Environmental evaluation of radioactivity levels and associated radiation hazards in groundwater around the WIPP site.

Groundwater may contain radioactive substances which can be dangerous to human health. Concentrations of natural radionuclides polonium (Po), thorium (Th), uranium (U), and radium (Ra) isotopes were measured in groundwater samples collected from different locations in the vicinity of the Waste Isolation Pilot Plant (WIPP) site in Carlsbad, New Mexico. The average values of gross activity concentrations of 210Po, 228Th, 238U, 234U, 226Ra and 228 Ra isotopes were determined to be 1.62 Bq L-1 in shallow groundwater and 5.88 Bq L-1 in deep groundwater, respectively. The total radioactivity in deep groundwater was higher than that in shallow groundwater, and most of the radioactivity in the water is from 226Ra. Furthermore, the effective doses for ingestion of natural radionuclides were about 0.333 mSv y-1 for shallow groundwater and about 1.338 mSv y-1 for deep groundwater samples, which are higher than the World Health Organization (WHO, 2017) guideline level (0.1 mSv y-1) for drinking water. Ra dominated the total ingestion dose, contributing 93.06 % and 75.40 % of the total effective doses to the deep and shallow groundwater, respectively. The ingrowth and decay of natural radionuclides suggested that 228Ra/226Ra ratio can be a useful indicator of the source of radioactive contamination. The radioactivity data obtained from the investigated groundwater samples can be used to establish a baseline for radioactivity levels in groundwater around the WIPP site.

Production of a bispecific antibody targeting TNF-α and C5a in Pichia pastoris and its therapeutic potential in rheumatoid arthritis.

OBJECTIVE: To provide an alternative therapeutic modality for rheumatoid arthritis (RA), a novel bispecific antibody (BsAb) targeting human tumor necrosis factor α (TNF-α) and human complement component C5a was constructed. RESULTS: BsAb was expressed in Pichia pastoris and secreted into the culture medium as a functional protein. In vitro functional study demonstrated that BsAb could simultaneously bind to TNF-α and C5a and neutralize their biological actions. Furthermore, BsAb showed significant improvements in both the antigen-binding affinity and the neutralizing ability as compared to its original antibodies produced in E. coli. It was also found that TNF-α and C5a had an additive/synergistic effect on promoting the production of inflammatory cytokines and chemokines and C5a receptor (C5aR) expression in human macrophages. Compared to single inhibition of TNF-α or C5a with respective antibody, BsAb showed a superior efficacy in blocking inflammatory cytokines, chemokines, and C5aR response, as well as in lowering the C5a-mediated chemotaxis of macrophages via C5aR in vitro. CONCLUSIONS: With improved production processing and the ability to simultaneously block TNF-α and C5a action, BsAb has a great potential to be developed into a therapeutic agent and may offer a better therapeutic index for RA.

(5R)-5-Hydroxytriptolide (LLDT-8) induces substantial epigenetic mediated immune response network changes in fibroblast-like synoviocytes from rheumatoid arthritis patients.

Tripterygium is a traditional Chinese medicine that has widely been used in the treatment of rheumatic disease. (5R)-5-hydroxytriptolide (LLDT-8) is an extracted compound from Tripterygium, which has been shown to have lower cytotoxicity and relatively higher immunosuppressive activity when compared to Tripterygium. However, our understanding of LLDT-8-induced epigenomic impact and overall regulatory changes in key cell types remains limited. Doing so will provide critically important mechanistic information about how LLDT-8 wields its immunosuppressive activity. The purpose of this study was to assess the effects of LLDT-8 on transcriptome including mRNAs and long non-coding RNA (lncRNAs) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) by a custom genome-wide microarray assay. Significant differential expressed genes were validated by QPCR. Our work shows that 394 genes (281 down- and 113 up-regulated) were significantly differentially expressed in FLS responding to the treatment of LLDT-8. KEGG pathway analysis showed 20 pathways were significantly enriched and the most significantly enriched pathways were relevant to Immune reaction, including cytokine-cytokine receptor interaction (P = 4.61 × 10-13), chemokine signaling pathway (P = 1.01 × 10-5) and TNF signaling pathway (P = 2.79 × 10-4). Furthermore, we identified 618 highly negatively correlated lncRNA-mRNA pairs from the selected significantly differential lncRNA and mRNA including 27 cis-regulated and 591 trans-regulated lncRNA-mRNAs modules. KEGG and GO based function analysis to differential lncRNA also shown the enrichment of immune response. Finally, lncRNA-transcription factor (TF) and lncRNA-TF-mRNA co-expression network were constructed with high specific network characteristics, indicating LLDT-8 would influence the expression network within the whole FLS cells. The results indicated that the LLDT-8 would mainly influence the FLS cells systemically and specially in the process of immune related pathways.

Oyster-Derived Zinc-Binding Peptide Modified by Plastein Reaction via Zinc Chelation Promotes the Intestinal Absorption of Zinc.

Zinc-binding peptides from oyster (Crassostrea gigas) have potential effects on zinc supplementation. The aim of this study was to prepare efficient zinc-binding peptides from oyster-modified hydrolysates by adding exogenous glutamate according to the plastein reaction and to further explore the zinc absorption mechanism of the peptide-zinc complex (MZ). The optimum conditions for the plastein reaction were as follows: pH 5.0, 40 °C, substrate concentration of 40%, pepsin dosage of 500 U/g, reaction time of 3 h and l-[1-13C]glutamate concentration of 10 mg/mL. The results of 13C isotope labelling suggested that the addition of l-[1-13C]glutamate contributed to the increase in the zinc-binding capacity of the peptide. The hydrophobic interaction was the main mechanism of action of the plastein reaction. Ultraviolet spectra and scanning electronic microscopy (SEM) revealed that the zinc-binding peptide could bind with zinc and form MZ. Furthermore, MZ could significantly enhance zinc bioavailability in the presence of phytic acid, compared to the commonly used ZnSO4. Additionally, MZ significantly promoted the intestinal absorption of zinc mainly through two pathways, the zinc ion channel and the small peptide transport pathway. Our work attempted to increase the understanding of the zinc absorption mechanism of MZ and to support the potential application of MZ as a supplementary medicine.

Flexible Modulation of CO-Release Using Various Nuclearity of Metal Carbonyl Clusters on Graphene Oxide for Stroke Remediation.

Utilizing the size-dependent adsorption properties of ruthenium carbonyl clusters (Ru-carbon monoxide (CO)) onto graphene oxide (GO), a facile CO-release platform for in situ vasodilation as a treatment for stroke-related vascular diseases is developed. The rate and amount of formation of the CO-release-active RuII (CO)2 species can be modulated by a simple mixing procedure at room temperature. The subsequent thermally induced oxidation of RuII (CO)2 to RuO2 on the GO surface results in the release of CO. Further modulation of thermal and CO-release properties can be achieved via a hybridization of medium- and high-nuclearity of Ru-CO clusters that produces a RuO2 /RuII (CO)2 /6 Ru-CO-GO composite, where 6 Ru-CO-GO provides a photothermally activated reservoir of RuII (CO)2 species and the combined infrared absorption properties of GO and RuO2 provides photothermal response for in situ CO-release. The RuO2 /RuII (CO)2 /6 Ru-CO-GO composite does not produce any cytotoxicity and the efficacy of the composite is further demonstrated in a cortical photothrombotic ischemia rat model.

Treatment effects of the traditional Chinese medicine Shenks in bleomycin-induced lung fibrosis through regulation of TGF-beta/Smad3 signaling and oxidative stress.

Pulmonary fibrosis is a kind of devastating interstitial lung disease due to the limited therapeutic strategies. Traditional Chinese medicine (TCM) practices have put forth Shenks as a promising treatment approach. Here, we performed in vivo study and in vitro study to delineate the anti-fibrotic mechanisms behind Shenks treatment for pulmonary fibrosis. We found that regardless of the prophylactic or therapeutic treatment, Shenks was able to attenuate BLM-induced-fibrosis in mice, down regulate extracellular matrix genes expression, and reduce collagen production. The aberrantly high Smad3 phosphorylation levels and SBE activity in TGF-ß-induced fibroblasts were dramatically decreased as a result of Shenks treatment. At the same time, Shenks was able to increase the expression of antioxidant-related genes, including Gclc and Ec-sod, while reduce the transcription levels of oxidative-related genes, such as Rac1 and Nox4 demonstrated by both in vivo and in vitro studies. Further investigations found that Shenks could decrease the oxidative productions of protein (3-nitrotyrosine) and lipid (malondialdehyde) and increase GSH content both in bleomycin treated mouse lungs and TGF-ß stimulated fibroblasts, as well as inhibit the production of ROS stimulated by TGF-ß to fight against oxidative stress. Overall, Shenks inhibited fibrosis by blocking TGF-ß pathway and modulating the oxidant/antioxidant balance.

Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-ß Signaling Pathway.

Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-ß-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-ß-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-ß signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis.

A label-free fluorescence turn-on sensor for rapid detection of cysteine.

A Hg(2+)-mediated fluorescence turn-on sensor for cysteine (Cys) detection was developed using the nucleic acid minor groove binding dye DAPI. In this work, two fully complementary DNA sequences, a T-rich single-stranded molecule (ssDNA) and an A-rich single-stranded molecule, were employed to constitute consecutive "AT/TA" base pairs, which could strongly enhance the fluorescence of DAPI. In the absence of cysteine, Hg(2+) reacted with T-rich single-stranded DNA and "T-Hg(2+)-T" base pairs formed, this seriously disrupted consecutive AT base pairs. As a result, the fluorescence of DAPI was not increased efficiently. However, considering that cysteine binds strongly to Hg(2+), the structure of the "T-Hg(2+)-T" complexes was destroyed in the presence of cysteine, resulting in the re-formation of consecutive AT base pairs and increased DAPI fluorescence. Obviously, the amount of cysteine could be easily measured based on the enhancement of DAPI fluorescence, and it took only 20 min to complete the whole cysteine-sensing process. Therefore, a label-free fluorescent "turn-on" sensor for the rapid detection of cysteine was designed, and the detection limit of this sensor was as low as 2.4 nM, which was much lower than those of the most of the previously reported cysteine sensors.

Oropharyngeal squamous cell carcinoma in the veteran population: Association with traditional carcinogen exposure and poor clinical outcomes.

BACKGROUND: A significant fraction of oropharyngeal squamous cell carcinoma (SCC) cases is associated with traditional carcinogens; in these patients, treatment response and clinical outcomes remain poor. METHODS: We evaluated patient, tumor, and treatment characteristics for 200 veterans with oropharyngeal SCC treated at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) between 2000 and 2012. RESULTS: Most patients (77%) were white and heavy smokers. Twenty-seven patients required tracheostomy and 63 required gastrostomy placement during treatment. Overall survival (OS) at 5 years was 40%. Survival was impacted by T classification, treatment intensity, completion of treatment, and p16 tumor status. Almost 30% of patients were unable to complete a treatment regimen consistent with National Comprehensive Cancer Network (NCCN) guidelines. CONCLUSION: Oropharyngeal SCC in veterans is associated with traditional carcinogens and poor clinical outcomes. Despite heavy smoking exposure, p16 tumor status significantly impacts survival. Careful consideration must be given to improving treatment paradigms for this cohort given their limited tolerance for treatment escalation.

Dissection of the mechanism of traditional Chinese medical prescription-Yiqihuoxue formula as an effective anti-fibrotic treatment for systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue fibrotic disease for which there is no effective treatment. Traditional Chinese Medicine (TCM), such as the Yiqihuoxue formula used in Shanghai TCM-integrated Hospital, has shown the efficacy of anti-fibrosis in clinical applications. This study was aiming to dissect the anti-fibrotic mechanism of Yiqihuoxue treatment for SSc. METHODS: Bleomycin-induced mice and SSc dermal fibroblasts were treated with Yiqihuoxue decoction; NIH-3T3 fibroblasts were exposed to exogenous TGF-ß1, and then cultured with or without Yiqihuoxue decoction. Luciferase reporter gene assay was used to determine the activity of Smad binding element (SBE). Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the mRNA levels of extracellular matrix (ECM) genes. The protein levels of type I collagen, Smad3 and phosphorylated-Smad3 (p-Smad3) were detected by western blotting. Student's t-tests were used to determine the significance of the results. RESULTS: Bleomycin-induced mice, SSc dermal fibroblasts and TGF-ß1-induced NIH/3T3 fibroblasts showed higher levels of ECM gene transcriptions and collagen production. In addition, the phosphorylation level of Smad3 and activity of SBE were significantly increased after exogenous TGF-ß1 induction. Whereas, Yiqihuoxue treatment could obviously attenuate fibrosis in bleomycin-induced mice, down regulate ECM gene expressions and collagen production in SSc dermal fibroblasts and TGF-ß1-induced NIH/3T3 fibroblasts. Furthermore, the aberrantly high phosphorylation level of Smad3 and activity of SBE in the TGF-ß1-induced NIH/3T3 fibroblasts were also dramatically decreased by Yiqihuoxue treatment. CONCLUSIONS: Yiqihuoxue treatment could effectively reduce collagen production via down-regulating the phosphorylation of Smad3 and then the activity of SBE, which are involved in the TGF-ß pathway and constitutively activated in the progression of SSc.

Fabrication and properties of TiO2 nanofilms on different substrates by a novel and universal method of Ti-ion implantation and subsequent annealing.

We report a new, novel and universal method to fabricate high-quality titanium dioxide (TiO2) nanofilms on different substrates by a solid phase growth process of ion implantation and subsequent annealing in oxygen atmosphere. Ti ions were implanted into fused silica, soda lime glass, Z-cut quartz, or (0001) α-sapphire by a metal vapor vacuum arc (MEVVA) ion source implanter to fluences of 0.75, 1.5 and 3 × 10(17) ions cm(-2) with a nominal accelerating voltage of 20 kV. To understand the influence of the annealing temperature, time, and substrate on the formation and phase transformation of the TiO2 nanofilms, the Ti-ion-implanted substrates were annealed in oxygen atmosphere from 500 to 1000 °C for 1-6 h. The formation of TiO2 nanofilms resulted from the slow out-diffusion of implanted Ti ions from the substrates which were then oxidized at the surfaces. The thickness and phase of the nanofilms can be tailored by controlling the implantation and annealing parameters. Since the TiO2 nanofilms are formed under high temperature and low growth rate, they show good crystallinity and antibacterial properties, with good film adhesion and stability, suggesting that the TiO2 nanofilms formed by this method have great potential in applications such as antibacterial and self-cleaning transparent glass.

Electroacupuncture improves orthostatic tolerance in healthy individuals via improving cardiac function and activating the sympathetic system.

AIMS: Orthostatic intolerance (OI) is a common clinical problem; however, effective and applicable clinical prevention/treatment is limited. The aim of this study was to investigate whether electroacupuncture (EA) is a novel effective treatment in attenuating OI in healthy individuals. METHODS AND RESULTS: This study used a randomized, controlled, crossover design using two protocols. Orthostatic intolerance was induced with a combination of head-up tilt (HUT) and lower body negative pressure (LBNP). Twenty healthy individuals in Protocol 1 and 10 healthy individuals in Protocol 2 received no EA, EA at PC-6 acupuncture points (acupoint), and EA at a non-acupoint in a random order with an interim of 1 week. Electroacupuncture was administered prior to HUT/LBNP in Protocol 1 and simultaneously during HUT/LBNP in Protocol 2. Electroacupuncture at PC-6 administered either before or during HUT/LBNP postponed the occurrence of pre-syncopal symptoms, improved haemodynamic responses to HUT/LBNP (including increased diastolic blood pressure, stroke volume, and total peripheral resistance and a decreased heart rate), blunted decreases of maximum velocity and velocity time integral of blood flow in the middle cerebral artery, and increased plasma noradrenalin and adrenalin concentrations. In addition, heart rate variability analysis revealed that EA at PC-6 either before or during HUT/LBNP decreased high-frequency ranges of R-R interval while increasing low-frequency ranges of R-R interval, which indicates an elevated heart sympathetic tone. CONCLUSION: Electroacupuncture at PC-6 is effective in improving orthostatic tolerance. Cardiac function improvement and sympathetic activation are responsible for the improved orthostatic tolerance after EA. EA represents a novel intervention against OI.

Evolution from unconventional spin density wave to superconductivity and a pseudogaplike phase in NaFe(1-x)Co(x)As.

We report the doping, temperature, and spatial evolutions of the electronic structure of NaFe(1-x)Co(x)As studied by scanning tunneling microscopy. In the parent state we directly observe the spin density wave gap, which exhibits unconventional features that are incompatible with simple Fermi surface nesting. The optimally doped sample has a single superconducting gap, but in the overdoped regime a novel pseudogaplike feature emerges. The pseudogaplike phase coexists with superconductivity in the ground state, persists well into the normal state, and shows strong spatial variations. The characteristics of the three distinct electronic states revealed here shed important new lights on the microscopic models for the iron-based superconductors.

Estrogen status alters tissue distribution and metabolism of selenium in female rats.

A reported association between estrogen and selenium status may be important in the regulation of selenium metabolism. In this study, the effect of estrogen status on the metabolism of orally administered (75)Se-selenite and tissue selenium status was investigated. Female Sprague-Dawley rats were bilaterally ovariectomized at 7 weeks of age and implanted with either a placebo pellet (OVX) or pellet containing estradiol (OVX+E2), or were sham operated (Sham). At 12 weeks of age, 60 µCi of (75)Se as selenite was orally administered to OVX and OVX+E2 rats. Blood and organs were collected 1, 3, 6 and 24 h after dosing. Estrogen status was associated with time-dependent differences in distribution of (75)Se in plasma, red blood cell (RBC), liver, heart, kidney, spleen, brain and thymus and incorporation of (75)Se into plasma selenoprotein P (Sepp1) and glutathione peroxidase (GPx). Estrogen treatment also significantly increased selenium concentration and GPx activity in plasma, liver and brain, selenium concentration in RBC and hepatic Sepp1 and GPx1 messenger RNA. These results suggest that estrogen status affects tissue distribution of selenium by modulating Sepp1, as this protein plays a central role in selenium transport.

Temperature measurement error reduction for MRI-guided HIFU treatment.

PURPOSE: We present a method to remove the temperature measurement errors due to the movement of the ultrasound applicator during MRI-guided high-intensity focused ultrasound (MRgHIFU) treatment. METHODS: MR thermometry, based on proton resonance frequency (PRF) shift, can provide high accuracy and temporal resolution of MR temperature imaging for tumour treatment by MRgHIFU. However, the challenge is that the movement of the ultrasound applicator causes temperature measurement errors due to the magnetic susceptibility of the applicator. In a clinical environment the applicator has to be moved to cover the whole tumour volume, even in the case of a phased array ultrasound applicator. With conventional PRF shift-based phase mapping method, a reference image must be repetitively acquired as the ultrasound applicator is repositioned and tissue cooling down time must be inserted before a new reference scan. Therefore, the treatment workflow becomes complex and time consuming. In this paper we propose a method to reduce temperature measurement error by compensating the ultrasound applicator susceptibility through a pre-measured or calculated magnetic field distribution of the applicator. RESULTS: The large temperature measurement error shown around the ultrasound focal region can be significantly reduced by compensating the ultrasound applicator-induced delta magnetic field. Accurate temperature maps can be obtained when the ultrasound applicator is repositioned without repetitively acquiring new reference images. CONCLUSIONS: The reference image can be repetitively used for the temperature imaging when the ultrasound applicator is repositioned. Therefore, the treatment workflow is simplified resulting in a reduction in total treatment time.

Effect of electroacupuncture stimulation of hindlimb on seizure incidence and supragranular mossy fiber sprouting in a rat model of epilepsy.

Recently, electroacupuncture (EA) has been gaining more and more attention as a treatment for epilepsy. However, concrete evidence is needed to better understand its antiepileptic effect and the mechanism underlying this effect. The present study was designed to assess the effect of EA stimulation of hindlimb on the incidence of behavioral seizures (spontaneous recurrent seizures, [SRS]) and electroencephalogram (EEG) seizures, and the extent of supragranular mossy fiber sprouting (MFS) using the lithium-pilocarpine rat model of epilepsy. Sham EA at the same point without electrical stimulation was set as the control. EA and the sham EA were performed bilaterally (at the symmetrical Zusanli acupoints on both hind legs) 30 times every two days. The numbers of behavioral seizures and EEG seizures were then analyzed to evaluate the antiepileptic effect. After confirmation of the antiepileptic effect, MFS in the dentate gyrus (DG) supragranular layer was investigated by Timm's staining. The results showed that the EA stimulation of hindlimb significantly reduced the behavioral seizures, EEG seizures, and supragranular MFS; however, the sham EA without electrical stimulation showed no significant effect on seizures or supragranular MFS. The findings indicate that EA stimulation of hindlimb possesses an antiepileptic effect, which is probably related to its suppressive effect on aberrant MFS in DG.

Enhancing effects of SonoVue, a microbubble sonographic contrast agent, on high-intensity focused ultrasound ablation in rabbit livers in vivo.

OBJECTIVE: The purpose of this study was to explore the enhancing biological effects of SonoVue (Bracco SpA, Milan, Italy), a sulfur hexafluoride sonographic contrast agent, on high-intensity focused ultrasound (HIFU) ablation in vivo. METHODS: Forty-five rabbits were randomly divided into 3 groups and underwent laparotomy. Animals in group 1 were given injections of 0.2 mL of SonoVue intravenously; animals in group 2 were given physiologic saline; and those in group 3 were not given injections as control. The exposure time was set at 2 seconds with the acoustic power at 600 W. After HIFU ablations, volumes of coagulated regions were measured. Liver tissues were examined under light microscopy with hematoxylin-eosin staining and under transmission electron microscopy. RESULTS: Coagulated volumes in group 1 (mean +/- SD, 2.41 +/- 0.44 cm(3)) were larger than those in group 2 (0.80 +/- 0.13 cm(3)) and group 3 (0.83 +/- 0.16 cm(3)) (P < .05). Separated from the surrounding area with a clear demarcation line, the targeted area in each group showed a few necrotic cells on light microscopy with the hematoxylin-eosin stain. More bubbles were observed under light microscopy in exposed areas in group 1 than in the other 2 groups (P < .05). Electron microscopy showed more severe cell ultrastructure disorder, including more interrupted cell nuclear membranes, in targeted areas in group 1 than in the other 2 groups. Conversely, in all the groups, untreated areas were not affected. CONCLUSIONS: SonoVue can substantially enhance the ablation effects of HIFU, suggesting that microbubble contrast agents may be useful for improving HIFU efficiency.