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1.  USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites 
Nature  2016;532(7599):398-401.
USP14 is a major regulator of the proteasome and one of three proteasome-associated deubiquitinating enzymes1–9. Its effects on protein turnover are substrate specific, for unknown reasons. We report that USP14 shows a dramatic preference for ubiquitin-cyclin B conjugates that carry more than one ubiquitin modification or chain. This specificity is conserved from yeast to humans and is independent of chain linkage type. USP14 has been thought to cleave single ubiquitin groups from the distal tip of a chain but we find that it removes chains from cyclin B en bloc, proceeding until a single chain remains. The suppression of degradation by USP14’s catalytic activity reflects its capacity to act on a millisecond time scale, before the proteasome can initiate degradation of the substrate. In addition, single-molecule studies showed that the dwell time of ubiquitin conjugates at the proteasome was reduced by USP14-dependent deubiquitination. In summary, the specificity of the proteasome can be regulated by rapid ubiquitin chain removal, which resolves substrates based on a novel aspect of ubiquitin chain architecture.
doi:10.1038/nature17433
PMCID: PMC4844788  PMID: 27074503
2.  Validating CFD Predictions of Pharmaceutical Aerosol Deposition with In Vivo Data 
Pharmaceutical research  2015;32(10):3170-3187.
Purpose
CFD provides a powerful approach to evaluate the deposition of pharmaceutical aerosols; however, previous studies have not compared CFD results of deposition throughout the lungs with in vivo data.
Methods
The in vivo datasets selected for comparison with CFD predictions included fast and slow clearance of monodisperse aerosols as well as 2D gamma scintigraphy measurements for a dry powder inhaler (DPI) and softmist inhaler (SMI). The CFD model included the inhaler, a characteristic model of the mouth-throat (MT) and upper tracheobronchial (TB) airways, stochastic individual pathways (SIPs) representing the remaining TB region, and recent CFD-based correlations to predict pharmaceutical aerosol deposition in the alveolar airways.
Results
For the monodisperse aerosol, CFD predictions of total lung deposition agreed with in vivo data providing a percent relative error of 6% averaged across aerosol sizes of 1-7μm. With the DPI and SMI, deposition was evaluated in the MT, central airways (bifurcations B1-B7), and intermediate plus peripheral airways (B8 through alveoli). Across these regions, CFD predictions produced an average relative error <10% for each inhaler.
Conclusions
CFD simulations with the SIP modeling approach were shown to accurately predict regional deposition throughout the lungs for multiple aerosol types and different in vivo assessment methods.
doi:10.1007/s11095-015-1695-1
PMCID: PMC4580521  PMID: 25944585
Computational fluid dynamics (CFD); predictions of aerosol deposition; airway dosimetry predictions; pharmaceutical aerosols; respiratory drug delivery
3.  The Number of Stenotic Intracranial Arteries Is Independently Associated with Ischemic Stroke Severity 
PLoS ONE  2016;11(9):e0163356.
Background
The severity of ischemic stroke symptoms varies among patients and is a critical determinant of patient outcome. To date, the association between the number of stenotic intracranial arteries and stroke severity remains unclear.
Aims
We aimed to investigate the association between the number of stenotic major intracranial arteries (NSMIA) and ischemic stroke severity, as well as the degree of stenosis and common stroke risk factors.
Methods
We performed a retrospective analysis of patients with digital subtraction angiography (DSA)-confirmed ischemic stroke. Clinical stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). The number of stenotic vessels was counted from the internal carotid arteries and vertebral arteries, bilaterally.
Results
Eighty three patients were recruited from a single center and included in the study. NSMIA was significantly correlated with stroke severity (Pearson Correlation Coefficient = 0.485, P < 0.001), but not with the degree of stenosis (Pearson Correlation Coefficient = 0.01, P = 0.90). Multivariate regression analysis revealed that NSMIA was significantly associated with the NIHSS score after adjusting for stroke risk factors. The adjusted odds ratio (per lateral) was 2.092 (95% CI, 0.865 to 3.308, P = 0.001). The degree of stenosis was also significantly associated with the NIHSS score after adjusting for common risk factors. The odds ratio (per 10%) was 0.712 (95% CI, 0.202 to 1.223, P = 0.007).
Conclusions
The number of stenotic intracranial major arteries is associated with the severity of ischemic stroke independent of the degree of stenosis and other stroke risk factors. To the best of our knowledge, this has not been previosuly studied in great detail using DSA. Our data highlight the importance of examining all major arteries in stroke patients.
doi:10.1371/journal.pone.0163356
PMCID: PMC5029900  PMID: 27649086
4.  Overexpression of gelsolin reduces the proliferation and invasion of colon carcinoma cells 
Molecular Medicine Reports  2016;14(4):3059-3065.
The enhanced motility of cancer cells via the remodeling of the actin cytoskeleton is crucial in the process of cancer cell invasion and metastasis. It was previously demonstrated that gelsolin (GSN) may be involved as a tumor or a metastasis suppressor, depending on the cell lines and model systems used. In the present study, the effect of GSN on the growth and invasion of human colon carcinoma (CC) cells was investigated using reverse transcription quantitative polymerase chain reaction and western blotting. It was observed that upregulation of the expression of GSN in human CC cells significantly reduced the invasiveness of these cells. The expression levels of GSN were observed to be reduced in CC cells, and the reduced expression level of GSN was often associated with a poorer metastasis-free survival rate in patients with CC (P=0.04). In addition, the overexpression of GSN inhibited the invasion of CC cells in vitro. Furthermore, GSN was observed to inhibit signal transducer and activator of transcription (STAT) 3 signaling in CC cells. Together, these results suggested that GSN is critical in regulating cytoskeletal events and inhibits the invasive and/or metastatic potential of CC cells. The results obtained in the present study may improve understanding of the functional and mechanistic links between GSN as a possible tumor suppressor and the STAT3 signaling pathway, with respect to the aggressive nature of CC. In addition, the present study demonstrated the importance of GSN in regulating the invasion and metastasis of CC cells at the molecular level, suggesting that GSN may be a potential predictor of prognosis and treatment success in CC.
doi:10.3892/mmr.2016.5652
PMCID: PMC5042772  PMID: 27573444
overexpression; gelsolin; colon carcinoma; signal transducer and activator of transcription 3; tumor metastasis; prognostic factor
5.  Relationship Between Interleukin-10 Gene C-819T Polymorphism and Gastric Cancer Risk: Insights From a Meta-Analysis 
Background
As a pleiotropic cytokine, interleukin-10 (IL-10) plays a regulatory role in carcinogenesis and tumor growth. The aim of this meta-analysis was to assess the susceptibility of the IL-10 gene C-819T polymorphism to gastric cancer.
Material/Methods
Study identification and data extraction were independently completed by 2 authors. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated and summarized.
Results
In total, 11 articles including 1960 gastric cancer patients and 3705 controls were qualified. Overall analyses revealed a 13% reduced risk of gastric cancer conferred by the −819T allele relative to the −819C allele (OR=0.87; 95% CI: 0.77–0.97; P=0.016), without heterogeneity (I2=35.1%). In subgroup analyses, a significant difference was identified in East Asian populations (OR=0.85; 95% CI: 0.73–0.98; P=0.029, I2=43.6%), for gastric adenocarcinoma (OR=0.80; 95% CI: 0.66–0.96; P=0.017, I2=0.0%), and in population-based studies (OR=0.81; 95% CI: 0.70–0.93; P=0.003, I2=0.0%). The visual funnel plots and Egger’s tests suggested no evidence of publication bias.
Conclusions
Extending previous findings, we demonstrate a protective role of the IL-10 gene −819T allele in susceptibility to gastric cancer, and this role was more evident for gastric adenocarcinoma.
doi:10.12659/MSM.895333
PMCID: PMC4993219  PMID: 27516059
Interleukin-10; Meta-Analysis; Polymorphism, Genetic; Stomach Neoplasms
6.  Rpn1 provides adjacent receptor sites for substrate binding and deubiquitination by the proteasome 
Science (New York, N.Y.)  2016;351(6275):10.1126/science.aad9421 aad9421.
Structured Abstract
INTRODUCTION
The ubiquitin-proteasome system comprises hundreds of distinct pathways of degradation, which converge at the step of ubiquitin recognition by the proteasome. Five proteasomal ubiquitin receptors have been identified, two that are intrinsic to the proteasome (Rpn10 and Rpn13) and three reversibly associated proteasomal ubiquitin receptors (Rad23, Dsk2, and Ddi1).
RATIONALE
We found that the five known proteasomal ubiquitin receptors of yeast are collectively nonessential for ubiquitin recognition by the proteasome. We therefore screened for additional ubiquitin receptors in the proteasome and identified subunit Rpn1 as a candidate. We used nuclear magnetic resonance (NMR) spectroscopy to characterize the structure of the binding site within Rpn1, which we term the T1 site. Mutational analysis of this site showed its functional importance within the context of intact proteasomes. T1 binds both ubiquitin and ubiquitin-like (UBL) proteins, in particular the substrate-delivering shuttle factor Rad23. A second site within the Rpn1 toroid, T2, recognizes the UBL domain of deubiquitinating enzyme Ubp6, as determined by hydrogen-deuterium exchange mass spectrometry analysis and validated by amino acid substitution and functional assays. The Rpn1 toroid thus serves a critical scaffolding role within the proteasome, helping to assemble multiple proteasome cofactors as well as substrates.
RESULTS
Our results indicate that proteasome subunit Rpn1 can recognize both ubiquitin and UBL domains of substrate shuttling factors that themselves bind ubiquitin and function as reversibly-associated proteasomal ubiquitin receptors. Recognition is mediated by the T1 site within the Rpn1 toroid, which supports proteasome function in vivo. We found that the capacity of T1 to recognize both ubiquitin and UBL proteins was shared with Rpn10 and Rpn13. The surprising multiplicity of ubiquitin-recognition domains within the proteasome may promote enhanced, multipoint binding of ubiquitin chains. The structures of the T1 site in its free state and complexed with monoubiquitin or K48-linked diubiquitin were solved, revealing that three neighboring outer helices from the T1 toroid engage two ubiquitins. This binding mode leads to a preference for certain ubiquitin chain types, especially K6- and K48-linked chains, in a distinct configuration that can position substrates close to the entry port of the proteasome. The fate of proteasome-docked ubiquitin conjugates is determined by a competition between deubiquitination and substrate degradation. We find that proximal to the T1 site within the Rpn1 toroid is a second UBL-binding site, T2, that does not assist in ubiquitin chain recognition, but rather in chain disassembly, by binding to the UBL domain of deubiquitinating enzyme Ubp6. Importantly, the UBL interactors at T1 and T2 are distinct, assigning substrate localization to T1 and substrate deubiquitination to T2.
CONCLUSION
A ligand-binding hotspot was identified in the Rpn1 toroid, consisting of two adjacent receptor sites, T1 and T2. The Rpn1 toroid represents a novel class of binding domains for ubiquitin and UBL proteins. This study thus defines a novel two-site recognition domain intrinsic to the proteasome that uses homologous ubiquitin/UBL-class ligands to assemble substrates, substrate shuttling factors, and a deubiquitinating enzyme in close proximity.
A ligand-binding hotspot in the proteasome for assembling substrates and cofactors
Schematic (top) and model structure (bottom, left) mapping the UBL-binding Rpn1 T1 (indigo) and T2 (orange) sites. (Bottom, right) Enlarged region of the proteasome to illustrate the Rpn1 T1 and T2 sites bound to a ubiquitin chain (yellow) and deubiquitinating enzyme Ubp6 (green), respectively. PDB 4CR2 and 2B9R were used for this figure.
Hundreds of pathways for degradation converge at ubiquitin recognition by proteasome. Here we found that the five known proteasomal ubiquitin receptors are collectively nonessential for ubiquitin recognition, and identified a sixth receptor, Rpn1. A site (T1) in the Rpn1 toroid recognized ubiquitin and ubiquitin-like (UBL) domains of substrate shuttling factors. T1 structures with monoubiquitin or K48 diubiquitin show three neighboring outer helices engaging two ubiquitins. T1 contributes a distinct substrate-binding pathway with preference for K48-linked chains. Proximal to T1 within the Rpn1 toroid is a second UBL-binding site (T2) that assists in ubiquitin chain disassembly, by binding the UBL of deubiquitinating enzyme Ubp6. Thus a two-site recognition domain intrinsic to the proteasome uses homologous ubiquitin/UBL-class ligands to assemble substrates, shuttling factors, and a deubiquitinating enzyme.
doi:10.1126/science.aad9421
PMCID: PMC4980823  PMID: 26912900
7.  Efficient Nose-to-Lung (N2L) Aerosol Delivery with a Dry Powder Inhaler 
Abstract
Purpose: Delivering aerosols to the lungs through the nasal route has a number of advantages, but its use has been limited by high depositional loss in the extrathoracic airways. The objective of this study was to evaluate the nose-to-lung (N2L) delivery of excipient enhanced growth (EEG) formulation aerosols generated with a new inline dry powder inhaler (DPI). The device was also adapted to enable aerosol delivery to a patient simultaneously receiving respiratory support from high flow nasal cannula (HFNC) therapy.
Methods: The inhaler delivered the antibiotic ciprofloxacin, which was formulated as submicrometer combination particles containing a hygroscopic excipient prepared by spray-drying. Nose-to-lung delivery was assessed using in vitro and computational fluid dynamics (CFD) methods in an airway model that continued through the upper tracheobronchial region.
Results: The best performing device contained a 2.3 mm flow control orifice and a 3D rod array with a 3-4-3 rod pattern. Based on in vitro experiments, the emitted dose from the streamlined nasal cannula had a fine particle fraction <5 μm of 95.9% and mass median aerodynamic diameter of 1.4 μm, which was considered ideal for nose-to-lung EEG delivery. With the 2.3-343 device, condensational growth in the airways increased the aerosol size to 2.5–2.7 μm and extrathoracic deposition was <10%. CFD results closely matched the in vitro experiments and predicted that nasal deposition was <2%.
Conclusions: The developed DPI produced high efficiency aerosolization with significant size increase of the aerosol within the airways that can be used to enable nose-to-lung delivery and aerosol administration during HFNC therapy.
doi:10.1089/jamp.2014.1158
PMCID: PMC4559155  PMID: 25192072
active dry powder inhaler (DPI) system; enhanced condensational growth (ECG); excipient enhanced growth (EEG); high flow nasal cannula (HFNC); noninvasive ventilation (NIV)
8.  VEGF-B inhibits hyperglycemia- and Macugen-induced retinal apoptosis 
Scientific Reports  2016;6:26059.
Vascular endothelial growth factor B (VEGF-B) was discovered a long time ago. However, its role in hyperglycemia- and VEGF-A inhibition-induced retinal apoptosis remains unknown thus far. Yet, drugs that can block VEGF-B are being used to treat patients with diabetic retinopathy and other ocular neovascular diseases. It is therefore urgent to have a better understanding of the function of VEGF-B in these pathologies. Here, we report that both streptozotocin (STZ)-induced diabetes in rats and Macugen intravitreal injection in mice leads to retinal apoptosis in retinal ganglion cell and outer nuclear layers respectively. Importantly, VEGF-B treatment by intravitreal injection markedly reduced retinal apoptosis in both models. We further reveal that VEGF-B and its receptors, vascular endothelial growth factor 1 (VEGFR1) and neuropilin 1 (NP1), are abundantly expressed in rat retinae and choroids and are upregulated by high glucose with concomitant activation of Akt and Erk. These data highlight an important function of VEGF-B in protecting retinal cells from apoptosis induced by hyperglycemia and VEGF-A inhibition. VEGF-B may therefore have a therapeutic potential in treating various retinal degenerative diseases, and modulation of VEGF-B activity in the eye needs careful consideration.
doi:10.1038/srep26059
PMCID: PMC4870690  PMID: 27189805
9.  Insights into mutualism mechanism and versatile metabolism of Ketogulonicigenium vulgare Hbe602 based on comparative genomics and metabolomics studies 
Scientific Reports  2016;6:23068.
Ketogulonicigenium vulgare has been widely used in vitamin C two steps fermentation and requires companion strain for optimal growth. However, the understanding of K. vulgare as well as its companion strain is still preliminary. Here, the complete genome of K. vulgare Hbe602 was deciphered to provide insight into the symbiosis mechanism and the versatile metabolism. K. vulgare contains the LuxR family proteins, chemokine proteins, flagellar structure proteins, peptides and transporters for symbiosis consortium. Besides, the growth state and metabolite variation of K. vulgare were observed when five carbohydrates (D-sorbitol, L-sorbose, D-glucose, D-fructose and D-mannitol) were used as carbon source. The growth increased by 40.72% and 62.97% respectively when K. vulgare was cultured on D-mannitol/D-sorbitol than on L-sorbose. The insufficient metabolism of carbohydrates, amino acids and vitamins is the main reason for the slow growth of K. vulgare. The combined analysis of genomics and metabolomics indicated that TCA cycle, amino acid and nucleotide metabolism were significantly up-regulated when K. vulgare was cultured on the D-mannitol/D-sorbitol, which facilitated the better growth. The present study would be helpful to further understand its metabolic structure and guide the engineering transformation.
doi:10.1038/srep23068
PMCID: PMC4793288  PMID: 26979567
10.  Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms 
Stem Cells and Development  2014;24(5):610-623.
Mesenchymal stem cells (MSCs) show great promise in blood vessel restoration and vascularization enhancement in many therapeutic situations. Typically, the co-implantation of MSCs with vascular endothelial cells (ECs) is effective for the induction of functional vascularization in vivo, indicating its potential applications in regenerative medicine. The effects of MSCs-ECs-induced vascularization can be modeled in vitro, providing simplified models for understanding their underlying communication. In this article, a contact coculture model in vitro and an RNA-seq approach were employed to reveal the active crosstalk between MSCs and ECs within a short time period at both morphological and transcriptional levels. The RNA-seq results suggested that angiogenic genes were significantly induced upon coculture, and this prevascularization commitment might require the NF-κB signaling. NF-κB blocking and interleukin (IL) neutralization experiments demonstrated that MSCs potentially secreted IL factors including IL1β and IL6 to modulate NF-κB signaling and downstream chemokines during coculture. Conversely, RNA-seq results indicated that the MSCs were regulated by the coculture environment to a smooth muscle commitment within this short period, which largely induced myocardin, the myogenic co-transcriptional factor. These findings demonstrate the mutual molecular mechanism of MSCs-ECs-induced prevascularization commitment in a quick response.
doi:10.1089/scd.2014.0330
PMCID: PMC4333618  PMID: 25299975
11.  Development of a New Technique for the Efficient Delivery of Aerosolized Medications to Infants on Mechanical Ventilation 
Pharmaceutical research  2014;32(1):321-336.
Purpose
To evaluate the efficiency of a new technique for delivering aerosols to intubated infants that employs a new Y-connector, access port administration of a dry powder, and excipient enhanced growth (EEG) formulation particles that change size in the airways.
Methods
A previously developed CFD model combined with algebraic correlations were used to predict delivery system and lung deposition of typical nebulized droplets (MMAD = 4.9 μm) and EEG dry powder aerosols. The delivery system consisted of a Y-connector [commercial (CM); streamlined (SL); or streamlined with access port (SL-port)] attached to a 4-mm diameter endotracheal tube leading to the airways of a 6-month-old infant.
Results
Compared to the CM device and nebulized aerosol, the EEG approach with an initial 0.9 μm aerosol combined with the SL and SL-port geometries reduced device depositional losses by factors of 3-fold and >10-fold, respectively. With EEG powder aerosols, the SL geometry provided the maximum tracheobronchial deposition fraction (55.7%), whereas the SL-port geometry provided the maximum alveolar (67.6%) and total lung (95.7%) deposition fractions, respectively.
Conclusions
Provided the aerosol can be administered in the first portion of the inspiration cycle, the proposed new method can significantly improve the deposition of pharmaceutical aerosols in the lungs of intubated infants.
doi:10.1007/s11095-014-1466-4
PMCID: PMC4286504  PMID: 25103332
Pharmaceutical aerosols; neonate; streamlined Y-connector; excipient enhanced growth (EEG); active dry powder inhaler system
12.  Variability in Nose-to-Lung Aerosol Delivery 
Journal of aerosol science  2014;78:11-29.
Nasal delivery of lung targeted pharmaceutical aerosols is ideal for drugs that need to be administered during high flow nasal cannula (HFNC) gas delivery, but based on previous studies losses and variability through both the delivery system and nasal cavity are expected to be high. The objective of this study was to assess the variability in aerosol delivery through the nose to the lungs with a nasal cannula interface for conventional and excipient enhanced growth (EEG) delivery techniques. A database of nasal cavity computed tomography (CT) scans was collected and analyzed, from which four models were selected to represent a wide range of adult anatomies, quantified based on the nasal surface area-to-volume ratio (SA/V). Computational fluid dynamics (CFD) methods were validated with existing in vitro data and used to predict aerosol delivery through a streamlined nasal cannula and the four nasal models at a steady state flow rate of 30 L/min. Aerosols considered were solid particles for EEG delivery (initial 0.9 μm and 1.5 μm aerodynamic diameters) and conventional droplets (5 μm) for a control case. Use of the EEG approach was found to reduce depositional losses in the nasal cavity by an order of magnitude and substantially reduce variability. Specifically, for aerosol deposition efficiency in the four geometries, the 95% confidence intervals (CI) for 0.9 and 5 μm aerosols were 2.3-3.1 and 15.5-66.3%, respectively. Simulations showed that the use of EEG as opposed to conventional methods improved delivered dose of aerosols through the nasopharynx, expressed as penetration fraction (PF), by approximately a factor of four. Variability of PF, expressed by the coefficient of variation (CV), was reduced by a factor of four with EEG delivery compared with the control case. Penetration fraction correlated well with SA/V for larger aerosols, but smaller aerosols showed some dependence on nasopharyngeal exit hydraulic diameter. In conclusion, results indicated that the EEG technique not only improved lung aerosol delivery, but largely eliminated variability in both nasal depositional loss and lung PF in a newly developed set of nasal airway models.
doi:10.1016/j.jaerosci.2014.08.003
PMCID: PMC4187112  PMID: 25308992
Nasal variability; nasal aerosol deposition; controlled condensational growth; submicrometer aerosols; excipient enhanced growth; respiratory drug delivery
13.  Prevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey 
Chinese Medical Journal  2015;128(21):2843-2850.
Background:
Nontraumatic osteonecrosis of the femoral head (NONFH) is a debilitating disease that represents a significant financial burden for both individuals and healthcare systems. Despite its significance, however, its prevalence in the Chinese general population remains unknown. This study aimed to investigate the prevalence of NONFH and its associated risk factors in the Chinese population.
Methods:
A nationally representative survey of 30,030 respondents was undertaken from June 2012 to August 2013. All participants underwent a questionnaire investigation, physical examination of hip, and bilateral hip joint X-ray and/or magnetic resonance imaging examination. Blood samples were taken after overnight fasting to test serum total cholesterol, triglyceride, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels. We then used multivariate logistic regression analysis to investigate the associations between various metabolic, demographic, and lifestyle-related variables and NONFH.
Results:
NONFH was diagnosed in 218 subjects (0.725%) and the estimated NONFH cases were 8.12 million among Chinese people aged 15 years and over. The prevalence of NONFH was significantly higher in males than in females (1.02% vs. 0.51%, χ2 = 24.997, P < 0.001). Among NONFH patients, North residents were subjected to higher prevalence of NONFH than that of South residents (0.85% vs. 0.61%, χ2 = 5.847, P = 0.016). Our multivariate regression analysis showed that high blood levels of triglycerides, total cholesterol, LDL-cholesterol, and non-HDL-cholesterol, male, urban residence, family history of osteonecrosis of the femoral head, heavy smoking, alcohol abuse and glucocorticoid intake, overweight, and obesity were all significantly associated with an increased risk of NONFH.
Conclusions:
Our findings highlight that NONFH is a significant public health challenge in China and underscore the need for policy measures on the national level. Furthermore, NONFH shares a number of risk factors with atherosclerosis.
doi:10.4103/0366-6999.168017
PMCID: PMC4756878  PMID: 26521779
Nontraumatic Osteonecrosis of the Femoral Head; Prevalence; Risk Factors
14.  Metagenomic Human Repiratory Air in a Hospital Environment 
PLoS ONE  2015;10(10):e0139044.
Hospital-acquired infection (HAI) or nosocomial infection is an issue that frequent hospital environment. We believe conventional regulated Petri dish method is insufficient to evaluate HAI. To address this problem, metagenomic sequencing was applied to screen airborne microbes in four rooms of Beijing Hospital. With air-in amount of sampler being setup to one person’s respiration quantity, metagenomic sequencing identified huge numbers of species in the rooms which had already qualified widely accepted petridish exposing standard, imposing urgency for new technology. Meanwhile,the comparative culture only got small portion of recovered species and remain blind for even cultivable pathogens reminded us the limitations of old technologies. To the best of our knowledge, the method demonstrated in this study could be broadly applied in hospital indoor environment for various monitoring activities as well as HAI study. It is also potential as a transmissible pathogen real-time modelling system worldwide.
doi:10.1371/journal.pone.0139044
PMCID: PMC4592066  PMID: 26431488
15.  Non-invasive treatment for severe complex pressure ulcers complicated by necrotizing fasciitis: a case report 
Introduction
Pressure ulceration is a common problem for long-term bedridden patients and individuals with traumatic paraplegia. Necrotizing fasciitis can be a life-threatening complication caused by pressure ulcers, especially for debilitated elderly patients. In this report, we describe the successful use of negative pressure wound therapy with instillation to treat severe complex pressure ulcers complicated with peri-anal necrotizing fasciitis.
Case presentation
A 58-year-old Chinese woman was admitted to our hospital with severe complex pressure ulcers on her bilateral ischial tuberosities, left hip, perineum, and left sacrococcygeal region. The wounds had been present for nearly 2 years. Her seventh and eighth thoracic vertebrae had been traumatically injured; she had been bedridden for 5 years. She was also diabetic. Her medical history and laboratory investigations confirmed severe complex pressure ulcers complicated with necrotizing fasciitis. Antibiotic therapy was initiated. Following negative pressure wound treatment with instillation, the topical infection subsided and final closure of the wound occurred after 130 days.
Conclusions
Negative pressure wound treatment with instillation is an effective treatment protocol. It can reduce healing time, and promote long-term functional and cosmetic outcomes in debilitated patients with severe complex pressure ulcers complicated with necrotizing fasciitis.
doi:10.1186/s13256-015-0703-8
PMCID: PMC4575497  PMID: 26385213
Necrotizing fasciitis; Negative pressure wound therapy with instillation; Pressure ulcers
16.  Association of APE1 Gene Asp148Glu Variant with Digestive Cancer: A Meta-Analysis 
Background
Apurinic/apyrimidinic endonuclease-1 (APE1) is a rate-limiting enzyme in DNA base excision repair and has been implicated in carcinogenesis. In this study, we summarize available data to examine the susceptibility of APE1 gene Asp148Glu variant to digestive cancer via a meta-analysis.
Material/Methods
Study selection and data abstraction were conducted independently by 2 authors. Random-effects model was utilized to pool effect estimates. Heterogeneity and publication bias were addressed.
Results
Sixteen articles involving 4916 digestive cancer patients and 7748 controls were qualified for this meta-analysis. Overall association showed an indicative association between Asp148Glu variant and digestive cancer under allelic (odds ratio or OR=1.11; 95% confidence interval or CI: 0.99–1.25; P=0.074) and dominant (OR=1.18; 95% CI: 1.00–1.40; P=0.056) models, with strong evidence of heterogeneity. Deviation from Hardy-Weinberg equilibrium was an obvious source of heterogeneity. In subgroup analyses by cancer sites, this variant was significantly associated with the increased risk for hepatocellular cancer under allelic (OR=1.50; 95% CI: 1.25–1.80; P<0.001) and homozygous genotypic (OR=1.55; 95% CI: 1.02–2.29; P=0.028) models. There were low probabilities of publication bias for the above comparisons.
Conclusions
The results of this meta-analysis collectively suggest that APE1 gene Asp148Glu variant is not a risk-conferring factor for digestive cancer. Further large and well-designed studies are required.
doi:10.12659/MSM.893954
PMCID: PMC4548740  PMID: 26292623
Digestive System Neoplasms; Genetic Association Studies; Meta-Analysis
17.  Circulating interleukin-6 and cancer: A meta-analysis using Mendelian randomization 
Scientific Reports  2015;5:11394.
Interleukin-6 (IL-6) plays a contributory role in the progression and severity of many forms of cancer; it however remains unclear whether the relevance between circulating IL-6 and cancer is causal. We therefore meta-analyzed published articles in this regard using IL-6 gene -174G/C variant as an instrument. Seventy-eight and six articles were eligible for the association of -174G/C variant with cancer and circulating IL-6, respectively. Overall analyses failed to identify any significance between -174G/C and cancer risk. In Asians, carriers of the -174CC genotype had an 1.95-fold increased cancer risk compared with the -174GG genotype carriers (P = 0.009). By cancer type, significance was only attained for liver cancer with the -174C allele conferring a reduced risk under allelic (odds ratio or OR = 0.74; P = 0.001), homozygous genotypic (OR = 0.59; P = 0.029) and dominant (OR = 0.67; P = 0.004) models. Carriers of the -174CC genotype (weighted mean difference or WMD = −4.23 pg/mL; P < 0.001) and -174C allele (WMD = −3.43 pg/mL; P < 0.001) had circulating IL-6 reduced significantly compared with the non-carriers. In further Mendelian randomization analysis, a reduction of 1 pg/mL in circulating IL-6 was significantly associated with an 12% reduced risk of liver cancer. Long-term genetically-reduced circulating IL-6 might be causally associated with a lower risk of liver cancer.
doi:10.1038/srep11394
PMCID: PMC4476043  PMID: 26096712
18.  Resveratrol relieves ischemia-induced oxidative stress in the hippocampus by activating SIRT1 
Resveratrol, a naturally occurring phytoalexin, acts as an activator of sirtuin 1 (SIRT1) and has been shown to have a neuroprotective role in various models. Healthy adult male Sprague-Dawley rats were subjected to cerebral ischemia in order to study the protective effect of resveratrol on the brain following ischemia, and to investigate the effects of SIRT1 activation on the hippocampus. Untreated and resveratrol-treated rats were anesthetized prior to undergoing surgery to induce middle cerebral artery occlusion followed by reperfusion. SIRT1 expression was evaluated by immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction, and SIRT1 activity was also evaluated. In addition, terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) and Nissl staining assays were conducted and the levels of reactive oxygen species were determined. It was observed that resveratrol significantly decreased the number of TUNEL-positive cells and increased the expression of SIRT1 mRNA in a dose-dependent manner. This was accompanied by increases in SIRT1 protein expression levels and SIRT1 activity. The results demonstrate the neuroprotective and antioxidant effects of resveratrol against ischemia-induced apoptosis in the rat hippocampus.
doi:10.3892/etm.2015.2555
PMCID: PMC4509412  PMID: 26622348
resveratrol; sirtuin 1; brain ischemia; reactive oxygen species; hippocampus
19.  Ubiquinol-10 Supplementation Activates Mitochondria Functions to Decelerate Senescence in Senescence-Accelerated Mice 
Antioxidants & Redox Signaling  2014;20(16):2606-2620.
Abstract
Aim: The present study was conducted to define the relationship between the anti-aging effect of ubiquinol-10 supplementation and mitochondrial activation in senescence-accelerated mouse prone 1 (SAMP1) mice. Results: Here, we report that dietary supplementation with ubiquinol-10 prevents age-related decreases in the expression of sirtuin gene family members, which results in the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a major factor that controls mitochondrial biogenesis and respiration, as well as superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2), which are major mitochondrial antioxidant enzymes. Ubiquinol-10 supplementation can also increase mitochondrial complex I activity and decrease levels of oxidative stress markers, including protein carbonyls, apurinic/apyrimidinic sites, malondialdehydes, and increase the reduced glutathione/oxidized glutathione ratio. Furthermore, ubiquinol-10 may activate Sirt1 and PGC-1α by increasing cyclic adenosine monophosphate (cAMP) levels that, in turn, activate cAMP response element-binding protein (CREB) and AMP-activated protein kinase (AMPK). Innovation and Conclusion: These results show that ubiquinol-10 may enhance mitochondrial activity by increasing levels of SIRT1, PGC-1α, and SIRT3 that slow the rate of age-related hearing loss and protect against the progression of aging and symptoms of age-related diseases. Antioxid. Redox Signal. 20, 2606–2620
doi:10.1089/ars.2013.5406
PMCID: PMC4025630  PMID: 24124769
20.  The Relationship Between Altered Mitochondrial DNA Copy Number And Cancer Risk: A Meta-Analysis 
Scientific Reports  2015;5:10039.
Currently, a comprehensive assessment between mitochondrial DNA (mtDNA) content and cancer risk is lacking. We designed this meta-analysis to test the hypothesis that altered mtDNA copy number might influence genetic susceptibility to some specific types of cancer. The processes of literature search, eligibility appraisal and data retrieval were independently completed in duplicate. The mtDNA copy number which was dichotomized or classified into tertiles was compared between cancer cases and controls. Twenty-six articles with 38 study groups were analyzed among 6682 cases and 9923 controls. When dichotomizing mtDNA copy number at the median value, there was an 11% increased cancer risk for carriers of high mtDNA content (P = 0.320). By cancer type, high mtDNA content was associated with an increased risk for lymphoma (OR = 1.76; P = 0.023) but a reduced risk for skeleton cancer (OR = 0.39; P = 0.001). Carriers of the 2nd and 3rd tertiles of mtDNA copy number had an 1.74-fold (P = 0.010) and 2.07-fold (P = 0.021) increased risk of lymphoma, respectively. By contrast, there was correspondingly a 56% (P < 0.001) and 80% (P < 0.001) reduced risk of skeleton cancer. Our findings suggested that elevated mtDNA content was associated with a higher risk for lymphoma, but a lower risk for skeleton cancer.
doi:10.1038/srep10039
PMCID: PMC4424798  PMID: 25952580
21.  Causal relevance of circulating high-density lipoprotein cholesterol with cancer: a Mendelian randomization meta-analysis 
Scientific Reports  2015;5:9495.
We summarized published data on the associations of apolipoprotein E (APOE) gene ε2/ε3/ε4 polymorphism with both cancer risk and circulating lipid profiles, aiming to examine the causal relevance between lipids and cancer risk. Article identification and data abstraction were conducted in duplicate and independently by two authors. Data were analyzed by STATA software. Twenty-five articles that examined the associations of APOE gene ε2/ε3/ε4 polymorphism with either cancer risk (n = 22) or circulating lipid changes (n = 4) were eligible. The presence of ε2 and ε4 alleles showed no overall associations with overall cancer risk when compared with ε3 allele. The ε4 allele was significantly associated with 1.40-fold (odds ratio or OR = 1.40; 95% confidence interval or CI: 1.00–1.94; P = 0.047) increased risk of developing cancer in Asian populations, and the presence of heterogeneity was low (I2 = 37.6%). Carriers of ε3/ε4 genotype had a significant reduction in circulating HDL-C (WMD = −2.62; 95% CI: −4.19 to −1.04; P = 0.001) without heterogeneity (I2 = 16.6%). The predicted odds of having cancer for 1 mg/dL reduction in circulating HDL-C was 1.14 (95% CI: 1.00 to 1.89). The findings of this Mendelian randomization meta-analysis demonstrate that reduced circulating HDL-C might be a potentially causal risk factor for the development of overall cancer in Asians.
doi:10.1038/srep09495
PMCID: PMC4377635  PMID: 25820350
22.  Targeted Lung Delivery of Nasally Administered Aerosols 
Using the nasal route to deliver pharmaceutical aerosols to the lungs has a number of advantages including co-administration during non-invasive ventilation. The objective of this study was to evaluate the growth and deposition characteristics of nasally administered aerosol throughout the conducting airways based on delivery with streamlined interfaces implementing two forms of controlled condensational growth technology. Characteristic conducting airways were considered including a nose-mouth-throat (NMT) geometry, complete upper tracheobronchial (TB) model through the third bifurcation (B3), and stochastic individual path (SIP) model to the terminal bronchioles (B15). Previously developed streamlined nasal cannula interfaces were used for the delivery of submicrometer particles using either enhanced condensational growth (ECG) or excipient enhanced growth (EEG) techniques. Computational fluid dynamics (CFD) simulations predicted aerosol transport, growth and deposition for a control (4.7 μm) and three submicrometer condensational aerosols with budesonide as a model insoluble drug. Depositional losses with condensational aerosols in the cannula and NMT were less than 5% of the initial dose, which represents an order-of-magnitude reduction compared to the control. The condensational growth techniques increased the TB dose by a factor of 1.1–2.6x, delivered at least 70% of the dose to the alveolar region, and produced final aerosol sizes ≥2.5 μm. Compared to multiple commercial orally inhaled products, the nose-to-lung delivery approach increased dose to the biologically important lower TB region by factors as large as 35x. In conclusion, nose-to-lung delivery with streamlined nasal cannulas and condensational aerosols was highly efficient and targeted deposition to the lower TB and alveolar regions.
doi:10.1080/02786826.2014.887829
PMCID: PMC4051279  PMID: 24932058
23.  Transgenic Cotton Plants Expressing Double-stranded RNAs Target HMG-CoA Reductase (HMGR) Gene Inhibits the Growth, Development and Survival of Cotton Bollworms 
RNA interference (RNAi) has been developed as a powerful technique in the research of functional genomics as well as plant pest control. In this report, double-stranded RNAs (dsRNA) targeting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) gene, which catalyze a rate-limiting enzymatic reaction in the mevalonate pathway of juvenile hormone (JH) synthesis in cotton bollworm, was expressed in cotton plants via Agrobacterium tumefaciens-mediated transformation. PCR and Sothern analysis revealed the integration of HMGR gene into cotton genome. RT-PCR and qRT-PCR confirmed the high transcription level of dsHMGR in transgenic cotton lines. The HMGR expression both in transcription and translation level was significantly downregulated in cotton bollworms (helicoverpa armigera) larvae after feeding on the leaves of HMGR transgenic plants. The transcription level of HMGR gene in larvae reared on transgenic cotton leaves was as much as 80.68% lower than that of wild type. In addition, the relative expression level of vitellogenin (Vg, crucial source of nourishment for offspring embryo development) gene was also reduced by 76.86% when the insect larvae were fed with transgenic leaves. The result of insect bioassays showed that the transgenic plant harboring dsHMGR not only inhibited net weight gain but also delayed the growth of cotton bollworm larvae. Taken together, transgenic cotton plant expressing dsRNAs successfully downregulated HMGR gene and impaired the development and survival of target insect, which provided more option for plant pest control.
doi:10.7150/ijbs.12463
PMCID: PMC4582153  PMID: 26435695
3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGR); cotton bollworm; RNA interference; transgenic cotton; double-stranded RNAs; pest control.
24.  The Use of Condensational Growth Methods for Efficient Drug Delivery to the Lungs during Noninvasive Ventilation High Flow Therapy 
Pharmaceutical research  2013;30(11):2917-2930.
Purpose
The objective of this study was to evaluate the delivery of nasally administered aerosols to the lungs during noninvasive ventilation using controlled condensational growth techniques.
Methods
An optimized mixer, combined with a mesh nebulizer, was used to generate submicrometer aerosol particles using drug alone (albuterol sulfate) and with mannitol or sodium chloride added as hygroscopic excipients. The deposition and growth of these particles were evaluated in an adult nose-mouth-throat (NMT) model using in vitro experimental methods and computational fluid dynamics simulations.
Results
Significant improvement in the lung dose (3–4x increase) was observed using excipient enhanced growth (EEG) and enhanced condensational growth (ECG) delivery modes compared to control studies performed with a conventional size aerosol (~5μm). This was due to reduced device retention and minimal deposition in the NMT airways. Increased condensational growth of the initially submicrometer particles was observed using the ECG mode and in the presence of hygroscopic excipients. CFD predictions for regional drug deposition and aerosol size increase were in good agreement with the observed experimental results.
Conclusions
These controlled condensational growth techniques for the delivery of submicrometer aerosols were found to be highly efficient methods for delivering nasally-administered drugs to the lungs.
doi:10.1007/s11095-013-1123-3
PMCID: PMC3800269  PMID: 23801087
Combination drug-excipient particles; enhanced condensational growth; excipient enhanced growth; hygroscopic growth; noninvasive aerosol therapy; nose-to-lung aerosol delivery
25.  Targeting Aerosol Deposition to and Within the Lung Airways Using Excipient Enhanced Growth 
Abstract
Background
Previous studies have characterized the size increase of combination submicrometer particles composed of a drug and hygroscopic excipient when exposed to typical airway thermodynamic conditions. The objective of this study was to determine the deposition and size increase characteristics of excipient enhanced growth (EEG) aerosols throughout the tracheobronchial (TB) airways and to evaluate the potential for targeted delivery.
Methods
Submicrometer particles composed of a poorly water-soluble drug (insulin) and hygroscopic excipient (sodium chloride) were considered at drug:excipient mass ratios of 50:50 and 25:75. A previously validated computational fluid dynamics model was used to predict aerosol size increase and deposition in characteristic geometries of the mouth–throat (MT), upper TB airways through the third bifurcation (B3), and remaining TB airways through B15. Additional validation experiments were also performed for albuterol sulfate:mannitol particles. Both growth of combination particles and deposition are reported throughout the conducting airways for characteristic slow and deep (SD) and quick and deep (QD) inhalations.
Results
For all EEG cases considered, MT deposition was less than 1% of the drug dose, which is at least one order of magnitude lower than with state-of-the-art and conventional inhalers. Final aerosol sizes exiting the TB region and entering the alveolar airways were all greater than 3 μm. For SD inhalation, deposition fractions of 20% were achieved in the lower TB region of B8–B15, which is a factor of 20–30×higher than conventional delivery devices. With QD inhalation, maximum alveolar delivery of 90% was observed.
Conclusions
Increasing the dose delivered to the lower TB region by a factor of 20–30×or achieving 90% delivery to the alveolar airways was considered effective aerosol targeting compared with conventional devices. The trend of higher flow rates resulting in better alveolar delivery of aerosols is unique to EEG and may be used to design highly efficient dry powder inhalers.
doi:10.1089/jamp.2012.0997
PMCID: PMC3826577  PMID: 23286828
respiratory drug delivery; excipient enhanced growth (EEG); nanoaerosols; hygroscopic droplet growth; engineered combination particles; stochastic individual path (SIP) airway modeling; computational fluid dynamics (CFD) simulations; in vitro aerosol experiments

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