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Τετάρτη 20 Σεπτεμβρίου 2017

Skin advanced glycation content reflects vaginal tissue glycation level in relation to pregnancy

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Publication date: Available online 19 September 2017
Source:Medical Hypotheses
Author(s): Homayemem Weli, Jason Cooper, Ying Yang
A few studies have revealed that the advanced glycation content of the vaginal wall in pelvic organ prolapse tissues is elevated. This elevation makes advanced glycation a significant association with the disease. Early detection of vaginal wall glycation could therefore be relevant in the prevention and management of pelvic organ prolapse. A vaginal wall biopsy to detect this would be ideal, but is invasive. Therefore the use of a more accessible organ to access, such as skin, would be beneficial. Our previous independent study suggests that conditions such as pregnancy, can induce a change in the vaginal tissues' glycation content. The aim of this study was to assess whether the skin glycation undergoes similar changes as observed in vaginal tissue glycation in the same subjects in order to prove the hypothesis that skin advanced glycation content can predict vaginal tissue glycation. A rat model was used. The vaginal tissues from non-pregnant and E15-E18 pregnant rats and skin tissues from the same rats were taken for the measurement of advanced glycation content. The glycation marker, pentosidine, was quantified by a high performance liquid chromatography. Our results demonstrated that glycation content in vaginal wall tissues from pregnant rats was lower than the tissues from non-pregnant ones, and a strong positive association between skin and vaginal wall pentosidine level was observed. We conclude that skin pentosidine is reflective of vaginal wall pentosidine. Skin glycation may therefore be a potential tool in the prediction and management of pelvic organ prolapse.



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Contextual effects of surprised expressions on the encoding and recognition of emotional target faces: an event-related potential (ERP) study

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Publication date: Available online 20 September 2017
Source:Biological Psychology
Author(s): Huiyan Lin, Claudia Schulz, Thomas Straube
Several studies reported that the encoding and recognition of emotional target faces are modulated by negative contextual expressions. However, it is unknown whether other contextual expressions, such as emotionally ambiguous expressions, affect the encoding and recognition of target faces. To this end, electroencephalography (EEG) was recorded during the presentation of angry or happy target faces after a random sequence of surprised or neutral contextual faces that did not differ in normative valence ratings. Subsequently, participants were asked to perform an unexpected old/new recognition task in which target faces were shown in either the encoded or a non-encoded expression. During the encoding phase, event-related potential (ERP) results showed that surprised as compared to neutral contextual faces led to smaller late positive potentials (LPP) for happy but not for angry target faces. Similar effects were also observed in the N170, even though the interaction of context and target expression failed to reach statistical significance. In the later recognition phase, recognition rates were lower for encoded happy faces when they had been encountered in surprised as compared to neutral context, regardless of whether the target face showed the encoded or a non-encoded expression. However, this context effect was not observed for angry-encoded faces. Taken together, the present study indicates that ambiguous contextual expressions, e.g., surprised faces, affect structural and cognitive encoding and later recognition of happy target faces to a larger extent than neutral contextual faces; whereas angry faces are more resistant to context effects.



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Shopping for food with children: A strategy for directing their choices toward novel foods containing vegetables

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Publication date: 1 January 2018
Source:Appetite, Volume 120
Author(s): Xavier Allirot, Edurne Maiz, Elena Urdaneta
Involving children in the different steps of meal preparation has been suggested as a strategy for enhancing dietary habits in childhood. It has previously been shown that involving children in cooking can increase their willingness to taste novel foods and direct their food choices towards foods containing vegetables. The objective of the present study was to assess the effect of involving children in food purchasing on food choices, intake, liking and appetite. A between-subject experiment was conducted with 86 children (from 8 to 10 years old). Forty-three children (PURCHASE group) participated in a workshop dedicated to purchasing the necessary ingredients online for the preparation of three unfamiliar foods containing vegetables: apple and beetroot juice, zucchini tortilla sandwich and spinach cookies. Forty-three children (CONTROL group) participated instead in a creativity workshop. Afterwards, all the children were invited to choose, for an afternoon snack, between three familiar vs. unfamiliar foods: orange vs. apple and beetroot juice, potatoes vs. zucchini tortilla sandwich and chocolate vs. spinach cookie. The mean number of unfamiliar foods chosen per child was higher in the PURCHASE (0.70 ± 0.14) vs. CONTROL (0.19 ± 0.07) group (P = 0.003). The liking for 1 of the 3 unfamiliar foods was higher in the PURCHASE group (P < 0.05). We did not find any difference between the two groups in food intake estimation and in the levels of subjective appetite. This study demonstrates that involving children in purchasing food can help in directing their food choices towards unfamiliar foods containing vegetables. It highlights the importance of involving children in the different steps of meal preparation for decreasing food neophobia.



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Reading Faces: From Features to Recognition

Publication date: Available online 19 September 2017
Source:Trends in Cognitive Sciences
Author(s): J. Swaroop Guntupalli, M. Ida Gobbini
Chang and Tsao recently reported that the monkey face patch system encodes facial identity in a space of facial features as opposed to exemplars. Here, we discuss how such coding might contribute to face recognition, emphasizing the critical role of learning and interactions with other brain areas for optimizing the recognition of familiar faces.



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Evidence-based severity assessment: Impact of repeated versus single open-field testing on welfare in C57BL/6J mice

Publication date: 15 January 2018
Source:Behavioural Brain Research, Volume 336
Author(s): Carina Bodden, Sophie Siestrup, Rupert Palme, Sylvia Kaiser, Norbert Sachser, S. Helene Richter
According to current guidelines on animal experiments, a prospective assessment of the severity of each procedure is mandatory. However, so far, the classification of procedures into different severity categories mainly relies on theoretic considerations, since it is not entirely clear which of the various procedures compromise the welfare of animals, or, to what extent. Against this background, a systematic empirical investigation of the impact of each procedure, including behavioral testing, seems essential. Therefore, the present study was designed to elucidate the effects of repeated versus single testing on mouse welfare, using one of the most commonly used paradigms for behavioral phenotyping in behavioral neuroscience, the open-field test. In an independent groups design, laboratory mice (Mus musculus f. domestica) experienced either repeated, single, or no open-field testing – procedures that are assigned to different severity categories. Interestingly, testing experiences did not affect fecal corticosterone metabolites, body weights, elevated plus-maze or home cage behavior differentially. Thus, with respect to the assessed endocrinological, physical, and behavioral outcome measures, no signs of compromised welfare could be detected in mice that were tested in the open-field repeatedly, once, or, not at all. These findings challenge current classification guidelines and may, furthermore, stimulate systematic research on the severity of single procedures involving living animals.



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Isolation of 236U and 239,240Pu from seawater samples and its determination by Accelerator Mass Spectrometry

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Mercedes López-Lora, Elena Chamizo, María Villa-Alfageme, Santiago Hurtado-Bermúdez, Núria Casacuberta, Manuel García-León
In this work we present and evaluate a radiochemical procedure optimised for the analysis of 236U and 239,240Pu in seawater samples by Accelerator Mass Spectrometry (AMS). The method is based on Fe(OH)3 co-precipitation of actinides and uses TEVA® and UTEVA® extraction chromatography resins in a simplified way for the final U and Pu purification. In order to improve the performance of the method, the radiochemical yields are analysed in 1 to 10L seawater volumes using alpha spectrometry (AS) and Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Robust 80% plutonium recoveries are obtained; however, it is found that Fe(III) concentration in the precipitation solution and sample volume are the two critical and correlated parameters influencing the initial uranium extraction through Fe(OH)3 co-precipitation. Therefore, we propose an expression that optimises the sample volume and Fe(III) amounts according to both the 236U and 239,240Pu concentrations in the samples and the performance parameters of the AMS facility. The method is validated for the current setup of the 1MV AMS system (CNA, Sevilla, Spain), where He gas is used as a stripper, by analysing a set of intercomparison seawater samples, together with the Laboratory of Ion Beam Physics (ETH, Zürich, Switzerland).

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Polyaniline-dicationic ionic liquid coated with magnetic nanoparticles composite for magnetic solid phase extraction of polycyclic aromatic hydrocarbons in environmental samples

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Mohamad Shariff Shahriman, Muggundha Raoov Ramachandran, Nur Nadhirah Mohamad Zain, Sharifah Mohamad, Ninie Suhana Abdul Manan, Suhaila Mohd Yaman
In this present study, magnetic nanoparticles (MNPs) nanocomposites modified with polyaniline (PANI) coated newly synthesised dicationic ionic liquid (DICAT) forming MNP-PANI-DICAT were successfully synthesised as new generation material for magnetic solid phase extraction (MSPE). MNP-PANI-DICAT was characterised by FT-IR NMR, CHN, BET, SEM, TEM, and VSM techniques and the results were compared with MNP-PANI and native MNP. This new material was applied as a magnetic adsorbent for the pre-concentration and separation of polycyclic aromatic hydrocarbons (PAHs) due to the π–π interaction between polyaniline shell and dicationic ionic liquid (DICAT) with PAHs compounds. Under the optimal conditions, the proposed method was evaluated and applied for the analysis of PAHs in environmental samples using gas chromatography-mass spectrometry (GC-MS). The validation method showed good linearity (0.005–500µgL−1) with the coefficient of determination (R2) > 0.999. The limits of detection (LOD) and quantification (LOQ) of the developed method (MNP-PANI-DICAT-MSPE) were in the range of 0.0008–0.2086µgL−1 and 0.0024–0.6320µgL−1, respectively. The enrichment factor (EF) of PAHs on MNP-PANI-DICAT-MSPE were in the range of 7.546–29.632. The extraction recoveries of natural water, sludge, and soil samples were ranged from 80.2% to 111.9% with relative standard deviation (RSD) less than 5.6%. The newly synthesised MNP-PANI-DICAT possess good sensitivity, reusability, and fast extraction of PAHs under the MSPE procedure in various environmental samples.

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Quantitative study of zinc and metallothioneins in the human retina and RPE cells by mass spectrometry-based methodologies

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Sara Rodríguez-Menéndez, Beatriz Fernández, Montserrat García, Lydia Álvarez, Maria Luisa Fernández, Alfredo Sanz-Medel, Miguel Coca-Prados, Rosario Pereiro, Héctor González-Iglesias
The retina contains the highest concentration of zinc in the human eye and it is primarily associated with the retinal pigment epithelium (RPE). Metallothioneins (MTs) are the main cytosolic zinc-ion-binding proteins, exerting a tight control in the number of atoms of Zn-bound to the MTs related with their antioxidant and neuroprotective functions. In order to study the Zn-MT system in retina and RPE, we have implemented mass spectrometry (MS)-based technologies: two complementary element detection methodologies (HPLC- and laser ablation (LA)-ICP-MS) have been successfully employed to study metal content in the human eye as well as to perform speciation studies of Zn-MTs. First, Zn-elemental distribution was studied on cryogenic ocular sections by LA-ICP-MS. Quantitative images of Zn along RPE cell layer and the retina were obtained with a laser beam diameter of 25µm, showing a preferential distribution in the RPE. We carried out then the quantitative speciation of Zn, Fe, and Cu in the water-soluble protein fractions of RPE and retina to study their protein binding profile using HPLC-ICP-MS, where Zn is mainly associated to low molecular mass proteins (i.e., MTs). Finally, the effect of addition of different inductors, such as metal (i.e., 68ZnSO4), dexamethasone (DEX) and erythropoietin, was investigated in an in vitro cellular model of human RPE cells (HRPEsv), again using HPLC-ICP-MS in combination with stable isotopes and mathematical calculations based on isotope dilution and isotope pattern deconvolution. Exogenous Zn and DEX were found to increase MT proteins synthesis and exerted a stoichiometric transition in MT proteins in HRPEsv cells.

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Immunosurveillance of Malignant Cells with Complex Karyotypes

Publication date: Available online 19 September 2017
Source:Trends in Cell Biology
Author(s): Alejandro López-Soto, Segundo Gonzalez, Carlos López-Larrea, Guido Kroemer
A wide array of cell-intrinsic surveillance mechanisms maintains the homeostasis of dividing cells and the integrity of the genome. Accumulating evidence also supports a role for cell-extrinsic mechanisms. Among them, the immune system, together with cell-autonomous checkpoint processes, eliminates cells that harbor unbalanced karyotypes generated by mitotic defects.



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Qualitative differences in offline improvement of procedural memory by daytime napping and overnight sleep: an fMRI study

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Publication date: Available online 20 September 2017
Source:Neuroscience Research
Author(s): Sho K. Sugawara, Takahiko Koike, Hiroaki Kawamichi, Kai Makita, Yuki H. Hamano, Haruka K. Takahashi, Eri Nakagawa, Norihiro Sadato
Daytime napping offers various benefits for healthy adults, including enhancement of motor skill learning. It remains controversial whether napping can provide the same enhancement as overnight sleep, and if so, whether the same neural underpinning is recruited. To investigate this issue, we conducted functional MRI during motor skill learning, before and after a short day-nap, in 13 participants, and compared them with a larger group (N=47) who were tested following regular overnight sleep. Training in a sequential finger-tapping task required participants to press a keyboard in the MRI scanner with their non-dominant left hand as quickly and accurately as possible. The nap group slept for 60minutes in the scanner after the training run, and the previously trained skill was subsequently re-tested. The whole-night sleep group went home after the training, and was tested the next day. Offline improvement of speed was observed in both groups, whereas accuracy was significantly improved only in the whole-night sleep group. Correspondingly, the offline increment in task-related activation was significant in the putamen of the whole-night group. This finding reveals a qualitative difference in the offline improvement effect between daytime napping and overnight sleep.



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Role of the epigenetic factor Sirt7 in neuroinflammation and neurogenesis

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Publication date: Available online 20 September 2017
Source:Neuroscience Research
Author(s): Nicolas Burg, Stefan Bittner, Erik Ellwardt
Epigenetic regulators are increasingly recognized as relevant modulators in the immune and nervous system. The class of sirtuins consists of NAD+-dependent histone deacetylases that regulate transcription. Sirtuin family member Sirt1 has already been shown to influence the disease course in an animal model of autoimmune neuroinflammation (experimental autoimmune encephalomyelitis (EAE)). A role of Sirt7, a related epigenetic regulator, on immune system regulation has been proposed before, as these mice are more susceptible to develop inflammatory cardiomyopathy. Sirt7−/− animals showed no differences in clinical score compared to wild-type littermates after EAE induction with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55, although we found subtle immune alterations at different phases of EAE and decreased survival of newly generated neurons in the hippocampus. Our data indicate that Sirt7 has a slight protective impact on both the adaptive immune system and neurogenesis. However, overall this epigenetic factor is not capable of impacting the acute or chronic phase of neuroinflammation.



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IFC (editorial board)

Publication date: October 2017
Source:Peptides, Volume 96





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The International Neuropeptide society pages

Publication date: October 2017
Source:Peptides, Volume 96





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Gayle & Richard Olson prize pages

Publication date: October 2017
Source:Peptides, Volume 96





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A Deep Learning Approach to Estimate Chemically-Treated Collagenous Tissue Nonlinear Anisotropic Stress-Strain Responses from Microscopy Images

Publication date: Available online 20 September 2017
Source:Acta Biomaterialia
Author(s): Liang Liang, Minliang Liu, Wei Sun
Biological collagenous tissues comprised of networks of collagen fibers are suitable for a broad spectrum of medical applications owing to their attractive mechanical properties. In this study, we developed a noninvasive approach to estimate collagenous tissue elastic properties directly from microscopy images using Machine Learning (ML) techniques. Glutaraldehyde-treated bovine pericardium (GLBP) tissue, widely used in the fabrication of bioprosthetic heart valves and vascular patches, was chosen to develop a representative application. A Deep Learning model was designed and trained to process second harmonic generation (SHG) images of collagen networks in GLBP tissue samples, and directly predict the tissue elastic mechanical properties. The trained model is capable of identifying the overall tissue stiffness with a classification accuracy of 84%, and predicting the nonlinear anisotropic stress-strain curves with average regression errors of 0.021 and 0.031. Thus, this study demonstrates the feasibility and great potential of using the Deep Learning approach for fast and noninvasive assessment of collagenous tissue elastic properties from microstructural images.Statement of SignificanceIn this study, we developed, to our best knowledge, the first Deep Learning-based approach to estimate the elastic properties of collagenous tissues directly from noninvasive second harmonic generation images. The success of this study holds promise for the use ofMachine Learning techniques to noninvasively and efficiently estimate the mechanical properties of many structure-based biological materials, and italso enables many potential applications such as serving as a quality control tool to select tissue for the manufacturing of medical devices (e.g. bioprosthetic heart valves).

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Poly-ADP ribosylation in DNA damage response and cancer therapy

Publication date: Available online 20 September 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Wei-Hsien Hou, Shih-Hsun Chen, Xiaochun Yu
Poly(ADP-ribosyl)ation (aka PARylation) is a unique protein post-translational modification (PTM) first described over 50 years ago. PARylation regulates a number of biological processes including chromatin remodeling, the DNA damage response (DDR), transcription, apoptosis, and mitosis. The subsequent discovery of poly(ADP-ribose) polymerase-1 (PARP-1) catalyzing DNA-dependent PARylation spearheaded the field of DDR. The expanding knowledge about the poly ADP-ribose (PAR) recognition domains prompted the discovery of novel DDR factors and revealed crosstalk with other protein PTMs including phosphorylation, ubiquitination, methylation and acetylation. In this review, we highlight the current knowledge on PAR-regulated DDR, PAR recognition domain, and PARP inhibition in cancer therapy.



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Quantitative study of zinc and metallothioneins in the human retina and RPE cells by mass spectrometry-based methodologies

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Sara Rodríguez-Menéndez, Beatriz Fernández, Montserrat García, Lydia Álvarez, Maria Luisa Fernández, Alfredo Sanz-Medel, Miguel Coca-Prados, Rosario Pereiro, Héctor González-Iglesias
The retina contains the highest concentration of zinc in the human eye and it is primarily associated with the retinal pigment epithelium (RPE). Metallothioneins (MTs) are the main cytosolic zinc-ion-binding proteins, exerting a tight control in the number of atoms of Zn-bound to the MTs related with their antioxidant and neuroprotective functions. In order to study the Zn-MT system in retina and RPE, we have implemented mass spectrometry (MS)-based technologies: two complementary element detection methodologies (HPLC- and laser ablation (LA)-ICP-MS) have been successfully employed to study metal content in the human eye as well as to perform speciation studies of Zn-MTs. First, Zn-elemental distribution was studied on cryogenic ocular sections by LA-ICP-MS. Quantitative images of Zn along RPE cell layer and the retina were obtained with a laser beam diameter of 25µm, showing a preferential distribution in the RPE. We carried out then the quantitative speciation of Zn, Fe, and Cu in the water-soluble protein fractions of RPE and retina to study their protein binding profile using HPLC-ICP-MS, where Zn is mainly associated to low molecular mass proteins (i.e., MTs). Finally, the effect of addition of different inductors, such as metal (i.e., 68ZnSO4), dexamethasone (DEX) and erythropoietin, was investigated in an in vitro cellular model of human RPE cells (HRPEsv), again using HPLC-ICP-MS in combination with stable isotopes and mathematical calculations based on isotope dilution and isotope pattern deconvolution. Exogenous Zn and DEX were found to increase MT proteins synthesis and exerted a stoichiometric transition in MT proteins in HRPEsv cells.

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Chemical-free fabrication of N, P dual-doped honeycomb-like carbon as an efficient electrocatalyst for oxygen reduction

Publication date: 15 January 2018
Source:Journal of Colloid and Interface Science, Volume 510
Author(s): Lianwen Zhu, Jun Wu, Qiao Zhang, Xiangkui Li, Yiming Li, Xuebo Cao
Heteroatom-doped nanoporous carbons are now emerging as alternatives to platinum and its alloys as electrocatalysts to facilitate oxygen reduction reaction in metal-air batteries and fuel cells. However, the synthesis of nanoporous carbons usually involve in complicated procedures and intensive chemicals, which may dramatically raise their manufacture cost that even surpasses that of precious platinum. Herein, we demonstrate the single-step, chemical-free fabrication of N, P dualdoped honeycomb carbon that has hierarchically porous structure and oxygen electrocatalysis activity close to the benchmark Pt/C. This material was fabricated through the direct pyrolysis of popcorn in a static, semi-opened environment. With this strategy, nitrous and phosphoric groups from proteins and phosphates within the popcorn are condensed with graphitic matrix to form NC and PC bonds, and pyrolysis byproducts (such as H2O and CO2) can etch disordered carbon domains to form hierarchical pores and edge carbons. Practical test of this honeycomb carbon as air electrode of a primary Zn-air battery shows an open-circuit potential of 1.44V and peak power density of 36.6mWcm−2 that is even better than Pt/C. The impact of this work is that it will facilitate the targeted design and cost-saved fabrication of metal-free catalysts for electrocatalytic applications.

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Mechanochemical destruction of DDTs with Fe-Zn bimetal in a high-energy planetary ball mill

Publication date: 15 January 2018
Source:Journal of Hazardous Materials, Volume 342
Author(s): Hong Sui, Yuzhou Rong, Jing Song, Dongge Zhang, Haibo Li, Peng Wu, Yangyang Shen, Yujuan Huang
Mechanochemical destruction has been proposed as a promising, non-combustion technology for the disposal of toxic, halogenated, organic pollutants. In the study presented, additives including Fe, Zn, Fe-Zn bimetal, CaO and Fe2O3 were tested for their effectiveness to remove DDTs by MC. The results showed that Fe-Zn bimetal was the most efficient additive, with 98% of DDTs removed after 4h. The Fe-Zn mass ratio was optimized to avoid possible spontaneous combustion of the ground sample during subsample collection. Inorganic water-soluble chloride in the ground sample increased by 91% after 4h of grinding, which indicated dechlorination during destruction of DDTs. In addition, relationships were established between the rate constant and the rotation speed or the charge ratio. Discrete Element Method (DEM) modeling was used to simulate the motion of the grinding ball and calculate both total impact energy and normal impact energy. The latter expressed a stronger, linear correlation with the rate constant. Therefore, normal impact energy is proposed to be the main driving force in the MC destruction of DDTs.



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A novel bioreactor system for simultaneous mutli-metal leaching from industrial pyrite ash: Effect of agitation and sulphur dosage

Publication date: 15 January 2018
Source:Journal of Hazardous Materials, Volume 342
Author(s): Sandeep Panda, Ata Akcil, Srabani Mishra, Ceren Erust
Simultaneous multi-metal leaching from industrial pyrite ash is reported for the first time using a novel bioreactor system that allows natural diffusion of atmospheric O2 and CO2 along with the required temperature maintenance. The waste containing economically important metals (Cu, Co, Zn & As) was leached using an adapted consortium of meso-acidophilic Fe2+ and S oxidising bacteria. The unique property of the sample supported adequate growth and activity of the acidophiles, thereby, driving the (bio) chemical reactions. Oxido-reductive potentials were seen to improve with time and the system's pH lowered as a result of active S oxidation. Increase in sulphur dosage (>1g/L) and agitation speed (>150rpm) did not bear any significant effect on metal dissolution. The consortium was able to leach 94.01% Cu (11.75% dissolution/d), 98.54% Co (12.3% dissolution/d), 75.95% Zn (9.49% dissolution/d) and 60.80% As (7.6% dissolution/d) at 150rpm, 1g/L sulphur, 30°C in 8days.

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A novel method for the sequential removal and separation of multiple heavy metals from wastewater

Publication date: 15 January 2018
Source:Journal of Hazardous Materials, Volume 342
Author(s): Li Fang, Liang Li, Zan Qu, Haomiao Xu, Jianfang Xu, Naiqiang Yan
A novel method was developed and applied for the treatment of simulated wastewater containing multiple heavy metals. A sorbent of ZnS nanocrystals (NCs) was synthesized and showed extraordinary performance for the removal of Hg2+, Cu2+, Pb2+ and Cd2+. The removal efficiencies of Hg2+, Cu2+, Pb2+ and Cd2+ were 99.9%, 99.9%, 90.8% and 66.3%, respectively. Meanwhile, it was determined that solubility product (Ksp) of heavy metal sulfides was closely related to adsorption selectivity of various heavy metals on the sorbent. The removal efficiency of Hg2+ was higher than that of Cd2+, while the Ksp of HgS was lower than that of CdS. It indicated that preferential adsorption of heavy metals occurred when the Ksp of the heavy metal sulfide was lower. In addition, the differences in the Ksp of heavy metal sulfides allowed for the exchange of heavy metals, indicating the potential application for the sequential removal and separation of heavy metals from wastewater. According to the cumulative adsorption experimental results, multiple heavy metals were sequentially adsorbed and separated from the simulated wastewater in the order of the Ksp of their sulfides. This method holds the promise of sequentially removing and separating multiple heavy metals from wastewater.

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Vitamin D and intestinal calcium transport after bariatric surgery

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Anne L. Schafer
Bariatric surgery is a highly effective treatment for obesity, but it may have detrimental effects on the skeleton. Skeletal effects are multifactorial but mediated in part by nutrient malabsorption. While there is increasing interest in non-nutritional mechanisms such as changes in fat-derived and gut-derived hormones, nutritional factors are modifiable and thus represent potential opportunities to prevent and treat skeletal complications. This review begins with a discussion of normal intestinal calcium transport, including recent advances in our understanding of its regulation by vitamin D, and areas of continued uncertainty. Human and animal studies of vitamin D and intestinal calcium transport after bariatric surgery are then summarized. In humans, even with optimized 25-hydroxyvitamin D levels and recommended calcium intake, fractional calcium absorption decreased dramatically after Roux-en-Y gastric bypass (RYGB). In rats, intestinal calcium absorption was lower after RYGB than after sham surgery, despite elevated 1,25-dihyroxyvitamin D levels and intestinal gene expression evidence of vitamin D responsiveness. Such studies have the potential to shed new light on the physiology of vitamin D and intestinal calcium transport. Moreover, understanding the effects of bariatric surgery on these processes may improve the clinical care of bariatric surgery patients.



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Highlights from the 19th Workshop on Vitamin D in Boston, March 29–31, 2016

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Sylvia Christakos, John H. White, Martin Hewison, JoEllen Welsh, Paul Lips, Roger Bouillon, Marie B. Demay




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25-hydroxyvitamin D is associated with adiposity and cardiometabolic risk factors in a predominantly vitamin D-deficient and overweight/obese but otherwise healthy cohort

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Aya Mousa, Negar Naderpoor, Maximilian P.J. de Courten, Robert Scragg, Barbora de Courten
Vitamin D deficiency has reached epidemic proportions worldwide and has recently been linked to cardiometabolic risk factors including obesity, insulin resistance, hypertension, dyslipidemia, as well as type 2 diabetes and cardiovascular disease. The objective of this study was to examine the associations between circulating 25-hydrovitamin D (25(OH)D) levels and cardiometabolic risk factors using direct measures of adiposity, glucose intolerance, and insulin resistance, as well as lipids, blood pressure, and plasma markers of inflammation. We measured circulating 25(OH)D, physical activity (International Physical Activity Questionnaire- IPAQ), anthropometry (body mass index (BMI), waist-to-hip ratio (WHR), % body fat (dual energy X-ray absorptiometry)), metabolic parameters (fasting and 2-h plasma glucose levels during oral glucose tolerance test; insulin sensitivity (M, hyperinsulinaemic-euglycaemic clamp), and cardiovascular and inflammatory profiles (blood pressure (BP), pulse pressure (PP), mean arterial pressure (MAP), plasma lipid levels, white blood cell count (WBC), and plasma high-sensitivity C-reactive protein levels (hsCRP)) in 111 healthy, non-diabetic adults (66 males/45 females; age 31.1±9.2years; % body fat 36.0±10.2%). Mean 25(OH)D was 39.8±19.8 nmol/L with no difference between genders (p=0.4). On univariate analysis, 25(OH)D was associated with% body fat (r=−0.27; p=0.005), 2-h glucose (r=−0.21; p=0.03), PP (r=0.26; p=0.006), and insulin sensitivity (r=0.20, p=0.04), but not with age, BMI, WHR, fasting glucose, BP, MAP, lipids, or inflammatory markers (all p>0.05). After adjusting for age and sex, 25(OH)D remained associated with% body fat (β=−0.12%; p=0.003), 2-h glucose (β=−0.13mmol/L; p=0.02), PP (β=0.12mmHg; p=0.009), and insulin sensitivity (β=0.22mg/kg/min; p=0.03), and became associated with fasting glucose (β=−0.04mmol/L; p=0.04) and hsCRP (β=−0.51mg/L; p=0.04). After adjusting for age, sex, and % body fat, 25(OH)D was no longer associated with insulin sensitivity, 2-h glucose, or hsCRP, but remained associated with fasting glucose (β=−0.05mmol/L; p=0.03) and PP (β=0.10mmHg; p=0.03). 25(OH)D remained associated with fasting glucose (β=−0.06mmol/L; p=0.02) after hsCRP and physical activity were added to the model with % body fat, age, and sex. ​These cross-sectional data suggest that associations between vitamin D and cardiometabolic risk among healthy, non-diabetic adults are largely mediated by adiposity. Large-scale intervention and mechanistic studies are needed to further investigate whether vitamin D has an independent role in the prevention and/or management of cardiometabolic risk and disease.



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Editorial board

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173





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Synthesis of the CYP24A1 major metabolite of 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Masashi Takano, Kaori Yasuda, Eri Tohyama, Erika Higuchi, Toshiyuki Sakaki, Atsushi Kittaka
Previously, we found that 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 (AH-1) showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect on ovariectomized (OVX) rats for enhancing bone mineral density than those of 1α,25(OH)2D3 without hypercalcemic side effects in vivo. Although CYP24A1 catalyzes multi-step oxidations toward the CD-ring side chain of the active vitamin D3 [1α,25(OH)2D3], the CYP24A1-dependent metabolism of AH-1 tended to stop at the first step hydroxylation at the C24-position of AH-1. Interestingly, the metabolite 24-hydroxy-AH-1 [24(OH)AH-1] showed potent VDR binding affinity, and the new chiral center of the 24-position might be the 24R configuration compared with the process of the natural 1α,25(OH)2D3 catabolism. This time, (24R)-2α-[2-(tetrazol-2-yl)ethyl]-1α,24,25-trihydroxyvitamin D3 [(24R-OH)AH-1] was synthesized as a candidate for the major metabolite of AH-1 using the Trost Pd-mediated coupling reaction between A-ring and CD-ring precursors to identify the metabolite and evaluate its biological activity. We confirmed that the CYP24A1-dependent major metabolite of AH-1 was (24R-OH)AH-1 by HPLC analyses.

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Correction of vitamin D deficiency using sublingually administered vitamin D2 in a Crohn’s disease patient with mal-absorption and a new ileostomy

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Patrick McCullough, Robert Heaney
Vitamin D deficiency has been shown to be associated with many adverse health problems. Studies have shown that patients with Crohn's disease who have low vitamin D levels have a poorer quality of life than those with more adequate levels. It has also been shown that patients with mal-absorption problems have a difficult time achieving normal vitamin D levels in spite of aggressive supplementation, and that exposure to UVB radiation may be the most effective treatment option for these patients. We present a case in which 25-hydroxyvitamin D levels were normalized within 2 weeks in a severely vitamin D deficient patient with Crohn's disease with mal-absorption and a new ileostomy, utilizing sublingually administered vitamin D2. A 58 year-old white female was admitted with a new ileostomy following partial bowel resection due to complications from Crohn's disease. She was found to be severely vitamin D deficient at the time of admission, with a level of 6.1ng/ml on hospital day 3. Her treatment with vitamin D was delayed for a few days. She was initially treated with 5000 units of vitamin D3 orally twice a day for 3days (days 7–10). After discussion with the patient and obtaining her consent, vitamin D3 was stopped, and she was then treated with a total of 8 doses of 50,000 units of vitamin D2 administered sublingually. She was given the first 3 doses on alternating days (days 11, 13, 15), and then 5 more doses on consecutive days (days 17–21). The rise in her 25-hydroxyvitamin D level in response to treatment with sublingual vitamin D2 was significant. On day 10, after receiving 3days of orally administered vitamin D3, her level was 9.8ng/ml. One week later, after receiving 3 sublingual doses of vitamin D2, it rose to 20.3ng/ml. It was then measured on alternating days twice over the next 4days, and it rose to 45.5ng/ml, and then to 47.4ng/ml on the day of discharge to home. The major finding of this study is that sublingual administration of vitamin D2 appears to work effectively when intestinal absorption is impaired. The optimal dosing regimen still needs to be determined for the average Crohn's disease patient.



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Vitamin D measurement standardization: The way out of the chaos

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): N. Binkley, B. Dawson-Hughes, R. Durazo-Arvizu, M. Thamm, L. Tian, J.M. Merkel, J.C. Jones, G.D. Carter, C.T. Sempos
Substantial variability is associated with laboratory measurement of serum total 25-hydroxyvitamin D [25(OH)D]. The resulting chaos impedes development of consensus 25(OH)D values to define stages of vitamin D status. As resolving this situation requires standardized measurement of 25(OH)D, the Vitamin D Standardization Program (VDSP) developed methodology to standardize 25(OH)D measurement to the gold standard reference measurement procedures of NIST, Ghent University and CDC. Importantly, VDSP developed protocols for standardizing 25(OH)D values from prior research based on availability of stored serum samples. The effect of such retrospective standardization on prevalence of "low" vitamin D status in national studies reported here for The Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) and the German Health Interview and Examination Survey for Children and Adolescents (KIGGS, 2003–2006) was such that in NHANES III 25(OH)D values were lower than original values while higher in KIGGS. In NHANES III the percentage with values below 30, 50 and 75 nmol/L increased from 4% to 6%, 22% to 31% and 55% to 71%, respectively. Whereas in KIGGS after standardization the percentage below 30, 50, and 70 nmol/L decreased from 28% to 13%, 64% to 47% and 87% to 85% respectively. Moreover, in a hypothetical example, depending on whether the 25(OH)D assay was positively or negatively biased by 12%, the 25(OH)D concentration which maximally suppressed PTH could vary from 20 to 35ng/mL. These examples underscore the challenges (perhaps impossibility) of developing vitamin D guidelines using unstandardized 25(OH)D data. Retrospective 25(OH)D standardization can be applied to old studies where stored serum samples exist. As a way forward, we suggest an international effort to identify key prior studies with stored samples for re-analysis and standardization initially to define the 25(OH)D level associated with vitamin D deficiency (rickets/osteomalacia). Subsequent work could focus on defining inadequacy. Finally, examples reported here highlight the importance of suspending publication of meta-analyses based on unstandardized 25(OH)D results.



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Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Naing Lin Shan, Joseph Wahler, Hong Jin Lee, Min Ji Bak, Soumyasri Das Gupta, Hubert Maehr, Nanjoo Suh
Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH)2D3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH)2D3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest that vitamin D compounds may serve as potential preventive agents to inhibit triple negative breast cancer by regulating cancer stem cells and differentiation.



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Vitamin D and type 2 diabetes

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Paul Lips, Marelise Eekhoff, Natasja van Schoor, Mirjam Oosterwerff, Renate de Jongh, Yvonne Krul-Poel, Suat Simsek
Vitamin D deficiency is associated with a decreased insulin release, insulin resistance and type 2 diabetes in experimental and epidemiological studies. Animal studies show that 1α,25–dihydroxyvitamin D3 (1,25(OH)2D3) stimulates the pancreatic β-cell to secrete insulin. The relationship between vitamin D deficiency and insulin resistance could develop through inflammation, as vitamin D deficiency is associated with increased inflammatory markers. In addition, genetic polymorphisms of vitamin D −related genes may predispose to impaired glycemic control and type 2 diabetes. Epidemiologic studies showed an association between low serum 25-hydroxyvitamin D3 (25(OH)D3) concentration and an increased risk for the metabolic syndrome and type 2 diabetes. This may be partly explained by an increased fat mass. A possible causal relationship between vitamin D deficiency and type 2 diabetes should be proven by randomized clinical trials showing that either type 2 diabetes can be prevented or insulin release and insulin sensitivity can be improved by vitamin D supplements. The results of randomized clinical trials on the effect of vitamin D versus placebo, sometimes combined with calcium, in patients with impaired glucose tolerance ("prediabetes") or type 2 diabetes are inconsistent. Some studies showed a slight decrease of fasting plasma glucose or improvement of insulin resistance, but often only in posthoc analyses. These effects are mainly visible in patients with vitamin D deficiency and impaired glucose tolerance at baseline. Meta-analyses of randomized clinical trials in general did not show significant effects of vitamin D supplementation on glycemic control. Currently, several large scale randomized clinical trials with vitamin D supplementation in doses of 1600–4000IU/d are ongoing with glycemic control or incidence of diabetes mellitus as outcome. Vitamin D deficiency needs to be prevented or cured, but until the results of these trials are published, high-dose vitamin D supplementation cannot be recommended for prevention or amelioration of type 2 diabetes.



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Integrative genomic approaches to dissect clinically-significant relationships between the VDR cistrome and gene expression in primary colon cancer

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Mark D. Long, Moray J. Campbell
Recently, we undertook a pan-cancer analyses of the nuclear hormone receptor (NR) superfamily in The Cancer Genome Atlas (TCGA), and revealed that the vitamin D receptor (NR1I1/VDR) was commonly and significantly down-regulated specifically in colon adenocarcinoma cohort (COAD). To examine the consequence of down-regulated VDR expression we re-analyzed VDR chromatin immunoprecipitation sequencing (ChIP-Seq) data from LS180 colon cancer cells (GSE31939). This analysis identified 1809 loci that displayed significant (p.adj<0.01) differential binding of the VDR in response 1,25(OH)2D3 treatment; 947 peaks annotated to 672 genes. We examined expression patterns in the COAD cohort of 286 tumors compared to 41 normal samples and revealed that VDR bound genes were significantly positively correlated to VDR expression compared to the background transcriptome, suggesting direct regulation by VDR. Gene set enrichment analyses revealed significant enrichment for genes known to be regulated by a number of other transcription factors including SMADs and JUN. Filtering VDR associated genes for those that were commonly and significantly altered in COAD revealed a cohort of 27 differentially expressed genes. The expression patterns of these genes clustered tumors and significantly associated with disease free survival. For instance, males with low expression of Lectin, Galactoside Binding Soluble 4 (LGALS4, encodes the colon tumor suppressor, Galactin 4) had significantly shorted disease free survival. These analyses suggest that reduced expression of VDR in colon cancer (but neither loss nor mutation) changes the actions of the VDR by both dampening the expression of tumor suppressors (e.g. LGALS4) whilst either stabilizing or not down-regulating expression of oncogenes (e.g. Carbonic Anhydrase 9 (CA9)). These integrative genomic approaches are relatively generic and applicable to the study of any transcription factor.



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Results of daily oral dosing with up to 60,000 international units (iu) of vitamin D3 for 2 to 6 years in 3 adult males

Publication date: October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 173
Author(s): Patrick McCullough, Jeffrey Amend
In the 1930's and 1940's, vitamin D was reported to be an effective treatment for a number of diseases, including asthma, psoriasis, rheumatoid arthritis, rickets and tuberculosis. High doses were used, 60,000 to 300,000 IU a day for asthma, and 200,000 to 600,000 IU a day for rheumatoid arthritis. Toxicity from hypercalcemia occurred after prolonged oral dosing with these supraphysiologic doses. Assays for measuring vitamin D in the blood were not available, and blood levels of vitamin D associated with hypercalcemia were unknown. A 2011 report on vitamin D toxicity showed that hypercalcemia resolved when 25-hydroxyvitamin D (25OHD) blood levels dropped below 400ng/ml in 2 patients with blood levels ranging from 645ng/ml to 1220ng/ml after accidental ingestion of massive doses of vitamin D. We now know that vitamin D is made in the skin in amounts ranging up to 25,000 IU a day with exposure to UVB radiation. There is little data on the safety and blood levels of 25OHD and calcium after prolonged daily intake of amounts of vitamin D in this range. In this report, one subject took increasing daily doses of vitamin D3 for 6 years starting in April 2009: 6500 IU for 6 months; increasing to 10,000 IU for 13 months; 20,000 IU for 24 months; 40,000 IU for 12 months; 50,000 IU for 10 months, and 60,000 IU since October 2014. 25OHD blood levels were 28, 81, 204, 216, 225, 166, and 218ng/ml. Subject 2 began 10,000 IU in Nov 2011, increased to 20,000 IU in Feb 2014, 25,000 IU in June 2014, and 30,000 IU in Oct 2014, and then decreased to 20,000 IU in June 2015. 25OHD blood levels were 96.6, 161.1 and 106.9ng/ml. He reported marked clinical improvement in his asthma. Subject 3 started on daily 10,000 IU in Sept 2013, increasing to 20,000 IU on Nov 2013. 25OHD blood levels were 31.4, 102, 164, 148, and 143ng/ml. No one developed hypercalcemia or any adverse events. The major finding of this case series is prolonged daily dosing of vitamin D3 with doses of 10,000 to 60,000 IU was safely tolerated.



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The spatial distribution and accumulation characteristics of heavy metals in steppe soils around three mining areas in Xilinhot in Inner Mongolia, China

Abstract

Metal deposition has become a major environmental problem in China due to its adverse effects on human and ecosystem health, particularly in Inner Mongolia, where frequent dust storms (due to steppe degradation and desertification) and soil pollution (associated with the increasing mining activities) have occurred in recent decades. To assess spatial distribution of heavy metals and the influences of mining activities on geochemical behavior of heavy metals in soils, soil samples with depth of 0–10, 10–20, and 20–30 cm at each site were collected from different directions in the vicinity of three mines (coal mine, gold mine, and fluorite mine) in a typical steppe zone of Inner Mongolia, China. Six elements (Cd, Pb, Zn, Cr, Cu, and Ni) in the soils were analyzed using inductively coupled plasma emission spectrometer (ICP-OES). The results indicated that the average concentrations of Cd, Pb, Zn, Cr, Cu, and Ni in the soil of the study area around three mines were lower than the second class level of the National Soil Environment Safety Standard, but mostly were higher than the background value of soil in the Inner Mongolia. Northwest, southwest, and northeast wind directions have a great influence on the distribution of metals in coal, gold, and fluorite mine area, respectively. The concentration of heavy metals in coal, gold, and fluorite increased with the distance from the center of the mine, then reached a peak, then decreased gradually. The vertical mobility of metals in soil profiles was slightly significant for Cd > Cr > Zn > Ni in coal mine area and was not significant in gold and fluorite mines. Multivariate statistical methods such as principal component analysis and cluster analysis, coupled with correlation coefficient analysis, showed that Cd, Cu, Cr, and Ni in the mining area came from the same source, while Zn and Pb came from the other source. That the sources of heavy metals in the mining area were discussed would not only enhance our knowledge regarding the soil pollution status in the study area but would also provide us information to manage the sources of these elements in the study area.



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Down-regulation of NOX2 activity in phagocytes mediated by ATM-kinase dependent phosphorylation

Publication date: December 2017
Source:Free Radical Biology and Medicine, Volume 113
Author(s): Sylvain Beaumel, Antoine Picciocchi, Franck Debeurme, Corinne Vivès, Anne-Marie Hesse, Myriam Ferro, Didier Grunwald, Heather Stieglitz, Pahk Thepchatri, Susan M.E. Smith, Franck Fieschi, Marie José Stasia
NADPH oxidases (NOX) have many biological roles, but their regulation to control production of potentially toxic ROS molecules remains unclear. A previously identified insertion sequence of 21 residues (called NIS) influences NOX activity, and its predicted flexibility makes it a good candidate for providing a dynamic switch controlling the NOX active site. We constructed NOX2 chimeras in which NIS had been deleted or exchanged with those from other NOXs (NIS1, 3 and 4). All contained functional heme and were expressed normally at the plasma membrane of differentiated PLB-985 cells. However, NOX2-ΔNIS and NOX2-NIS1 had neither NADPH-oxidase nor reductase activity and exhibited abnormal translocation of p47phox and p67phox to the phagosomal membrane. This suggested a functional role of NIS. Interestingly after activation, NOX2-NIS3 cells exhibited superoxide overproduction compared with wild-type cells. Paradoxically, the Vmax of purified unstimulated NOX2-NIS3 was only one-third of that of WT-NOX2. We therefore hypothesized that post-translational events regulate NOX2 activity and differ between NOX2-NIS3 and WT-NOX2. We demonstrated that Ser486, a phosphorylation target of ataxia telangiectasia mutated kinase (ATM kinase) located in the NIS of NOX2 (NOX2-NIS), was phosphorylated in purified cytochrome b558 after stimulation with phorbol 12-myristate-13-acetate (PMA). Moreover, ATM kinase inhibition and a NOX2 Ser486Ala mutation enhanced NOX activity whereas a Ser486Glu mutation inhibited it. Thus, the absence of Ser486 in NIS3 could explain the superoxide overproduction in the NOX2-NIS3 mutant. These results suggest that PMA-stimulated NOX2-NIS phosphorylation by ATM kinase causes a dynamic switch that deactivates NOX2 activity. We hypothesize that this downregulation is defective in NOX2-NIS3 mutant because of the absence of Ser486.

Graphical abstract

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Vascularite cutanée induite par l’amiodarone

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Publication date: Available online 19 September 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): M. Ndiaye, B. Lebrun-Vignes, N. Ortonne, L. Fardet
IntroductionLes vascularites médicamenteuses peuvent être provoquées par une large variété de médicaments. Nous décrivons le cas d'un patient présentant une vascularite induite par l'amiodarone.ObservationUn homme de 57 ans rapportait un prurit d'apparition récente, rapidement associé à de larges plaques érythémateuses inflammatoires et nécrotiques des membres inférieurs et du dos. Ces lésions étaient apparues 6 semaines après l'introduction d'un traitement par amiodarone, prescrit pour des troubles du rythme supra-ventriculaires. Le diagnostic histologique (biopsie cutanée standard et immunofluorescence directe) était celui d'une vascularite avec présence de dépôts d'IgM et de C3 sur les vaisseaux. Le reste du bilan était sans particularité, notamment sans auto-anticorps ni cryoglobulinémie. Le patient imputait ses symptômes à l'introduction récente du traitement par amiodarone et l'arrêtait spontanément, sans avis médical. Aucun autre traitement n'était prescrit. Toutes les lésions, présentes depuis plus de 4 mois, disparaissaient alors rapidement et ne récidivaient pas (recul de 12 mois). Le diagnostic de vascularite médicamenteuse à l'amiodarone était retenu sur des critères d'imputabilité intrinsèque et extrinsèque compatibles et sur un recul de plusieurs mois sans récidive.DiscussionMoins de dix cas de vascularite induite par l'amiodarone sont disponibles dans la littérature médicale. On ne sait pas si cette entité est exceptionnelle, sous-diagnostiquée ou sous-rapportée.BackgroundA wide variety of drugs can cause cutaneous vasculitis. Herein we report a case of immune complex vasculitis induced by amiodarone.Patients and methodsA 57-year-old patient reported a recent history of pruritus associated with large erythematous, inflammatory, necrotic plaques localized on the lower limbs and back. These cutaneous lesions had appeared less than 2 months after initiation of amiodarone for supra-ventricular arrhythmia. Histological and direct immunofluorescence examinations of a skin biopsy sample revealed vasculitis with the presence of IgM and C3 immune complexes in vessels. The remaining laboratory tests were unremarkable (in particular, cryoglobulin and autoantibody tests were negative). The patient himself attributed his symptoms to the recent administration of amiodarone and spontaneously stopped the drug without medical advice. No other therapy was prescribed. Following drug withdrawal, the lesions that had been present for more than 4 months completely disappeared. No recurrence occurred after follow-up of over 6 months. The diagnosis of amiodarone-induced vasculitis was retained.DiscussionFewer than 10 cases of amiodarone-induced vasculitis have been reported in the medical literature. It is not known whether this entity is rare, under-diagnosed or under-reported.



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Transient increase in sAPPα secretion in response to Aß1-42 oligomers: an attempt of neuronal self-defense?

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Publication date: Available online 19 September 2017
Source:Neurobiology of Aging
Author(s): Christiane Rose, Emilie Dorard, Mickael Audrain, Lucie Gorisse-Hussonnois, Nathalie Cartier, Jérome Braudeau, Bernadette Allinquant
Amyloid Precursor Protein (APP), key molecule of Alzheimer disease is metabolized in two antagonist pathways generating the sAPPα having neuroprotective properties and the amyloid peptide (Aß) at the origin of neurotoxic oligomers, particularly Aß1-42. Whether extracellular Aß1-42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aß1-42 oligomers to primary cortical neurons induced a transient increase in alpha secretase activity and secreted sAPPα 6-9 h later. Preventing the generation of sAPPα by using siRNAs for the alpha secretases ADAM10 and ADAM17, or for APP led to increased Aß1-42 oligomer-induced cell death after 24 h. Neuronal injuries due to oxidative stress or growth factor deprivation also generated sAPPα 7h later. Finally, acute injection of Aß1-42 oligomers into wild type mouse hippocampi induced transient secretion of sAPPα 48-72 h later. Altogether, these data suggest that neurons respond to stress by generating sAPPα for their survival. These data must be taken into account when interpreting sAPPα levels as a biomarker in neurological disorders.



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Heroin-induced suppression of saccharin intake in OPRM1 A118G mice

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Publication date: Available online 20 September 2017
Source:Brain Research Bulletin
Author(s): Christopher S. Freet, Danielle N. Alexander, Caesar G. Imperio, Victor Ruiz-Velasco, Patricia S. Grigson
The single nucleotide polymorphism of the μ-opioid receptor, OPRM1 A118G, has been associated with greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present studies, we employed a 'humanized' mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in a model of heroin-induced devaluation of an otherwise palatable saccharin cue when repeated saccharin-heroin pairings occurred every 24h (Experiment 1) or every 48h (Experiment 2). The results showed that, while both the 118AA and 118GG mice demonstrated robust avoidance of the heroin-paired saccharin cue following daily taste-drug pairings, only the 118AA mice suppressed intake of the heroin-paired saccharin cue when 48h elapsed between each taste-drug pairing. Humanized 118GG mice, then, defend their intake of the sweet cue despite saccharin-heroin pairings and this effect is illuminated by the use of spaced, rather than massed, trials. Given that this pattern of strain difference is not evident with saccharin-cocaine pairings (Freet et al., 2015), reduced avoidance of the heroin-paired saccharin cue by the 118GG mice may be due to an interaction between the opiate and the subjects' drive for the sweet or, alternatively, to differential downstream sensitivity to the aversive kappa mediated properties of the drug. These alternative hypotheses are addressed.



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Developing Neutrophils Must Eat…Themselves!

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Zhichao Fan, Klaus Ley
In this issue of Immunity, Riffelmacher et al. (2017) show that autophagy is necessary for the release of free fatty acids from intracellular stores within neutrophil precursor cells. This limits glycolysis, increases oxidative phosphorylation, and is essential for neutrophil maturation.

Teaser

In this issue of Immunity, Riffelmacher et al. (2017) show that autophagy is necessary for the release of free fatty acids from intracellular stores within neutrophil precursor cells. This limits glycolysis, increases oxidative phosphorylation, and is essential for neutrophil maturation.


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Fishing for Answers in Human Mycobacterial Infections

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Miriam Bolz, Joel D. Ernst
Two recent studies (Cambier et al., 2017; Madigan et al., 2017) reveal in vivo functions for specific phenolic glycolipids (PGLs) in the mycobacteria that cause tuberculosis or leprosy. M. tuberculosis (and M. marinum) PGL promotes bacterial spread to growth-permissive macrophages, while M. leprae PGL-1 induces macrophages to cause nerve demyelination characteristic of human leprosy.

Teaser

Two recent studies (Cambier et al., 2017; Madigan et al., 2017) reveal in vivo functions for specific phenolic glycolipids (PGLs) in the mycobacteria that cause tuberculosis or leprosy. M. tuberculosis (and M. marinum) PGL promotes bacterial spread to growth-permissive macrophages, while M. leprae PGL-1 induces macrophages to cause nerve demyelination characteristic of human leprosy.


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A Tale of Two Genes: Microglial Apoe and Trem2

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Anna A. Pimenova, Edoardo Marcora, Alison M. Goate
Microglial cell function is implicated in the etiology of Alzheimer's disease by human genetics. In this issue of Immunity, Krasemann et al. (2017) describe a gene expression signature associated with an APOE- and TREM2-dependent response of microglia to brain tissue damage that accumulates in aging and disease, defining an axis that might be amenable to therapeutic targeting.

Teaser

Microglial cell function is implicated in the etiology of Alzheimer's disease by human genetics. In this issue of Immunity, Krasemann et al. (2017) describe a gene expression signature associated with an ApoE- and Trem2-dependent response of microglia to brain tissue damage that accumulates in aging and disease, defining an axis that might be amenable to therapeutic targeting.


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Take DAT, Flu!

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Lior Lobel, Wendy S. Garrett
Some microbial metabolites can be immunomodulatory, but there is limited understanding of how these contribute to inter-individual variation in response to infection. In a recent study in Science, Steed et al. (2017) show that the bacterial metabolite desaminotyrosine (DAT) increases type I interferon expression, resulting in an improved immune response to influenza infection.

Teaser

Some microbial metabolites can be immunomodulatory, but there is limited understanding of how these contribute to inter-individual variation in response to infection. In a recent study in Science, Steed et al. (2017) show that the bacterial metabolite desaminotyrosine (DAT) increases type I interferon expression, resulting in an improved immune response to influenza infection.


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Lnc’ing Id2 to ILC1

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Mengxi Sun, Barbara L. Kee
The transcriptional repressor Id2 is constitutively expressed in all innate lymphoid cells (ILCs) and is required for their development. In this issue of Immunity, Mowel et al. (2017) demonstrate that Id2 expression is regulated by a cell type-specific cis-regulatory element in group 1 ILCs that is demarcated by a long non-coding RNA.

Teaser

The transcriptional repressor Id2 is constitutively expressed in all innate lymphoid cells (ILCs) and is required for their development. In this issue of Immunity, Mowel et al. (2017) demonstrate that Id2 expression is regulated by a cell type-specific cis-regulatory element in group 1 ILCs that is demarcated by a long non-coding RNA.


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Foundations of Immunometabolism and Implications for Metabolic Health and Disease

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Gökhan S. Hotamisligil
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health.

Teaser

It is now well established that the immune and metabolic systems physically and functionally interact to maintain homeostasis, and abnormalities in these interactions are critical contributors to metabolic diseases. This review from Gökhan Hotamisligil summarizes the foundation and growth of the dynamic field of immunometabolism.


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Defined Sensing Mechanisms and Signaling Pathways Contribute to the Global Inflammatory Gene Expression Output Elicited by Ionizing Radiation

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Prabhat K. Purbey, Philip O. Scumpia, Peter J. Kim, Ann-Jay Tong, Keisuke S. Iwamoto, William H. McBride, Stephen T. Smale
Environmental insults are often detected by multiple sensors that activate diverse signaling pathways and transcriptional regulators, leading to a tailored transcriptional output. To understand how a tailored response is coordinated, we examined the inflammatory response elicited in mouse macrophages by ionizing radiation (IR). RNA-sequencing studies revealed that most radiation-induced genes were strongly dependent on only one of a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, which regulated many IR-response genes, including interferon response genes, via an atypical IRF1-dependent, STING-independent mechanism. Moreover, small, defined sets of genes activated by p53 and NRF2 accounted for the selective response to radiation in comparison to a microbial inducer of inflammation. Our findings reveal that genes comprising an environmental response are activated by defined sensing mechanisms with a high degree of selectivity, and they identify distinct components of the radiation response that might be susceptible to therapeutic perturbation.

Graphical abstract

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Teaser

Purbey et al. define the transcriptional response to ionizing radiation in macrophages, revealing a strong dependency on a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, the tumor suppressor p53, and the ROS-induced transcription factor NRF2. Their findings point to selectivity in damage-sensing mechanisms, and identify components of the radiation response as potential therapeutic targets.


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IL-1 Family Cytokines Use Distinct Molecular Mechanisms to Signal through Their Shared Co-receptor

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Sebastian Günther, Daniel Deredge, Amanda L. Bowers, Alessandra Luchini, Daniel A. Bonsor, Robert Beadenkopf, Lance Liotta, Patrick L. Wintrode, Eric J. Sundberg
Within the interleukin 1 (IL-1) cytokine family, IL-1 receptor accessory protein (IL-1RAcP) is the co-receptor for eight receptor-cytokine pairs, including those involving cytokines IL-1β and IL-33. Unlike IL-1β, IL-33 does not have a signaling complex that includes both its cognate receptor, ST2, and the shared co-receptor IL-1RAcP, which we now present here. Although the IL-1β and IL-33 complexes shared structural features and engaged identical molecular surfaces of IL-1RAcP, these cytokines had starkly different strategies for co-receptor engagement and signal activation. Our data suggest that IL-1β binds to IL-1RI to properly present the cytokine to IL-1RAcP, whereas IL-33 binds to ST2 in order to conformationally constrain the cognate receptor in an IL-1RAcP-receptive state. These findings indicate that members of the IL-1 family of cytokines use distinct molecular mechanisms to signal through their shared co-receptor, and they provide the foundation from which to design new therapies to target IL-33 signaling.

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Teaser

IL-1RAcP is the co-receptor shared by most cytokines in the IL-1 family. Günther et al. demonstrate that although IL-1RAcP interacts with different cytokine-receptor pairs through a conserved architecture, it uses starkly different strategies to engage IL-1β and IL-33 and form signaling-competent ternary complexes.


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Aryl Hydrocarbon Receptor Controls Monocyte Differentiation into Dendritic Cells versus Macrophages

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Christel Goudot, Alice Coillard, Alexandra-Chloé Villani, Paul Gueguen, Adeline Cros, Siranush Sarkizova, Tsing-Lee Tang-Huau, Mylène Bohec, Sylvain Baulande, Nir Hacohen, Sebastian Amigorena, Elodie Segura
After entering tissues, monocytes differentiate into cells that share functional features with either macrophages or dendritic cells (DCs). How monocyte fate is directed toward monocyte-derived macrophages (mo-Macs) or monocyte-derived DCs (mo-DCs) and which transcription factors control these differentiation pathways remains unknown. Using an in vitro culture model yielding human mo-DCs and mo-Macs closely resembling those found in vivo in ascites, we show that IRF4 and MAFB were critical regulators of monocyte differentiation into mo-DCs and mo-Macs, respectively. Activation of the aryl hydrocarbon receptor (AHR) promoted mo-DC differentiation through the induction of BLIMP-1, while impairing differentiation into mo-Macs. AhR deficiency also impaired the in vivo differentiation of mouse mo-DCs. Finally, AHR activation correlated with mo-DC infiltration in leprosy lesions. These results establish that mo-DCs and mo-Macs are controlled by distinct transcription factors and show that AHR acts as a molecular switch for monocyte fate specification in response to micro-environmental factors.

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How monocytes differentiate into dendritic cells versus macrophages is poorly understood. Goudot et al. show that IRF4 and MAFB are essential for dendritic cell or macrophage differentiation, respectively, and identify aryl hydrocarbon receptor as a major regulator of monocyte fate.


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Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Victoria M. Steffes, Meena M. Murali, Yoonsang Park, Bretton J. Fletcher, Kai K. Ewert, Cyrus R. Safinya
Lipid-based particles are used worldwide in clinical trials as carriers of hydrophobic paclitaxel (PTXL) for cancer chemotherapy, albeit with little improvement over the standard-of-care. Improving efficacy requires an understanding of intramembrane interactions between PTXL and lipids to enhance PTXL solubilization and suppress PTXL phase separation into crystals. We studied the solubility of PTXL in cationic liposomes (CLs) composed of positively charged 2,3-dioleyloxypropyltrimethylammonium chloride (DOTAP) and neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) as a function of PTXL membrane content and its relation to efficacy. Time-dependent kinetic phase diagrams were generated from observations of PTXL crystal formation by differential-interference-contrast microscopy. Furthermore, a new synchrotron small-angle x-ray scattering in situ methodology applied to DOTAP/DOPC/PTXL membranes condensed with DNA enabled us to detect the incorporation and time-dependent depletion of PTXL from membranes by measurements of variations in the membrane interlayer and DNA interaxial spacings. Our results revealed three regimes with distinct time scales for PTXL membrane solubility: hours for >3 mol% PTXL (low), days for ≈ 3 mol% PTXL (moderate), and ≥20 days for < 3 mol% PTXL (long-term). Cell viability experiments on human cancer cell lines using CLPTXL nanoparticles (NPs) in the distinct CLPTXL solubility regimes reveal an unexpected dependence of efficacy on PTXL content in NPs. Remarkably, formulations with lower PTXL content and thus higher stability show higher efficacy than those formulated at the membrane solubility limit of ≈3 mol% PTXL (which has been the focus of most previous physicochemical studies and clinical trials of PTXL-loaded CLs). Furthermore, an additional high-efficacy regime is seen on occasion for liposome compositions with PTXL ≥9 mol% applied to cells at short time scales (hours) after formation. At longer time scales (days), CLPTXL NPs with ≥3 mol% PTXL lose efficacy while formulations with 1–2 mol% PTXL maintain high efficacy. Our findings underscore the importance of understanding the relationship of the kinetic phase behavior and physicochemical properties of CLPTXL NPs to efficacy.

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A novel DOPA-albumin based tissue adhesive for internal medical applications

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Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Wenzhen Zhu, Yvonne Peck, Jabed Iqbal, Dong-An Wang
To date, existing tissue adhesives have various weak points in gluing kinetics and stability – particularly, in biocompatibility, which make most of them remain suboptimal for internal conditions. Herein, a novel mussel-inspired "BCD" tissue glue made of bovine serum albumin (BSA), citrate acid (CA) and dopamine was developed aiming at internal medical applications. BSA was employed as a natural and biocompatible macromolecular backbone; CA was introduced as a dual-functional intermediate to increase reactive carboxyl sites for engraftment of dopamine onto BSA backbone and also block the competing reactive amines from the proteinic backbone. Timely curing and stable adhesion were achieved between biological tissue substrates via instant chelation and gradual conjugation of DOPA-catechol groups in BCD glue. Within 30 min, this newly developed BCD tissue glue can provide over 10-fold greater adhesion stress than that of commercially available fibrin glue in wet environment. As a tissue adhesive for internal use, its superior properties also include ideal gelation kinetics and swelling behaviour, appropriate degradation rate, sound cytocompatibility in vitro, as well as fine biocompatibility in vivo. More importantly, successful animal experimentations in seroma prevention and instant hemostasis ultimately validated BCD tissue glue's preclinical efficacy as a tissue adhesive for various internal medical applications.



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Visual in vivo degradation of injectable hydrogel by real-time and non-invasive tracking using carbon nanodots as fluorescent indicator

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Lei Wang, Baoqiang Li, Feng Xu, Ying Li, Zheheng Xu, Daqing Wei, Yujie Feng, Yaming Wang, Dechang Jia, Yu Zhou
Visual in vivo degradation of hydrogel by fluorescence-related tracking and monitoring is crucial for quantitatively depicting the degradation profile of hydrogel in a real-time and non-invasive manner. However, the commonly used fluorescent imaging usually encounters limitations, such as intrinsic photobleaching of organic fluorophores and uncertain perturbation of degradation induced by the change in molecular structure of hydrogel. To address these problems, we employed photoluminescent carbon nanodots (CNDs) with low photobleaching, red emission and good biocompatibility as fluorescent indicator for real-time and non-invasive visual in vitro/in vivo degradation of injectable hydrogels that are mixed with CNDs. The in vitro/in vivo toxicity results suggested that CNDs were nontoxic. The embedded CNDs in hydrogels did not diffuse outside in the absence of hydrogel degradation. We had acquired similar degradation kinetics (PBS-Enzyme) between gravimetric and visual determination, and established mathematical equation to quantitatively depict in vitro degradation profile of hydrogels for the predication of in vivo hydrogel degradation. Based on the in vitro data, we developed a visual platform that could quantitatively depict in vivo degradation behavior of new injectable biomaterials by real-time and non-invasive fluorescence tracking. This fluorescence-related visual imaging methodology could be applied to subcutaneous degradation of injectable hydrogel with down to 7 mm depth in small animal trials so far. This fluorescence-related visual imaging methodology holds great potentials for rational design and convenient in vivo screening of biocompatible and biodegradable injectable hydrogels in tissue engineering.

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ImmunoPEGliposomes for the targeted delivery of novel lipophilic drugs to red blood cells in a falciparum malaria murine model

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Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Ernest Moles, Silvia Galiano, Ana Gomes, Miguel Quiliano, Cátia Teixeira, Ignacio Aldana, Paula Gomes, Xavier Fernàndez-Busquets
Most drugs currently entering the clinical pipeline for severe malaria therapeutics are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution volumes. Low amounts of these compounds do consequently accumulate in circulating Plasmodium-infected red blood cells, exhibiting limited antiparasitic activity. These drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for human blood infections by Plasmodium falciparum. Using immunoliposomes targeted against a surface protein characteristic of the murine erythroid lineage, the protocol has been applied to two novel antimalarial lipophilic drug candidates, an aminoquinoline and an aminoalcohol. Large encapsulation yields of >90% were obtained using a citrate-buffered pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting and retention efficacies of >80%. In P. yoelii-infected mice, the immunoliposomized aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated malaria parasite densities (i.e. from ≥25% to ca. 5%), whereas the same amount of drug encapsulated in non-targeted liposomes had no significant effect on parasite growth. Pharmacokinetic analysis indicated that this good performance was obtained with a rapid clearance of immunoliposomes from the circulation (blood half-life of ca. 2 h), suggesting a potential for improvement of the proposed model.



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Amphiphilic semiconducting polymer as multifunctional nanocarrier for fluorescence/photoacoustic imaging guided chemo-photothermal therapy

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Yuyan Jiang, Dong Cui, Yuan Fang, Xu Zhen, Paul Kumar Upputuri, Manojit Pramanik, Dan Ding, Kanyi Pu
Chemo-photothermal nanotheranostics has the advantage of synergistic therapeutic effect, providing opportunities for optimized cancer therapy. However, current chemo-photothermal nanotheranostic systems generally comprise more than three components, encountering the potential issues of unstable nanostructures and unexpected conflicts in optical and biophysical properties among different components. We herein synthesize an amphiphilic semiconducting polymer (PEG-PCB) and utilize it as a multifunctional nanocarrier to simplify chemo-photothermal nanotheranostics. PEG-PCB has a semiconducting backbone that not only serves as the diagnostic component for near-infrared (NIR) fluorescence and photoacoustic (PA) imaging, but also acts as the therapeutic agent for photothermal therapy. In addition, the hydrophobic backbone of PEG-PCB provides strong hydrophobic and π-π interactions with the aromatic anticancer drug such as doxorubicin for drug encapsulation and delivery. Such a trifunctionality of PEG-PCB eventually results in a greatly simplified nanotheranostic system with only two components but multimodal imaging and therapeutic capacities, permitting effective NIR fluorescence/PA imaging guided chemo-photothermal therapy of cancer in living mice. Our study thus provides a molecular engineering approach to integrate essential properties into one polymer for multimodal nanotheranostics.

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Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Jing Wei, Xiaoyu Shuai, Rui Wang, Xueling He, Yiwen Li, Mingming Ding, Jiehua Li, Hong Tan, Qiang Fu
Targeted delivery of therapeutics and diagnostics using nanotechnology holds great promise to minimize the side effects of conventional chemotherapy and enable specific and real-time detection of diseases. To realize this goal, we report a clickable and imageable nanovehicle assembled from multiblock polyurethanes (MPUs). The soft segments of the polymers are based on detachable poly(ethylene glycol) (PEG) and degradable poly(ε-caprolactone) (PCL), and the hard segments are constructed from lysine- and cystine-derivatives bearing reduction-responsive disulfide linkages and click-active alkynyl moieties, allowing for post-conjugation of targeting ligands via a click chemistry. It was found that the cleavage of PEG corona bearing a pH-sensitive benzoic-imine linkage (BPEG) could act as an on-off switch, which is capable of activating the clicked targeting ligands under extracellular acidic condition, followed by triggering the core degradation and payload release within tumor cells. In combination with superparamagnetic iron oxide nanoparticles (SPION) clustered within the micellar core, the MPUs exhibit excellent magnetic resonance imaging (MRI) contrast effects and T2 relaxation in vitro, as well as magnetically guided MR imaging and multimodal targeting of therapeutics to tumor precisely, leading to significant inhibition of cancer with minimal side effect. This work provides a safe and versatile platform for the further development of smart theranostic systems for potential magnetically-targeted and imaging-guided personalized medicine.

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Polyglycerolated nanocarriers with increased ligand multivalency for enhanced in vivo therapeutic efficacy of paclitaxel

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Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Trang Huyen Le Kim, Jeong Heon Yu, Hwiseok Jun, Moon Young Yang, Mi-Jin Yang, Jae-Woo Cho, Jin Woong Kim, Jee Seon Kim, Yoon Sung Nam
Despite the excellent biocompatibility and antifouling effect of poly(ethylene glycol) (PEG), the high steric hindrance, limited chemical functionality, and low ligand multivalency of PEGylated nanocarriers often lead to inefficient cell targeting and intracellular trafficking. Hence, a new structure of hydrophilic corona allowing a higher ligand density without loss of excellent biocompatibility is highly desirable. Here we introduce tumor-targeted polyglycerolated (PGylated) nanocarriers that dramatically enhance the in vivo therapeutic efficacy of incorporated paclitaxel simply by increasing the surface density of hydrophobic tumor-targeting ligands. Linear polyglycerol-poly (ε-caprolactone) block copolymer (PG-b-PCL) is used to prepare PGylated lipiodol nanoemulsions, where PG serves as a corona conjugated with a large number of folic acid (FA) for efficient tumor targeting. Unlike FA-PEGylated nanoemulsions, FA-PGylated nanoemulsions can display a larger number of FA without structural destabilization. This property enables excellent anti-cancer activities and effective tumor regression in a cervical cancer xenograft murine model at a cumulative drug dose of ∼5 mg kg−1, which is about four fold smaller than that of commercial Taxol formulation. This study highlights the importance of surface chemistry of nanocarriers that enable multivalent ligand functionalization and high tolerance to the conjugation of hydrophobic ligands, which make PG as a very effective hydrophilic corona for in vivo drug delivery.



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Editorial board

Publication date: November 2017
Source:Biomaterials, Volume 145





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FRET-enabled monitoring of the thermosensitive nanoscale assembly of polymeric micelles into macroscale hydrogel and sequential cognate micelles release

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Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Pingsheng Huang, Huijuan Song, Yumin Zhang, Jinjian Liu, Zhen Cheng, Xing-Jie Liang, Weiwei Wang, Deling Kong, Jianfeng Liu
Thermosensitive "micellar hydrogel" is prepared based on poly(ε-caprolactone-co- 1,4,8-trioxa[4.6]spiro-9-undecanone)-b-poly(ethylene glycol)- b-poly(ε-caprolactone- co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) triblock copolymer. Fluorescence resonance energy transfer (FRET) is adopted to explore its assembly (formation) and disassembly (degradation) mechanism within the range of 10 nm. Results prove that the thermosensitive non-covalent aggregation of micelles facilitates the hydrogel formation and the sustained shedding of cognate micelles induces the hydrogel degradation, during which polymers are steadily incorporated in micelles without any micelle disassembly or reassembly. It is confirmed that using multiple-tags based imaging technology, such as FRET imaging, the fate of macro biodegradable materials in vitro and in vivo can be followed at a precise nano even molecular level. Such an unique hydrogel composed of nothing more than PECT micelles can act as not only an injectable nanomedicine reservoir by subcutaneous or peri-tissue administration, but also an advanced "combo" macroscale platform for co-delivery of multi-modal therapeutic agents. Our findings also indicate that biological stimuli (e.g., temperature, enzymes)-induced non-covalent micelle self-assembly may provide us an effective strategy to prepare a macroscale device from nanoscale subunits.



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Evolution of the degradation mechanism of pure zinc stent in the one-year study of rabbit abdominal aorta model

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Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Hongtao Yang, Cong Wang, Chaoqiang Liu, Houwen Chen, Yifan Wu, Jintao Han, Zichang Jia, Wenjiao Lin, Deyuan Zhang, Wenting Li, Wei Yuan, Hui Guo, Huafang Li, Guangxin Yang, Deling Kong, Donghui Zhu, Kazuki Takashima, Liqun Ruan, Jianfeng Nie, Xuan Li, Yufeng Zheng
In the present study, pure zinc stents were implanted into the abdominal aorta of rabbits for 12 months. Multiscale analysis including micro-CT, scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM) and histological stainings was performed to reveal the fundamental degradation mechanism of the pure zinc stent and its biocompatibility. The pure zinc stent was able to maintain mechanical integrity for 6 months and degraded 41.75 ± 29.72% of stent volume after 12 months implantation. No severe inflammation, platelet aggregation, thrombosis formation or obvious intimal hyperplasia was observed at all time points after implantation. The degradation of the zinc stent played a beneficial role in the artery remodeling and healing process. The evolution of the degradation mechanism of pure zinc stents with time was revealed as follows: Before endothelialization, dynamic blood flow dominated the degradation of pure zinc stent, creating a uniform corrosion mode; After endothelialization, the degradation of pure zinc stent depended on the diffusion of water molecules, hydrophilic solutes and ions which led to localized corrosion. Zinc phosphate generated in blood flow transformed into zinc oxide and small amounts of calcium phosphate during the conversion of degradation microenvironment. The favorable physiological degradation behavior makes zinc a promising candidate for future stent applications.



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Liposome-supported enzymatic peritoneal dialysis

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Anna Pratsinis, Stefanie Zuercher, Vincent Forster, Eric J. Fischer, Paola Luciani, Jean-Christophe Leroux
Compared to hemodialysis, peritoneal dialysis represents a more straightforward and less invasive alternative, though current solutions are not as effective. Herein, the feasibility of liposome-supported enzymatic peritoneal dialysis (LSEPD) is explored to increase the functionality of peritoneal dialysis for the model indication acute alcohol poisoning. Enzyme-loaded liposomes (E-Liposomes) containing alcohol metabolizing enzymes, alcohol oxidase and catalase, are developed and their in vitro and in vivo performances investigated. The E-Liposomes outperform the free enzymes in stability, overcoming the thermal instability of alcohol oxidase and enhancing the in vitro ethanol elimination, which is further accelerated by hydrogen peroxide, due to the rapid generation of oxygen by catalase. Compared to the free enzymes, the E-Liposomes exhibit reduced systemic exposure and organ distribution. In a rodent ethanol intoxication model, LSEPD enhances ethanol metabolism as evidenced by an increased acetaldehyde production, ethanol's primary metabolite. In conclusion, LSEPD presents an innovative platform to temporarily enhance xenobiotic metabolism, in view of the improved enzyme stability and peritoneal retention.

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Low molecular weight hydrogels derived from urea based-bolaamphiphiles as new injectable biomaterials

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Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Michael A. Ramin, Laurent Latxague, Kotagudda Ranganath Sindhu, Olivier Chassande, Philippe Barthélémy
There is a critical need for soft materials in the field of regenerative medicine and tissue engineering. However, designing injectable hydrogel scaffolds encompassing both adequate mechanical and biological properties remains a key challenge for in vivo applications. Here we use a bottom-up approach for synthesizing supramolecular gels to generate novel biomaterial candidates. We evaluated the low molecular weight gels candidates in vivo and identified one urea-containing molecule, compound 16, that avoid foreign body reactions in mice. The self-assembly of bolaamphiphiles creates a unique hydrogel supramolecular structures featuring fast gelation kinetics, high elastic moduli, thixotropic, and thermal reversibility properties. This soft material, which inhibits recognition by macrophages and fibrous deposition, exhibits long-term stability after in vivo injection.



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Synergistic antitumor effect mediated by a paclitaxel-conjugated polymeric micelle-coated oncolytic adenovirus

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Dayananda Kasala, Soo-Hwan Lee, Jin Woo Hong, Joung-Woo Choi, Kihoon Nam, Yoon Ho Chung, Sung Wan Kim, Chae-Ok Yun
Combination treatment consisting of oncolytic adenovirus (Ad) and paclitaxel (PTX) is a promising strategy to achieve synergistic antitumor effect. However, a co-administration approach is subject to inherent limitations due to the poor solubility of PTX and chemoresistance of tumor cells. In order to overcome these limitations, an oncolytic Ad expressing a p53 variant (oAd-vp53) that is resistant to p53 inactivation in the tumor microenvironment was complexed with PEGylated and PTX-conjugated polymeric micelle (APP). This approach generated an oAd-vp53/APP complex (176.4 nm in diameter) that could concurrently deliver both oncolytic Ad and the nanoparticulate drug APP to tumors. APP-complexed replication-incompetent Ad (dAd/APP) exhibited 12-fold higher transduction efficiency than naked dAd in coxsackie adenovirus receptor (CAR)-negative cancer cells. This increased efficiency was attributed to more efficient cellular internalization mediated by charge interactions between APP and anionic cell membranes. Furthermore, oAd-vp53/APP elicited synergistically higher cancer cell killing than naked oAd-vp53, APP, or oAd-vp53 in combination with PTX (oAd-vp53 + PTX); this synergistic effect was shown to be due to superior induction of apoptosis and viral replication. Importantly, oAd-vp53/APP induced more potent and synergistic antitumor effect through both local and systemic administration by enhancing replication of oncolytic Ad and induction of apoptosis in tumor tissue. Further, the APP coating on the surface of Ad markedly attenuated the host immune response against Ad and decreased hepatic sequestration, resulting in minimal hepatotoxicity and a good safety profile. These attributes enabled oAd-vp53/APP to elicit potent antitumor effect over multiple treatment cycles. Altogether, we demonstrate that concurrent delivery of oncolytic Ad and APP as a single nanocomplex is a promising strategy for achieving synergistic antitumor effect.

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Tissue-engineered human 3D model of bladder cancer for invasion study and drug discovery

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Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Cassandra Ringuette Goulet, Geneviève Bernard, Stéphane Chabaud, Amélie Couture, Alexandre Langlois, Bertrand Neveu, Frédéric Pouliot, Stéphane Bolduc
The tumour microenvironment is critical to both the initiation and maintenance of tumorigenesis. Reconstitution of the microenvironment is a major challenge for in vitro cancer models. Indeed, conventional 2D culture systems cannot replicate the complexity, diversity and dynamic nature of the tumour microenvironment. In this study, we have developed a 3D endotheliazed vesical equivalent by using tissue engineering from primary human cells in which non-invasive or invasive bladder cancer (BCa) cell lines, cultured as compact spheroids, were incorporated. Invasive BCa cells cross the basement membrane and invade the stromal compartment whereas non-invasive BCa cells are confined to the urothelium. Our 3D BCa model could be used as a reliable model for assessing drug responses, potentially reducing or partially replacing animal experiments, and thus should have applications in the identification of novel targets as well as toxicological evaluation of anti-cancer therapies.



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Reprint of “Updating Markov models to integrate cross-sectional and longitudinal studies”

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Publication date: Available online 19 September 2017
Source:Artificial Intelligence in Medicine
Author(s): Allan Tucker, Yuanxi Li, David Garway-Heath
Clinical trials are typically conducted over a population within a defined time period in order to illuminate certain characteristics of a health issue or disease process. Cross-sectional studies provide a snapshot of these disease processes over a large number of people but do not allow us to model the temporal nature of disease, which is essential for modelling detailed prognostic predictions. Longitudinal studies, on the other hand, are used to explore how these processes develop over time in a number of people but can be expensive and time-consuming, and many studies only cover a relatively small window within the disease process. This paper explores the application of intelligent data analysis techniques for building reliable models of disease progression from both cross-sectional and longitudinal studies. The aim is to learn disease 'trajectories' from cross-sectional data by building realistic trajectories from healthy patients to those with advanced disease. We focus on exploring whether we can 'calibrate' models learnt from these trajectories with real longitudinal data using Baum–Welch re-estimation so that the dynamic parameters reflect the true underlying processes more closely. We use Kullback–Leibler distance and Wilcoxon rank metrics to assess how calibration improves the models to better reflect the underlying dynamics.



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A hierarchical classifier based on human blood plasma fluorescence for non-invasive colorectal cancer screening

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Publication date: Available online 20 September 2017
Source:Artificial Intelligence in Medicine
Author(s): Felipe Soares, Karin Becker, Michel J. Anzanello
Colorectal cancer (CRC) a leading cause of death by cancer, and screening programs for its early identification are at the heart of the increasing survival rates. To motivate population participation, non-invasive, accurate, scalable and cost-effective diagnosis methods are required. Blood fluorescence spectroscopy provides rich information that can be used for cancer identification. The main challenges in analyzing blood fluorescence data for CRC classification are related to its high dimensionality and inherent variability, especially when analyzing a small number of samples. In this paper, we present a hierarchical classification method based on plasma fluorescence to identify not only CRC, but also adenomas and other non-malignant colorectal findings that may require further medical investigation. A feature selection algorithm is proposed to deal with the high dimensionality and select discriminant fluorescence wavelengths. These are used to train a binary support vector machine (SVM) in the first level to identify the CRC samples. The remaining samples are then presented to a one-class SVM trained on healthy subjects to detect deviant samples, and thus non-malignant findings. This hierarchical design, together with the one class-SVM, aims to reduce the effects of small samples and high variability. Using a dataset analyzed in previous studies comprised of 12,341 wavelengths, we achieved much superior results. Sensitivity and specificity are 0.87 and 0.95 for CRC detection, and 0.60 and 0.79 for non-malignant findings, respectively. Compared to related work, the proposed method presented a better accuracy, required fewer features, and provides a unified approach that expands CRC detection to non-malignant findings.



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Targeted Drug Delivery to Melanoma

Publication date: Available online 19 September 2017
Source:Advanced Drug Delivery Reviews
Author(s): Qi Liu, Manisit Das, Yun Liu, Leaf Huang
Melanoma derived from melanocytes is the most aggressive genre of skin cancer. Although the considerable advancement in the study of human cancer biology and drug discovery, most advanced melanoma patients are inevitably unable to be cured. With the emergence of nanotechnology, the use of nano-carriers is widely expected to alter the landscape of melanoma treatment. In this review, we will discuss melanoma biology, current treatment options, mechanisms behind drug resistance, and nano-based solutions for effective anti-cancer therapy, followed by challenges and perspectives in both pre-clinical and clinical settings.

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