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1.  Mitochondrial Phylogenomics yields Strongly Supported Hypotheses for Ascaridomorph Nematodes 
Scientific Reports  2016;6:39248.
Ascaridomorph nematodes threaten the health of humans and other animals worldwide. Despite their medical, veterinary and economic importance, the identification of species lineages and establishing their phylogenetic relationships have proved difficult in some cases. Many working hypotheses regarding the phylogeny of ascaridomorphs have been based on single-locus data, most typically nuclear ribosomal RNA. Such single-locus hypotheses lack independent corroboration, and for nuclear rRNA typically lack resolution for deep relationships. As an alternative approach, we analyzed the mitochondrial (mt) genomes of anisakids (~14 kb) from different fish hosts in multiple countries, in combination with those of other ascaridomorphs available in the GenBank database. The circular mt genomes range from 13,948-14,019 bp in size and encode 12 protein-coding genes, 2 ribosomal RNAs and 22 transfer RNA genes. Our analysis showed that the Pseudoterranova decipiens complex consists of at least six cryptic species. In contrast, the hypothesis that Contracaecum ogmorhini represents a complex of cryptic species is not supported by mt genome data. Our analysis recovered several fundamental and uncontroversial ascaridomorph clades, including the monophyly of superfamilies and families, except for Ascaridiidae, which was consistent with the results based on nuclear rRNA analysis. In conclusion, mt genome analysis provided new insights into the phylogeny and taxonomy of ascaridomorph nematodes.
doi:10.1038/srep39248
PMCID: PMC5159812  PMID: 27982084
2.  Identification of CHD1L as an Important Regulator for Spermatogonial Stem Cell Survival and Self-Renewal 
Stem Cells International  2016;2016:4069543.
Chromodomain helicase/ATPase DNA binding protein 1-like gene (Chd1l) participates in chromatin-dependent processes, including transcriptional activation and DNA repair. In this study, we have found for the first time that Chd1l is mainly expressed in the testicular tissues of prepubertal and adult mice and colocalized with PLZF, OCT4, and GFRα1 in the neonatal mouse testis and THY1+ undifferentiated spermatogonia or spermatogonial stem cells (SSCs). Knockdown of endogenous Chd1l in cultured mouse undifferentiated SSCs inhibited the expression levels of Oct4, Plzf, Gfrα1, and Pcna genes, suppressed SSC colony formation, and reduced BrdU incorporation, while increasing SSC apoptosis. Moreover, the Chd1l gene expression is activated by GDNF in the cultured mouse SSCs, and the GDNF signaling pathway was modulated by endogenous levels of Chd1l; as demonstrated by the gene expression levels of GDNF, inducible transcripts Etv5, Bcl6b, Pou3f, and Lhx1, but not that of GDNF-independent gene, Taf4b, were significantly downregulated by Chd1l knockdown in mouse SSCs. Taken together, this study provides the first evidence to support the notion that Chd1l is an intrinsic and novel regulator for SSC survival and self-renewal, and it exerts such regulation at least partially through a GDNF signaling pathway.
doi:10.1155/2016/4069543
PMCID: PMC5149700  PMID: 28003832
3.  The Benefit and Safety of Aspirin for Primary Prevention of Ischemic Stroke: A Meta-Analysis of Randomized Trials 
Background: Although aspirin is effective in the secondary prevention of stroke among men and women, its use in primary prevention remains controversial. We conducted a meta-analysis of randomized trials to evaluate the benefit and safety of aspirin for the primary prevention of ischemic stroke.
Methods: We searched three electronic databases (Medline, the Cochrane Central Register of Controlled Trials, and Embase) for articles published before August 1st, 2016. Randomized trials reporting the effect of aspirin on the primary prevention of ischemic stroke and its side effects (hemorrhagic stroke and severe gastrointestinal bleeding) were included. We used a fixed-effect model to quantify the effect of aspirin on the primary prevention of stroke when the heterogeneity was low, or else applied the random-effect model.
Results: Fourteen randomized trials were included. Overall, aspirin use was associated with a decreased risk of ischemic stroke compared with non-aspirin use (OR: 0.83, 95% CI: 0.74–0.93, P = 0.45). In subgroup analyses, the effect of aspirin on ischemic stroke in apparently healthy adults remained significant (OR: 0.83, 95% confidence interval: 0.74–0.94, I2 = 22%, P = 0.28); while in patients with cardiovascular diseases there was no difference in the risk of ischemic stroke between aspirin and non-aspirin groups (OR: 0.75, 95% confidence interval: 0.44–1.29, P = 0.46). As for adverse effects, the prophylactic use of aspirin potentially increased the risk of serious bleeding events in a population of apparently healthy individuals and in patients with previous cardiovascular diseases.
Conclusion: This meta-analysis of randomized trials indicated that both the apparently healthy adults and patients with cardiovascular diseases will derive little protective benefit from aspirin considering the increased risk of severe bleeding events.
doi:10.3389/fphar.2016.00440
PMCID: PMC5114305  PMID: 27917124
aspirin; stroke; safety; gastrointestinal bleeds; prevention
4.  SPECT Imaging of Inflammatory Response in Ischemic–Reperfused Rat Hearts Using a 99mTc-Labeled Dual-Domain Cytokine Ligand 
Soluble tumor necrosis factor (TNF) receptor-2 (TNFR2) and interleukin-1 receptor antagonist (IL-1ra) were fused to the Fc portion of IgG1 using recombinant DNA technology. The resulting dual-domain cytokine ligand, TNFR2-Fc-IL-1ra, specifically binds to TNF and to the type I IL-1 receptor (IL-1RI). This study was designed to characterize the kinetic profile of 99mTc-labeled TNFR2-Fc-IL-1ra (TFI) for imaging inflammatory response in an ischemic–reperfused (IR) rat heart model.
Methods
The IR model was created by ligating the left coronary artery for 45 min, followed by 2-h reperfusion. Cardiac SPECT images of TFI in the IR model (n = 6) were dynamically acquired for 3 h. Correlative data of myocardial TFI distribution versus microsphere-determined tissue blood flow were acquired in 3 extra IR hearts. Inflammation targeting affinity of TFI was compared with 2 individual cytokine radioligands, 99mTc-IL-1ra-Fc (IF) and 99mTc-TNFR2-Fc (TF) (n = 6 each group). Myocardial cytokine expression was evaluated by immunochemical assay.
Results
Increased TFI uptake was found in the ischemic area and correlated with the severity of ischemia. At 3 h after injection, the ratio of hot-spot accumulation in the ischemic area to a remote viable zone was 5.39 ± 1.11 for TFI, which was greater than that for IF (3.28 ± 0.81) and TF (3.29 ± 0.75) (P < 0.05). The in vivo uptake profiles of TFI, TF, and IF were consistent with ex vivo radioactive measurements and correlated with upregulated IL-1 and TNF expression.
Conclusion
The dual-domain TFI is promising for noninvasive detection of inflammatory reactions in IR myocardium because of its more potent affinity to the inflammatory sites compared with TF and IF.
doi:10.2967/jnumed.113.123497
PMCID: PMC5055402  PMID: 24179185
interleukin-1; tumor necrosis factor; inflammation; 99mTc; myocardial ischemia-reperfusion
5.  IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein 
Cell reports  2015;13(1):145-156.
SUMMARY
The interferon-induced transmembrane (IFITM) proteins have been recently shown to restrict HIV-1 and other viruses. Here we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env), thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus strain-dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection, and provides insight into the specialized role of IFITMs in HIV infection.
Graphical Abstract
doi:10.1016/j.celrep.2015.08.055
PMCID: PMC4602366  PMID: 26387945
IFITM; HIV-1; Envelope; Cell-to-cell infection
6.  Association of Human Leukocyte Antigen DRB1*15 and DRB1*15:01 Polymorphisms with Response to Immunosuppressive Therapy in Patients with Aplastic Anemia: A Meta-Analysis 
PLoS ONE  2016;11(9):e0162382.
This study aimed to review and quantitatively analyze (1) the association of aplastic anemia (AA) with human leukocyte antigen (HLA)-DRB1*15 and HLA-DRB1*15:01 polymorphisms and (2) the association of HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms with response to immunosuppressive therapy (IST) in AA. Published studies have reported conflicting and heterogeneous results regarding the association of HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms with response to IST in AA. The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese BioMedical Literature, Wangfang and Chinese Social Sciences Citation Index databases were searched. All relevant publications were searched through December 2015. Odds ratio (OR), risk ratio (RR), and 95% confidence intervals (CI) for the comparison between case–control or cohort studies were evaluated. Finally, 24 articles were identified. For HLA-DRB1*15 and HLA-DRB1*15:01, the OR (95% CI) was 2.24(1.33–3.77), P < 0.01 and 2.50(1.73–3.62), P < 0.01, respectively; and the overall pooled RR was 1.72 (1.30–2.29), P < 0.01 and 1.59 (1.29–1.96), P < 0.01, respectively. Statistical evidence showed no publication bias (P > 0.05). Sensitivity analyses revealed that the results were statistically robust. The meta-analysis suggested that HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms might be associated with increased AA risk in Asians. IST might be more effective in HLA-DRB1*15+ and HLA-DRB1*15:01+ Asian patients with AA than in HLA-DRB1*15− and HLA-DRB1*15:01− Asian patients with AA. Future studies with adequate methodological quality on gene–gene and gene–environment interactions and gene treatment may yield valid results.
doi:10.1371/journal.pone.0162382
PMCID: PMC5017877  PMID: 27611583
7.  Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice 
Human Gene Therapy  2015;26(9):622-634.
Despite nearly three decades of research, a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) has yet to be achieved. More recently, the discovery of highly potent anti-gp160 broadly neutralizing antibodies (bNAbs) has garnered renewed interest in using antibody-based prophylactic and therapeutic approaches. Here, we encoded bNAbs in first-generation adenoviral (ADV) vectors, which have the distinctive features of a large coding capacity and ease of propagation. A single intramuscular injection of ADV-vectorized bNAbs in humanized mice generated high serum levels of bNAbs that provided protection against multiple repeated challenges with a high dose of HIV-1, prevented depletion of peripheral CD4+ T cells, and reduced plasma viral loads to below detection limits. Our results suggest that ADV vectors may be a viable option for the prophylactic and perhaps therapeutic use of bNAbs in humans.
doi:10.1089/hum.2014.146
PMCID: PMC4575530  PMID: 25953321
8.  An Indoor Pedestrian Positioning Method Using HMM with a Fuzzy Pattern Recognition Algorithm in a WLAN Fingerprint System 
Sensors (Basel, Switzerland)  2016;16(9):1447.
With the rapid development of smartphones and wireless networks, indoor location-based services have become more and more prevalent. Due to the sophisticated propagation of radio signals, the Received Signal Strength Indicator (RSSI) shows a significant variation during pedestrian walking, which introduces critical errors in deterministic indoor positioning. To solve this problem, we present a novel method to improve the indoor pedestrian positioning accuracy by embedding a fuzzy pattern recognition algorithm into a Hidden Markov Model. The fuzzy pattern recognition algorithm follows the rule that the RSSI fading has a positive correlation to the distance between the measuring point and the AP location even during a dynamic positioning measurement. Through this algorithm, we use the RSSI variation trend to replace the specific RSSI value to achieve a fuzzy positioning. The transition probability of the Hidden Markov Model is trained by the fuzzy pattern recognition algorithm with pedestrian trajectories. Using the Viterbi algorithm with the trained model, we can obtain a set of hidden location states. In our experiments, we demonstrate that, compared with the deterministic pattern matching algorithm, our method can greatly improve the positioning accuracy and shows robust environmental adaptability.
doi:10.3390/s16091447
PMCID: PMC5038725  PMID: 27618053
pedestrian positioning; fuzzy pattern recognition algorithm; RSSI variation trend; hidden markov model; smartphone; fingerprint system
9.  New multiplex real-time PCR approach to detect gene mutations for spinal muscular atrophy 
BMC Neurology  2016;16:141.
Background
Spinal muscular atrophy (SMA) is the most common autosomal recessive disease in children, and the diagnosis is complicated and difficult, especially at early stage. Early diagnosis of SMA is able to improve the outcome of SMA patients. In our study, Real-time PCR was developed to measure the gene mutation or deletion of key genes for SMA and to further analyse genotype-phenotype correlation.
Methods
The multiple real-time PCR for detecting the mutations of survival of motor neuron (SMN), apoptosis inhibitory protein (NAIP) and general transcription factor IIH, polypeptide 2 gene (GTF2H2) was established and confirmed by DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). The diagnosis and prognosis of 141 hospitalized children, 100 normal children and further 2000 cases of dry blood spot (DBS) samples were analysed by this multiple real-time PCR.
Results
The multiple real-time PCR was established and the accuracy of it to detect the mutations of SMN, NAIP and GTF2H2 was at least 98.8 % comparing with DNA sequencing and MLPA. Among 141 limb movement disorders children, 75 cases were SMA. 71 cases of SMA (94.67 %) were with SMN c.840 mutation, 9 cases (12 %) with NAIP deletion and 3 cases (4 %) with GTF2H2 deletion. The multiple real-time PCR was able to diagnose and predict the prognosis of SMA patients. Simultaneously, the real-time PCR was applied to detect trace DNA from DBS and able to make an early diagnosis of SMA.
Conclusion
The clinical and molecular characteristics of SMA in Southwest of China were presented. Our work provides a novel way for detecting SMA in children by using real-time PCR and the potential usage in newborn screening for early diagnosis of SMA.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-016-0651-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12883-016-0651-y
PMCID: PMC4989483  PMID: 27534852
Spinal muscular atrophy; Multiplex real-time PCR; Newborn screening
10.  Effects of race and sex on cerebral hemodynamics, oxygen delivery and blood flow distribution in response to high altitude 
Scientific Reports  2016;6:30500.
To assess racial, sexual, and regional differences in cerebral hemodynamic response to high altitude (HA, 3658 m). We performed cross-sectional comparisons on total cerebral blood flow (TCBF = sum of bilateral internal carotid and vertebral arterial blood flows = QICA + QVA), total cerebrovascular resistance (TCVR), total cerebral oxygen delivery (TCOD) and QVA/TCBF (%), among six groups of young healthy subjects: Tibetans (2-year staying) and Han (Han Chinese) at sea level, Han (2-day, 1-year and 5-year) and Tibetans at HA. Bilateral ICA and VA diameters and flow velocities were derived from duplex ultrasonography; and simultaneous measurements of arterial pressure, oxygen saturation, and hemoglobin concentration were conducted. Neither acute (2-day) nor chronic (>1 year) responses showed sex differences in Han, except that women showed lower TCOD compared with men. Tibetans and Han exhibited different chronic responses (percentage alteration relative to the sea-level counterpart value) in TCBF (−17% vs. 0%), TCVR (22% vs. 12%), TCOD (0% vs. 10%) and QVA/TCBF (0% vs. 2.4%, absolute increase), with lower resting TCOD found in SL- and HA-Tibetans. Our findings indicate racial but not sex differences in cerebral hemodynamic adaptations to HA, with Tibetans (but not Han) demonstrating an altitude-related change of CBF distribution.
doi:10.1038/srep30500
PMCID: PMC4977556  PMID: 27503416
11.  Efficacy of Chinese Herbal Medicine for Diarrhea-Predominant Irritable Bowel Syndrome: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials 
Objective. To explore the efficacy of Chinese herbal medicine in treating diarrhea-predominant irritable bowel syndrome (D-IBS). Methods. Four English and four Chinese databases were searched through November, 2015. Randomized, double-blind and placebo-controlled trials were selected. Data extraction and quality evaluation were performed by two authors independently. RevMan 5.2.0 software was applied to analyze the data of included trials. Results. A total of 14 trials involving 1551 patients were included. Meta-analysis demonstrated superior global symptom improvement (RR = 1.62; 95% CI 1.31, 2.00; P < 0.00001; number needed to treat = 3.6), abdominal pain improvement (RR = 1.95; 95% CI 1.61, 2.35; P < 0.00001), diarrhea improvement (RR = 1.87; 95% CI 1.60, 2.20; P < 0.00001), pain threshold assessment (MD = 54.53; 95% CI 38.76, 70.30; P < 0.00001), and lower IBS Symptom Severity Score (SMD = −1.01; 95% CI −1.72, −0.30; P = 0.005), when compared with placebo, while for defecation threshold assessment, quality of life, and adverse events, no differences were found between treatment groups and controlled groups. Conclusion. This meta-analysis shows that Chinese herbal medicine is an effective and safe treatment for D-IBS. However, due to the small sample size and high heterogeneity, further studies are required.
doi:10.1155/2016/4071260
PMCID: PMC4983371  PMID: 27547226
12.  Frequency of ED revisits and death among older adults after a fall 
Introduction
Falls among older adults (aged ≥65 years) are the leading cause of both injury deaths and emergency department (ED) visits for trauma. We examine the characteristics and prevalence of older adult ED fallers as well as the recurrent ED visit and mortality rate.
Methods
This was a retrospective analysis of a cohort of elderly fall patients who presented to the ED between 2005 and 2011 at two urban, level-1 trauma, teaching hospitals with approximately 80,000-95,000 annual visits. We examined the frequency of ED revisits and death at 3 days, 7 days, 30 days, and 1 year controlling for certain covariates.
Results
Our cohort included 21,340 patients. The average age was 78.6. An increasing proportion of patients revisited the ED over the course of a year, ranging from 2% of patients at 3 days to 25% at 1 year. Death rates increased from 1.2% at 3 days to 15% at 1 year. 10,728 (50.2%) patients returned to the ED at some point during our 7-year study period and 36% of patients had an ED revisit or death within 1 year. In multivariate logistic regression, male sex and comorbidities were associated with ED revisits and death.
Conclusion
Over a third of older adult ED fall patients had an ED revisit or died within one year. Falls are one of the geriatric syndromes that contribute to frequent ED revisits and death rates. Future research should determine whether falls increase the risk of such outcomes and how to prevent future fall and death.
doi:10.1016/j.ajem.2015.04.023
PMCID: PMC4962693  PMID: 25983268
geriatrics; emergency care; trauma
13.  A Dynamic Model of Human and Livestock Tuberculosis Spread and Control in Urumqi, Xinjiang, China 
We establish a dynamical model for tuberculosis of humans and cows. For the model, we firstly give the basic reproduction number R0. Furthermore, we discuss the dynamical behaviors of the model. By epidemiological investigation of tuberculosis among humans and livestock from 2007 to 2014 in Urumqi, Xinjiang, China, we estimate the parameters of the model and study the transmission trend of the disease in Urumqi, Xinjiang, China. The reproduction number in Urumqi for the model is estimated to be 0.1811 (95% confidence interval: 0.123–0.281). Finally, we perform some sensitivity analysis of several model parameters and give some useful comments on controlling the transmission of tuberculosis.
doi:10.1155/2016/3410320
PMCID: PMC4976259  PMID: 27525034
14.  Surgical treatment of primary hyperparathyroidism due to parathyroid tumor: A 15-year experience 
Oncology Letters  2016;12(3):1989-1993.
The aim of this study was to highlight our experience over a 15-year period in dealing with primary hyperparathyroidism (PHPT) due to a parathyroid tumor. Parathyroidectomy is the standard therapy for patients with PHPT. Our study included all patients with PHPT treated by parathyroidectomy at the Affiliated Cancer Hospital of Zhengzhou University, China. Between 1998 and 2013, a total of 107 patients were recruited. Their clinical data, presentation, laboratory examinations, imageological diagnoses and surgical approaches were analyzed retrospectively. Eighty-four cases (78.5%) were followed up. During a median follow-up period of 5.7 years, a total of 80 patients were without recurrence and metastasis. The main symptoms of PHPT patients were palpable neck mass, joint pains and pathological fracture. The high levels of preoperative parathyroid hormone (PTH) and serum calcium in PHPT patients decreased to below the normal upper limit within 3 days of surgery. The sensitivity of neck ultrasonography, sestamibi scanning, CT, MRI and the combination of three or four types of test were 86.0%, 90.4%, 80.8%, 79.6% and 96.1%, respectively. A 50% or greater drop in PTH levels within 20 min compared with the highest PTH levels before surgery occurred in 95/107 cases (88.8%). Transient hypocalcemia was the most common surgical complication. The ultrasonography and sestamibi scan is the most effective examination for parathyroid tumor. The 20 min PTH measurement appears to be extremely useful, and avoids unnecessary bilateral exploration.
doi:10.3892/ol.2016.4905
PMCID: PMC4998171  PMID: 27602126
primary hyperparathyroidism; parathyroidectomy; parathyroid; parathyroid hormone; intra-operative parathyroid hormone
15.  Revisits within 48 Hours to a Thai Emergency Department 
Emergency Medicine International  2016;2016:8983573.
Objective. Emergency department (ED) revisits are a common ED quality measure. This study was undertaken to ascertain the contributing factors of revisits within 48 hours to a Thai ED and to explore physician-related, illness-related, and patient-related factors behind those revisits. Methods. This study was a chart review from one tertiary care, urban Thai hospital from October 1, 2009, to September 31, 2010. We identified patients who returned to the ED within 48 hours for the same or related complaints after their initial discharge. Three physicians classified revisit as physician-related, illness-related, and patient-related factors. Results. Our study included 172 ED patients' charts. 86/172 (50%) were male and the mean age was 38 ± 5.6 (SD) years. The ED revisits contributing factors were physician-related factors [86/172 (50.0%)], illness-related factors [61/172 (35.5%)], and patient-related factor [25/172 (14.5%)], respectively. Among revisits classified as physician-related factors, 40/86 (46.5%) revisits were due to misdiagnosis and 36/86 (41.9%) were due to suboptimal management. Abdominal pain [27/86 (31.4%)] was the majority of physician-related chief complaints, followed by fever [16/86 (18.6%)] and dyspnea [15/86 (17.4%)]. Conclusion. Misdiagnosis and suboptimal management contributed to half of the 48-hour repeat ED visits in this Thai hospital.
doi:10.1155/2016/8983573
PMCID: PMC4961813  PMID: 27478642
16.  Targeting Transforming Growth Factor-Beta1 (TGF-β1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NF-κB-PUMA Signaling 
Background
The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in promoting tumor growth. TGF-β1was found to be overexpressed in anaplastic thyroid cancer (ATC). We therefore tested our hypothesis that targeting TGF-β1 inhibits tumorigenesis of ATC cells.
Material/Methods
Effects of TGF-β1 stimulation or TGF-β1 inhibition by small interfering RNA (TGF-β1siRNA) on proliferation, colony formation, and apoptosis in 8505C cells in vitro was detected using siRNAs and inhibitors to examine the TGF-β1 signaling pathway. A subcutaneously implanted tumor model of 8505C cells in nude mice was used to assess the effects of TGF-β1 inhibition on tumorigenesis development.
Results
TGF-β1siRNAs decreased proliferation and colony formation, and increased apoptosis in 8505C cells in vitro and inhibited tumor growth in vivo. TGF-β1siRNA inhibited phosphorylation ERK1/2 (pERK1/2) and increased p65-dependant PUMA mRNA and protein expression. Knockdown of p65 or PUMA by siRNA reduced TGF-β1siRNA-induced apoptosis, as well as caspase-3 and PARP activation. Upregulation of p65 or PUMA expression by TGF-β1siRNA requires pERK1/2 inhibition. TGF-β1 shRNA inhibited tumor growth in vivo.
Conclusions
Therapies targeting the TGF-β1 pathway may be more effective to prevent primary tumor formation. The ability of this therapy to decrease tumorigenesis may be related to ERK1/2/NF-κB/PUMA signaling.
doi:10.12659/MSM.898702
PMCID: PMC4933554  PMID: 27356491
Apoptosis Inducing Factor; Genes, Neoplasm; MAP Kinase Signaling System; NF-kappa B; Transforming Growth Factor beta1
17.  Acoustic Cavitation Enhances Focused Ultrasound Ablation with Phase-Shift Inorganic Perfluorohexane Nanoemulsions: An In Vitro Study Using a Clinical Device 
BioMed Research International  2016;2016:7936902.
Purpose. To investigate whether acoustic cavitation could increase the evaporation of a phase-shift inorganic perfluorohexane (PFH) nanoemulsion and enhance high intensity focused ultrasound (HIFU) ablation. Materials and Methods. PFH was encapsulated by mesoporous silica nanocapsule (MSNC) to form a nanometer-sized droplet (MSNC-PFH). It was added to a tissue-mimicking phantom, whereas phosphate buffered saline (PBS) was added as a control (PBS-control). HIFU (Pac = 150 W, t = 5/10 s) exposures were performed in both phantoms with various duty cycles (DC). US images, temperature, and cavitation emissions were recorded during HIFU exposure. HIFU-induced lesions were measured and calculated. Results. Compared to PBS-control, MSNC-PFH nanoemulsion could significantly increase the volume of HIFU-induced lesion (P < 0.01). Peak temperatures were 78.16 ± 5.64°C at a DC of 100%, 70.17 ± 6.43°C at 10%, 53.17 ± 4.54°C at 5%, and 42.00 ± 5.55°C at 2%, respectively. Inertial cavitation was much stronger in the pulsed-HIFU than that in the continuous-wave HIFU exposure. Compared to 100%-DC exposure, the mean volume of lesion induced by 5 s exposure at 10%-DC was significantly larger, but smaller at 2%-DC. Conclusions. MSNC-PFH nanoemulsion can significantly enhance HIFU ablation. Appropriate pulsed-HIFU exposure could significantly increase the volume of lesion and reduce total US energy required for HIFU ablation.
doi:10.1155/2016/7936902
PMCID: PMC4935909  PMID: 27419138
18.  Vitamin D Insufficiency and Its Association with Biochemical and Anthropometric Variables of Young Children in Rural Southwestern China 
Chinese Medical Journal  2016;129(11):1273-1279.
Background:
With recognition of the important roles of Vitamin D (VitD) in various physiological processes, increasing attention has been drawn to the status of VitD in early life. However, the VitD status of young children and the related factors in rural areas of Southwestern China remain unclear. This study aimed to explore VitD status and its seasonal variation in 18-month-old children living in rural Southwestern China. The association of VitD with biochemical and anthropometric variables was also investigated.
Methods:
A total of 177 18-month-old children in a rural area of Yunnan Province, Southwestern China, were enrolled. Serum concentrations of 25-hydroxy Vitamin D (25(OH)D) were measured through high-performance liquid chromatogram-tandem mass spectrometry. Parathyroid hormone (PTH) levels were measured with a chemiluminescence assay. Serum concentrations of calcium, phosphorus, and alkaline phosphatase (ALP) were also measured. Anthropometric data and the outdoor activity time of each participant were collected.
Results:
The serum 25(OH)D concentration was 26.61 ± 7.26 ng/ml; concentrations lower than 30 ng/ml accounted for 70.6% of the participants and concentrations lower than 20 ng/ml accounted for 16.4%. The level of serum 25(OH)D was not significantly different among four seasons (P >0.05). A positive relationship was found between 25(OH)D concentration and the time of outdoor activities (r = 0.168, P < 0.05). Serum PTH concentration was negatively correlated with 25(OH)D concentration (r = −0.163, P < 0.05). A positive relationship was found between the serum concentrations of 25(OH)D and calcium (r = 0.154, P < 0.05). No significant association was observed between 25(OH)D and ALP, phosphorus, or anthropometric variables.
Conclusions:
The prevalence of VitD insufficiency is high among young children in the rural Southwestern China regardless of the seasons. VitD supplementation is still essential to maintain VitD sufficiency for children living in rural area.
doi:10.4103/0366-6999.182834
PMCID: PMC4894035  PMID: 27231162
25-Hydroxy Vitamin D; Infant; Rural Area; Vitamin D; Vitamin D Deficiency
19.  Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV 
PLoS ONE  2016;11(6):e0156739.
Interferon-induced transmembrane (IFITM) proteins are potent antiviral factors shown to restrict the infection of many enveloped viruses, including HIV. Here we report cloning and characterization of a panel of nonhuman primate IFITMs. We show that, similar to human IFITM, nonhuman primate IFITM proteins inhibit HIV and other primate lentiviruses. While some nonhuman primate IFITM proteins are more potent than human counterparts to inhibit HIV-1, they are generally not effective against HIV-2 similar to that of human IFITMs. Notably, depending on SIV strains and also IFITM species tested, nonhuman primate IFITM proteins exhibit distinct activities against SIVs; no correlation was found to support the notion that IFITM proteins are most active in non-natural primate hosts. Consistent with our recent findings for human IFITMs, nonhuman primate IFITM proteins interact with HIV-1 Env and strongly act in viral producer cells to impair viral infectivity and block cell-to-cell transmission. Accordingly, knockdown of primate IFITM3 increases HIV-1 replication in nohuman primate cells. Interestingly, analysis of DNA sequences of human and nonhuman primate IFITMs suggest that IFITM proteins have been undergoing purifying selection, rather than positive selection typical for cellular restriction factors. Overall, our study reveals some new and unexpected features of IFITMs in restricting primate lentiviruses, which enhances our understanding of virus-host interaction and AIDS pathogenesis.
doi:10.1371/journal.pone.0156739
PMCID: PMC4892622  PMID: 27257969
20.  C-reactive protein directly suppresses T helper 1 cell differentiation and alleviates experimental autoimmune encephalomyelitis 
Human C-reactive protein (CRP) is a serum soluble pattern recognition receptor (PRR) that serves as a marker of inflammation and directly contributes to innate immunity. Herein we show that human CRP also directly contributes to adaptive immunity, i.e. native CRP binds specifically to human Jurkat T cells and to mouse naïve CD4+ T cells and modulates their T helper (Th) 1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naïve CD4+ T cells. In vivo for human CRP transgenic (CRPtg) compared to wild type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover in both CRPtg mice and in wild type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition-independent actions of CRP directly on T cells highlights the potential for this soluble PRR to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease.
doi:10.4049/jimmunol.1402909
PMCID: PMC4433796  PMID: 25917100
C-reactive protein; T cell differentiation; inflammation; autoimmune diseases; experimental autoimmune encephalomyelitis
21.  Strategies to Optimize Adult Stem Cell Therapy for Tissue Regeneration 
Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells) commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous). The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells), early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium), using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration), timing for cell therapy (immediate vs. a few days after injury), single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications.
doi:10.3390/ijms17060982
PMCID: PMC4926512  PMID: 27338364
stem cells; stem cell therapy; optimizing strategy; tissue repair; tissue regeneration
22.  MAL62 overexpression and NTH1 deletion enhance the freezing tolerance and fermentation capacity of the baker’s yeast in lean dough 
Background
Trehalose is related to several types of stress responses, especially freezing response in baker’s yeast (Saccharomyces cerevisiae). It is desirable to manipulate trehalose-related genes to create yeast strains that better tolerate freezing-thaw stress with improved fermentation capacity, which are in high demand in the baking industry.
Results
The strain overexpressing MAL62 gene showed increased trehalose content and cell viability after prefermention-freezing and long-term frozen. Deletion of NTH1 in combination of MAL62 overexpression further strengthens freezing tolerance and improves the leavening ability after freezing-thaw stress.
Conclusions
The mutants of the industrial baker’s yeast with enhanced freezing tolerance and leavening ability in lean dough were developed by genetic engineering. These strains had excellent potential industrial applications.
doi:10.1186/s12934-016-0453-3
PMCID: PMC4819290  PMID: 27039899
Baker’s yeast; MAL62; NTH1; Freezing tolerance; Cell viability; Leavening ability
23.  Removal of regulatory T cells prevents secondary chronic infection but increases the mortality of subsequent sub-acute infection in sepsis mice 
Oncotarget  2016;7(10):10962-10975.
The immunosuppression following initial septic insult impairs resistance to secondary infection. Modulation of lymphocytes population may help to develop an effective therapeutic strategy. In this study, lipopolysaccharide (LPS)-induced endotoxemia was employed as the initial septic insult. 24 hours later, mice underwent cecal ligation and puncture to induce chronic or sub-acute peritonitis. Potential usefulness of T regs deletion antibody (anti-CD25) in improving LPS-induced immunosuppression and the survival of subsequent different infections were evaluated. LPS injection induced lymphocyte loss and led to decreased IL-6, TNF-α and IFN-γ, and weakened bacteria clearance upon chronic peritonitis at 24 h post-LPS, whereas reconstitution with lymphocytes reversed these changes. LPS-induced T regs expansion contributed to T and NK cells decrease in number and activity during sepsis. Depletion of T regs using anti-CD25 antibodies partly prevented lymphocyte loss and increased the responses of T and NK cells to subsequent stimulation, resulting in significantly increased bacterial clearance and survival in a 2-hit model of chronic peritonitis, but which significantly increased early mortality upon subsequently sub-acute infection. Yet, using lower dosage of anti-CD25 antibodies to moderate down-regulate T regs levels could partly improve bacterial clearance and survival in either chronic or sub-acute infection. These results demonstrate that using anti-CD25 antibodies to deplete T regs can ameliorate immunosuppression through increasing T cells and NK cells responses in sepsis, which is beneficial for preventing subsequently chronic infection, but will probably bring some deleterious effects for subsequent sub-acute infection.
doi:10.18632/oncotarget.7682
PMCID: PMC4905451  PMID: 26918357
sepsis; immunosuppression; lymphocyte; immunotherapeutic approach; secondary infection; Immunology and Microbiology Section; Immune response; Immunity
24.  MicroRNA-101 targets von Hippel-Lindau tumor suppressor (VHL) to induce HIF1α mediated apoptosis and cell cycle arrest in normoxia condition 
Scientific Reports  2016;6:20489.
The activation/inactivation of HIF1α is precisely regulated in an oxygen-dependent manner. HIF1α is essential for hypoxia induced apoptosis and cell cycle arrest. Several recent studies indicated that the expression of miRNAs can be modulated by hypoxia. However, the involvement of miRNAs in the regulation of HIF1α induction remains elusive. In present study, we demonstrated that miR-101 was rapidly and transiently induced after hypoxia in breast cancer cells. Over-expression of miR-101 significantly inhibited cell proliferation in breast cancer cells through increased apoptosis and cell cycle arrest in normoxia condition. This inhibitory phenomenon seems due to miR-101-mediated induction of HIF1α, because we identified that VHL, a negative regulator of HIF1α, is a novel target of miR-101 and over-expression of miR-101 decreased VHL levels and subsequently stabilized HIF1α and induced its downstream target VEGFA. Furthermore, we demonstrated that siRNA-mediated knockdown of VHL or HIF1α overexpression could also induce apoptosis and cell cycle arrest whereas enforced expression of VHL, administration of anti-miR-101 oligos or treatment of 2-MeOE2, an inhibitor of HIF1α, could rescue cells from such inhibition. These results reveal a novel regulatory mechanism of HIF1α induction in normoxia and suggest that miR-101 mediated proliferation inhibition may through HIF1α mediated apoptosis and cell cycle arrest.
doi:10.1038/srep20489
PMCID: PMC4740907  PMID: 26841847
25.  Giant non-functional parathyroid cyst: A case report 
Oncology Letters  2016;11(3):2237-2240.
Giant parathyroid cysts (PCs) are a rare entity and possess a benign clinical course. PCs may be functional or non-functional, depending on the ability of the cyst to secrete parathyroid hormone (PTH). The present study reports a rare case of a giant PC in a 56-year-old male who presented to the Affiliated Tumor Hospital, Zhengzhou University (Zhengzhou, Henan, China) with a 10-month history of exertional dyspnea, associated with mild dysphagia that had persisted for 3 months. The present study reviews the clinical situation, laboratory examination, radiographic findings, treatment and prognosis of the patient, and provides a brief discussion regarding the associated literature. Giant PCs may manifest with compressive symptoms of the surrounding tissues. The diagnosis of a giant PC is based on increased levels of PTH in the fluid collected during the aspiration of the cyst. Management by surgical excision is recommended for giant PCs that cause local cervical symptoms.
doi:10.3892/ol.2016.4181
PMCID: PMC4774514  PMID: 26998155
parathyroid cyst; non-functioning; parathyroid lesion; mediastinal lesion; surgical excision

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