
Road traffic crashes are one of the leading causes of injury and death among teenagers worldwide. Better understanding of the individual pathways to driving risk may lead to better-targeted intervention in this vulnerable group.
OBJECTIVE
To examine the relationship between cortisol, a neurobiological marker of stress regulation linked to risky behavior, and driving risk.
DESIGN, SETTING, AND PARTICIPANTS
The Naturalistic Teenage Driving Study was designed to continuously monitor the driving behavior of teenagers by instrumenting vehicles with kinematic sensors, cameras, and a global positioning system. During 2006–2008, a community sample of 42 newly licensed 16-year-old volunteer participants in the United States was recruited and driving behavior monitored. It was hypothesized in teenagers that higher cortisol response to stress is associated with (1) lower crash and near-crash (CNC) rates during their first 18 months of licensure and (2) faster reduction in CNC rates over time.
MAIN OUTCOMES AND MEASURES
Participants’ cortisol response during a stress-inducing task was assessed at baseline, followed by measurement of their involvement in CNCs and driving exposure during their first 18 months of licensure. Mixed-effect Poisson longitudinal regression models were used to examine the association between baseline cortisol response and CNC rates during the follow-up period.
RESULTS
Participants with a higher baseline cortisol response had lower CNC rates during the follow-up period (exponential of the regression coefficient, 0.93; 95%CI, 0.88–0.98) and faster decrease in CNC rates over time (exponential of the regression coefficient, 0.98; 95%, CI, 0.96–0.99).
CONCLUSIONS AND RELEVANCE
Cortisol is a neurobiological marker associated with teenaged-driving risk. As in other problem-behavior fields, identification of an objective marker of teenaged-driving risk promises the development of more personalized intervention approaches.
doi:10.1001/jamapediatrics.2013.5387
PMCID: PMC4139916  PMID: 24710522

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