Novel fluconazole derivatives with promising antifungal activity

Publication date: Available online 17 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Nishad Thamban Chandrika, Sanjib K. Shrestha, Huy X. Ngo, Kaitlind C. Howard, Sylvie Garneau-Tsodikova
The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activities of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.

Graphical abstract

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Design, synthesis, and biological evaluation of inhibitors of the NADPH oxidase, Nox4

Publication date: Available online 17 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Qian Xu, Amol A. Kulkarni, Sajith Meleveetil, Dilbi Hussein, David Brown, Osman F. Güner, M. Damoder Reddy, E. Blake Watkins, Bernard Lassègue, Kathy K. Griendling, J. Phillip Bowen
NADPH oxidases (Nox enzymes) are critical mediators of both physiologic and pathophysiologic processes. Nox enzymes catalyze NADPH-dependent generation of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Until recently, Nox4 was proposed to be involved exclusively in normal physiologic functions. Compelling evidence, however, suggests that Nox4 plays a critical role in fibrosis, as well as a host of pathologies and diseases. These considerations led to a search for novel, small molecule inhibitors of this important enzyme. Ultimately, a series of novel tertiary sulfonylureas (23-25) was designed using pharmacophore modeling, synthesized, and evaluated for inhibition of Nox4-dependent signaling.

Graphical abstract

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Transcriptome analysis of ultraviolet A-induced photoaging cells with deep sequencing

Abstract

Gene expression changes associate with many biological processes. However, the relative consequences of the genetic alterations induced by ultraviolet (UV)-A radiation on skin photoaging are still not clear. Here, we performed deep sequencing of the transcriptome and explored altered genes related to biological changes in repeated UV-A-irradiated human dermal fibroblasts (HDF) to better understand the skin photoaging mechanisms. The repeatedly UV-A-irradiated group (HDF were induced by 10 J/cm² UV-A twice daily for 7 days) and the control group (HDF without irradiation) were evaluated. Expression genes profile was measured and compared using high-throughput sequencing on an Illumina HiSeq 2500 platform and DEGseq. Functional annotation and metabolic pathway analysis of genes with altered expression were preformed via National Center for Biotechnology Information, Uniprot, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Genes related to skin photoaging were verified by quantitative reverse transcription polymerase chain reaction. Transcriptome comparison revealed that 607 genes exhibited significant changes (P < 0.05), of which 238 genes were upregulated and 369 downregulated in UV-A-irradiated HDF. Functional annotations showed that genes altered by UV-A irradiation took part in a variety of biological process, cellular component synthesis, molecular function and metabolic pathway. Photoaging-related genes encoding elastin, sprout, cathepsin K, cathepsin D, cathepsin B ribose-phosphate diphosphokinase and phosphoglucomutase were identified to be changed. We obtained the comprehensive transcriptome and altered genes in repeated UV-A-irritated HDF and identified that the modulated genes were related to a wide panel of pathways and functions. Our results provide new insights into photoaging molecular mechanisms and suggest some novel targets for interfering in skin photoaging.

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Azathioprine monotherapy in autoimmune blistering diseases: A feasible option for mild to moderate cases

Abstract

Azathioprine (AZP) is used as a corticosteroid (CS)-sparing medication to treat autoimmune blistering diseases. In this study, we examined the efficacy of AZP and the feasibility of using AZP monotherapy (without CS) to treat pemphigus and pemphigoid. We performed a retrospective study of 10 Japanese patients (seven with pemphigus and three with pemphigoid) with mild to moderate disease activity who had been treated using AZP. The treatment efficacy was evaluated based on decreases in the disease activity scores and autoantibody titers. The results demonstrate that seven out of 10 cases (70%) were treated successfully using AZP monotherapy with no severe adverse effects. The disease activity scores of the successfully-treated patients decreased to zero after 1–37.5 months (average, 11.9) and the average disease activity scores in these cases decreased significantly at 2 months (38.2 ± 36.6%) compared with the scores of the three patients who required additional systemic CS therapy (77.5 ± 3.5%) (P < 0.05). Additionally, the autoantibody titers of five cases treated successfully using AZP decreased by half at 6 months. In conclusion, our findings suggest that AZP monotherapy is a viable treatment option for mild to moderate pemphigus and pemphigoid.

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Complications of botulinum toxin injection for masseter hypertrophy: Incidence rate from 2036 treatments and summary of causes and preventions

Summary

Background

Masseter hypertrophy is a common, prominent feature in many Asian patients, and correction procedures are often requested for esthetic reasons. Toxin masseter injections have a high efficacy and safety profile, but the risks of a variety of side effects or complications remain.

Objectives

The categorization of various complications was based on etiology, with a presentation of the author's own incidence rates for consideration and comparison.

Methods

Six hundred and eighty patients received a total of 2036 sessions of toxin injection for masseter hypertrophy from 2011 to 2016, and complications or complaints were recorded through follow-up on a by-treatment basis. Complications were grouped together based on etiology and discussed.

Results

Of 2036 sessions, temporary mastication force decrease was reported after 611 (30%), bruising after 51 (2.5%), headaches after 12 (0.58%), smile limitation after 3 (0.15%), paradoxical bulging after 10 (0.49%), sunken cheeks (subzygomatic volume loss) after 9 (0.44%), and sagging after 4 (0.20%).

Conclusions

Masseter injections remain very safe. To further decrease the incidence rate, injections should only be inside the recommended safety zone, a quadrilateral within the muscle that avoids most important local structures. Keeping injections inside the safe zone, and ideally in 3-4 different locations at least 1 cm from any border, is crucial for the prevention of complications.

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Possible role of interleukin-17 and macrophage migration inhibitory factor in cutaneous warts

Summary

Background/Objectives

Cutaneous warts (CW), or verrucae, are benign proliferation of skin that result from infection with human papilloma viruses. Cellular immune reactivity plays a significant role in wart regression. The aim of this study was to elucidate the cellular immune status of patients with CW through measurements of their serum levels of interleukin-17 (IL-17) and macrophage migration inhibitory factor (MIF,) and, identify the possible role of IL-17 and MIF in CW. We assessed serum IL-17 and MIF levels in patients with different forms of CW and compare the results with controls.

Patient and methods

Serum levels of IL-17 and MIF were measured using commercially available ELISA assay kits in 60 patients with CW and 20 healthy controls.

Results

Serum levels of IL-17 and MIF were significantly lower in patients with CW when compared with the controls (P-value <.01, <.05, respectively). There was nonsignificant correlation between IL-17 and MIF.

Conclusion

Low IL-17 and MIF levels may have a contributory role in occurrence, maintenance, severity, and recurrence of different types of CW which depend mainly on the defect of cell-mediated immunity. This may shed new light on nontraditional strategies for the future medical treatments of CW through regulation of IL-17 and MIF.

http://ift.tt/2ja9Zmh

Electroactive biomaterials: Vehicles for controlled delivery of therapeutic agents for drug delivery and tissue regeneration

Publication date: Available online 17 December 2017
Source:Advanced Drug Delivery Reviews
Author(s): Biranche Tandon, Adrián Magaz, Richard Balint, Jonny J. Blaker, Sarah H. Cartmell
Electrical stimulation for delivery of biochemical agents such as genes, proteins and RNA molecules amongst others, holds great potential for controlled therapeutic delivery and in promoting tissue regeneration. Electroactive biomaterials have the capability of delivering these agents in a localized, controlled, responsive and efficient manner. These systems have also been combined for the delivery of both physical and biochemical cues and can be programmed to achieve enhanced effects on healing by establishing control over the microenvironment. This review focuses on current state-of-the-art research in electroactive-based materials towards the delivery of drugs and other therapeutic signalling agents for wound care treatment. Future directions and current challenges for developing effective electroactive approach based therapies for wound care are discussed.

Graphical abstract

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Facile preparation of fluorescent nanodiamond-based polymer composites through a metal-free photo-initiated RAFT process and their cellular imaging

Publication date: Available online 17 December 2017
Source:Chemical Engineering Journal
Author(s): Junyu Chen, Meiying Liu, Qiang Huang, Long Huang, Hongye Huang, Fengjie Deng, Yuanqing Wen, Jianwen Tian, Xiaoyong Zhang, Yen Wei
Nanodiamond (ND)-based fluorescent probes have been extensively researched in cell imaging applications. Several outstanding properties of fluorescent NDs (FNDs), such as their excellent biocompatibility, intensive fluorescence and chemical stability in organisms, have made them the most promising carbon materials in biomedicine. However, the production of FNDs with nitrogen-vacancy defect centers was rather complicated and costly, which limited their wide application in the biomedical field. Moreover, the particle size of these types of FNDs was much larger than that of NDs produced by the detonation method; thus, it is difficult for them to penetrate the cell membrane. In this present work, a facile and ultrafast photo-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization was introduced for the fabrication of FND-based polymer composites. The photo-initiated RAFT polymerization is time saving, environmentally friendly and highly efficient. To prepare these FNDs, fluorescein was converted into diacryloyl fluorescein (AcFl), which was used not only as the photocatalyst but also a fluorescent comonomer. The functional monomer 2-methacryloyloxyethyl phosphorylcholine (MPC) was introduced to improve the water dispersibility of the FNDs. The successful fabrication of FNDs-polyMPC composites was proven by a series of characterization methods. These FNDs-polyMPC composites show high water dispersibility, strong fluorescence and low toxicity. The cell uptake behavior suggested that FNDs-polyMPC composites can be facilely internalized by cells. Taken together, FNDs-polyMPC composites can be fabricated by a photo-initiated RAFT polymerization. These FNDs-polyMPC composites possess excellent physicochemical and biological properties and are promising candidates for cell imaging applications.

Graphical abstract

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Reinterpreting recent thymic emigrant function: defective or adaptive?

Cody A Cunningham | Eric Y Helm | Pamela J Fink

http://ift.tt/2j8kuGR

Variability in Center of Pressure Position and Muscle Activation During Walking with Chronic Ankle Instability

Publication date: Available online 16 December 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Rachel M. Koldenhoven, Mark A. Feger, John J. Fraser, Jay Hertel
Chronic ankle instability (CAI) patients exhibit altered gait mechanics. The objective was to identify differences in stride-to-stride variability in the position of the center of pressure (COP) and muscle activity during walking between individuals with and without CAI. Participants (17 CAI;17 Healthy) walked on a treadmill at 1.3m/s while surface electromyography (sEMG) of the fibularis longus (FL) and plantar pressure were recorded. The medial-lateral COP position was averaged for each 10% interval of stance and group standard deviations (SD), coefficient of variation (COV), and range for the COP position were compared between groups via independent t-tests. Ensemble curves for sEMG amplitude SD were graphed for the entire stride cycle to determine significant differences. The CAI group had increased COP position variability (SD (CAI=0.79±0.47mm, Control=0.48±0.17mm), COV (CAI=1.47±0.87mm, Control=0.93±0.33mm), range (CAI=2.97±2.07mm, Control=1.72±0.33mm, P<.05 for all analyses)) during the first 10% of stance. The CAI group had lower FL sEMG amplitude variability from 1-10% (mean difference=0.014±0.006), 32-38% (mean difference=0.013±0.004) and 56-100% (mean difference=0.026±0.01) of the gait cycle. Increased COP variability at initial contact may increase risk of lateral ankle sprains in CAI patients. Decreased sEMG amplitude variability may indicate a constrained sensorimotor system contributing to an inability to adapt to changing environmental demands.



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Improve regional distribution and source apportionment of PM2.5 trace elements in China using inventory-observation constrained emission factors

Publication date: 15 May 2018
Source:Science of The Total Environment, Volume 624
Author(s): Qi Ying, Miao Feng, Danlin Song, Li Wu, Jianlin Hu, Hongliang Zhang, Michael J. Kleeman, Xinghua Li
Contributions to 15 trace elements in airborne particulate matter with aerodynamic diameters <2.5μm (PM2.5) in China from five major source sectors (industrial sources, residential sources, transportation, power generation and windblown dust) were determined using a source-oriented Community Multiscale Air Quality (CMAQ) model. Using emission factors in the composite speciation profiles from US EPA's SPECIATE database for the five sources leads to relatively poor model performance at an urban site in Beijing. Improved predictions of the trace elements are obtained by using adjusted emission factors derived from a robust multilinear regression of the CMAQ predicted primary source contributions and observation at the urban site. Good correlations between predictions and observations are obtained for most elements studied with R>0.5, except for crustal elements Al, Si and Ca, particularly in spring. Predicted annual and seasonal average concentrations of Mn, Fe, Zn and Pb in Nanjing and Chengdu are also consistently improved using the adjusted emission factors. Annual average concentration of Fe is as high as 2.0μgm⁻³ with large contributions from power generation and transportation. Annual average concentration of Pb reaches 300–500ngm⁻³ in vast areas, mainly from residential activities, transportation and power generation. The impact of high concentrations of Fe on secondary sulfate formation and Pb on human health should be evaluated carefully in future studies.

Graphical abstract

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An Update of a Prospective Study of SBRT for Post-chemoradiation Residual Disease in Stage II/III Non-small Cell Lung Cancer. In Reply to Dr. P. Hurmuz

Publication date: Available online 16 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sameera S. Kumar, Ronald C. McGarry




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Rapid and comprehensive discovery of unreported shellfish allergens using large-scale transcriptomic and proteomic resources

Publication date: Available online 16 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Roni Nugraha, Sandip D. Kamath, Elecia Johnston, Kyall R. Zenger, Jennifer M. Rolland, Robyn E. O'Hehir, Andreas L. Lopata




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Balloon Angioplasty Versus Stenting for the Treatment of Failing Arteriovenous Grafts: A Meta-Analysis

Publication date: Available online 16 December 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): George N. Kouvelos, Konstantinos Spanos, George A. Antoniou, Ioannis Vassilopoulos, Christos Karathanos, Miltiadis I. Matsagkas, Athanasios D. Giannoukas
PurposeTo assess the outcomes of plain balloon angioplasty versus stenting for the treatment of failed or malfunctioning chronic haemodialysis arteriovenous grafts (AVGs).MethodsA systematic search of the literature was undertaken using the PUBMED, EMBASE, and Cochrane databases from January 2000 to September 2016 for articles comparing balloon angioplasty versus stenting in the management of failed or malfunctioning chronic haemodialysis AVGs. Results are reported as OR and 95% CI.ResultsThe search identified eight studies (1051 patients). Balloon angioplasty alone was used in 521 patients (49.6%) and stenting in 530 patients (50.4%). At the time of the endovascular re-intervention, the mean life of AVGs was 807.7±115.4 days for the balloon angioplasty and 714.2±96.3 days for the stenting group (p=.92). All AVGs were located in the arm. Most procedures (98.1%) were performed across the venous anastomosis, while 88% of the patients in the stenting group received a stent graft. The technical success rate was significantly higher in the stenting group (OR 0.16, 95% CI 0.08–0.31, p<.001). At 12 months, loss of primary and secondary patency was significantly higher in patients undergoing plain balloon angioplasty compared with stenting (OR 3.54, 95% CI 2.18–5.74, p<.001, and OR 1.82, 95% 1.17–2.82, p=.008, respectively).ConclusionStenting is associated with better technical success and patency rates compared with plain angioplasty in treating failed or malfunctioning chronic haemodialysis AVGs, and thus it should be considered as the first line therapeutic option.



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Insulin antagonises pigment epithelium-derived factor (PEDF)-induced modulation of lineage commitment of myocytes and heterotrophic ossification.

Publication date: Available online 16 December 2017
Source:Molecular and Cellular Endocrinology
Author(s): Revathy Carnagarin, Mina Elahy, Arun M. Dharmarajan, Crispin R. Dass
Extensive bone defects arising as a result of trauma, infection and tumour resection and other bone pathologies necessitates the identification of effective strategies in the form of tissue engineering, gene therapy and osteoinductive agents to enhance the bone repair process. PEDF is a multifunctional glycoprotein which plays an important role in regulating osteoblastic differentiation and bone formation. PEDF treatment of mice and human skeletal myocytes at physiological concentration inhibited myogenic differentiation and activated Erk1/2 MAPK- dependent osteogenic transdifferentiation of myocytes. In mice, insulin, a promoter of bone regeneration, attenuated PEDF-induced expression of osteogenic markers such as osteocalcin, alkaline phosphatase and mineralisation for bone formation in the muscle and surrounding adipose tissue. These results provide new insights into the molecular aspects of the antagonising effect of insulin on PEDF-dependent modulation of the differentiation commitment of musculoskeletal environment into osteogenesis, and suggest that PEDF may be developed as an effective clinical therapy for bone regeneration as its heterotopic ossification can be controlled via co-administration of insulin.

Graphical abstract

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Systematic intrafraction shifts of mediastinal lymph node targets between setup imaging and radiation treatment delivery in lung cancer patients

Publication date: Available online 16 December 2017
Source:Radiotherapy and Oncology
Author(s): Mai Lykkegaard Schmidt, Lone Hoffmann, Ditte S. Møller, Marianne Marquard Knap, Torben Riis Rasmussen, Birgitte Holst Folkersen, Per Rugaard Poulsen
Background and purposeInternal target motion results in geometrical uncertainties in lung cancer radiotherapy. In this study, we determined the intrafraction motion and baseline shifts of mediastinal lymph node (LN) targets between setup imaging and treatment delivery.Material and methodsTen lung cancer patients with 2–4 fiducial markers implanted in LN targets received intensity-modulated radiotherapy with a daily setup cone-beam CT (CBCT) scan used for online soft-tissue match on the primary tumor. At a total of 122 fractions, 5 Hz fluoroscopic kV images were acquired orthogonal to the MV treatment beam during treatment delivery. Offline, the 3D trajectory of the markers was determined from their projected trajectory in the CBCT projections and in the intra-treatment kV images. Baseline shifts and changes in the respiratory motion amplitude between CBCT and treatment delivery were determined from the 3D trajectories.ResultsSystematic mean LN baseline shifts of 2.2 mm in the cranial direction (standard deviation (SD): 1.8 mm) and 1.0 mm in the posterior direction (SD: 1.2 mm) occurred between CBCT imaging and treatment delivery. The mean motion amplitudes during CBCT and treatment delivery agreed within 0.2 mm in all directions.ConclusionsSystematic cranial and posterior intrafraction baseline shifts between CBCT and treatment delivery were observed for mediastinal LN targets. Intrafraction motion amplitudes were stable.



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Calcium and Vitamin D in Human Health: Hype or Real?

Publication date: Available online 16 December 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Sunil J. Wimalawansa, DSc.Mohammed S. Razzaque, Nasser M. Al-Daghri
The incidence and the prevalence of vitamin D deficiency are increasing worldwide. It is estimated that over 50% of population in the world have low in vitamin D (i.e., hypovitaminosis D; levels below 30 ng/mL). 80% of our vitamin D requirement comes from the ultraviolet rays from sunlight, and for the remainder, we rely from the diet and supplements. The latter become important when one is exposing to less than optimal amounts of sunlight, inability of the skin to generate vitamin D efficiently, and/or having secondary causes that leads to increase catabolism of vitamin D. The normal serum vitamin D level is thought to be about 30 ng/mL (75 nmol/L); a range between 30 and 60 ng/mL (75 and 150 nmol/L). The Institute of Medicine (IOM) report of 2011 suggests, 600 IU is adequate for people below the age 71 who are not exposed to sunshine. Although IOM amount might be of relevance to the ambulatory healthy individuals, in disease conditions, very few patients would manage to reach serum vitamin D level above 30 ng/mL, which most scientists consider the minimum adequate level for optimal health. While the natural way to obtain vitamin D is through safe sunlight exposure, an additional daily intake of 1,000 IU of vitamin D is needed for people with lighter-skin color. With suboptimal sun exposure in those with dark-skinned and older adults need an additional 2,000 IU/day or more, vitamin D to maintain serum 25-hydroxyvitamin D levels over 30 ng/mL; the safe upper limit of oral daily supplementation is considered as 5,000 IU. However, vulnerable groups including those who are disabled, obese, and those with gastrointestinal abnormalities and/or malabsorption syndromes, institutionalized people (e.g., nursing homes and in prisons), and during pregnancy and lactation, needs approximately 4,000 IU per day for optimal physiological activities. Vitamin D is critical for enhancing gastrointestinal calcium absorption and mineralization of the osteoid tissue. In is also important for other physiological functions, such as muscle strength and neuromuscular coordination, release of hormones, subduing autoimmunity, and curtailing the development of certain cancers.



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Vitamin D: Effects on Human Reproduction, Pregnancy, and Fetal Well-being

Publication date: Available online 17 December 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): E.L. Heyden, S.J. Wimalawansa
Pregnancy places exceptional demands on vitamin D and calcium availability; thus, their deficiencies during pregnancy threaten the woman and her fetus. Globally, vitamin D and other micronutrient deficiencies are common during pregnancy, especially in developing countries where pregnant women have less access to supplements. Vitamin D deficiency has been reported to be as high as 40% among pregnant women. As a pregnancy progresses, the requirements for vitamin D increase and can worsen preexisting hypovitaminosis D. Consequently, hypovitaminosis D is associated with a higher incidence of fetal miscarriage, preeclampsia, gestational diabetes, bacterial vaginosis, and impaired fetal and childhood growth and development. This review explores the recent advances in the understanding of vitamin D and the pivotal role it plays in human reproduction, with an emphasis on pregnancy. Given the seriousness of the issue, there is a pressing need for clinicians to become aware of the risks associated with not identifying and correcting vitamin D deficiency. Identifying and correcting vitamin D deficiency, including safe exposure to sunlight, is particularly relevant for those who seek assistance with fertility issues or prenatal counseling and those in the beginning of their pregnancy. The data point to a significant protective effects of vitamin D during pregnancy when the 25(OH)D serum level exceeds 30 ng/mL before pregnancy and during the first trimester and, sufficient levels are maintained throughout the pregnancy.

Graphical abstract

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Dexamethasone-induced upregulation of CaV3.2 T-type Ca2+ channels in rat cardiac myocytes

Publication date: Available online 17 December 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): D. Falcón, R. González-Montelongo, E. Sánchez de Rojas-de Pedro, A. Ordóñez, J. Ureña, A. Castellano
Glucocorticoids are widely used to treat acute and chronic diseases. Unfortunately, their therapeutic use is associated with severe side effects. Glucocorticoids are known to regulate several ion channels in cardiac myocytes, including voltage-dependent Ca²⁺ channels. Low-voltage-activated T-type Ca²⁺ channels are expressed in ventricular myocytes during the fetal and perinatal period, but are practically absent in the adult. However, these channels can be re-expressed in adult cardiomyocytes under some pathological conditions. We have investigated the glucocorticoid regulation of T-type Ca²⁺ channels in rat cardiomyocytes. Molecular studies revealed that dexamethasone induces the upregulation of CaV3.2 mRNA in neonatal rat ventricular myocytes, whereas CaV3.1 mRNA is only slightly affected. Patch-clamp recordings confirmed that T-type Ca²⁺ channel currents were upregulated in dexamethasone treated cardiomyocytes, and the addition of 50 μmol/L NiCl2 demonstrated that the CaV3.2 channel is responsible for this upregulation. The effect of dexamethasone on CaV3.2 is mediated by the activation and translocation to the cell nucleus of the glucocorticoid receptor (GR). We have isolated the upstream promoter of the Cacna1h gene and tested its activity in transfected ventricular myocytes. The initial in silico analysis of Cacna1h promoter revealed putative glucocorticoid response elements (GREs). Transcriptional activity assays combined with deletion analyses and chromatin immunoprecipitation assays demonstrated that GR binds to a region a GRE located in -1006/-985 bp of Cacna1h promoter. Importantly, upregulation of the CaV3.2 channel is also observed in vitro in adult rat ventricular myocytes, and in vivo in a rat model of excess of glucocorticoids.



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Occurrence of sulfonated steroids and ovarian expression of steroid sulfatase and SULT1E1 in cyclic cows

Publication date: Available online 17 December 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Carina Blaschka, Gerhard Schuler, Alberto Sánchez-Guijo, Bettina Zimmer, Sabine Feller, Franziska Kotarski, Stefan A. Wudy, Christine Wrenzycki
Historically sulfonated steroids were primarily considered as inactive metabolites destined for elimination. However, more recently they have been increasingly recognized as precursors for the production of bioactive steroids in target tissues and as functional molecules without preceding hydrolysis. In order to comprehensively characterize their occurrence in cyclic cows and their formation and hydrolysis in bovine ovarian steroidogenesis, ovaries from cyclic cows were screened for the expression of oestrogen sulfotransferase (SULTE1) and steroid sulfatase (STS) by Western blot and immunohistochemistry. Moreover, a broad spectrum of 13 sulfonated steroids was measured applying liquid chromatography-tandem mass spectrometry (LC-MS/MS) in blood samples collected from three cycling heifers during defined stages of the ovarian cycle and in fluid obtained from ovarian follicles of different size. SULT1E1 was undetectable in ovarian tissues. For STS only a weak immunostaining was found predominantly in granulosa cells of larger follicles. However, no specific band occurred in Western blot. In blood, concentrations of all sulfonated steroids investigated were below the limit of quantification (LOQ). In follicular fluid, only cholesterol sulfate was measured in considerable concentrations (328.3 ± 63.8 ng/ml). However, the role of cholesterol sulfate in bovine follicular steroidogenesis remains unclear as concentrations were obviously unrelated to follicular size. The remaining sulfonated steroids investigated were undetectable or only slightly exceeded LOQ in a minor proportion of samples. The results are clearly contrary to a role of sulfonated steroids as important precursors, intermediates or products of bovine ovarian steroidogenesis.



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Peptides as a strategy against biofilm-forming microorganisms: Structure-activity relationship perspectives

Publication date: 1 March 2018
Source:European Journal of Pharmaceutical Sciences, Volume 114
Author(s): Rafael Gomes Von Borowski, Alexandre José Macedo, Simone Cristina Baggio Gnoatto
Biofilm forming microorganisms substantially enhance their virulence and drug resistance causing and alternatives are need to combat this health problem. In this context, peptides are an exceptional strategy in drug design and pharmaceutical innovation due to their diverse chemical features, biological activity and biotechnological relevance. Therefore, this study proposes a comprehensive assessment of a wide range of peptides, targeting biofilms. It provides chemical and molecular information and a Structural Activity Relationship perspective in order to delineate minimal requirements for antibiofilm activity and contributing to the development of new antibiofilm agents. In light of this, it was possible to propose a peptide design model (X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20) to be tested in the war against resistant microorganisms.

Graphical abstract

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Effect of milling on the plastic and the elastic stiffness of lactose particles

Publication date: 1 March 2018
Source:European Journal of Pharmaceutical Sciences, Volume 114
Author(s): Samaneh Pazesh, Ann-Sofie Persson, Jonas Berggren, Göran Alderborn
The purpose of this study was to investigate the effect of degree of disorder of a series of α-lactose monohydrate powders, prepared by milling for different time periods, on the plastic and the elastic stiffness of the particles. As references, a series of physical mixtures consisting of original crystalline particles and amorphous particles obtained by spray-drying was used. In addition, the effect of powder pre-storage humidity on the mechanical properties was investigated.For milled particles of a low degree of disorder, a decreased particle size increased the particle plastic stiffness. For milled particles of constant particle size, the plastic stiffness decreased with an increased degree of disorder while the elastic stiffness seemed nearly independent of the degree of disorder. The presence of moisture caused a recrystallisation of milled particles with low degree of disorder which increased their plastic stiffness.For the physical mixtures of crystalline and amorphous particles, similar relationships between plastic stiffness and amorphous content as for the milled powders were obtained. A reasonable explanation is that the nature of the milled particles is represented by a two-state system with crystalline and amorphous domains.

Graphical abstract

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Modelling uncertainties in the diffusion-advection equation for radon transport in soil using interval arithmetic

Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): S. Chakraverty, B.K. Sahoo, T.D. Rao, P. Karunakar, B.K. Sapra
Modelling radon transport in the earth crust is a useful tool to investigate the changes in the geo-physical processes prior to earthquake event. Radon transport is modeled generally through the deterministic advection-diffusion equation. However, in order to determine the magnitudes of parameters governing these processes from experimental measurements, it is necessary to investigate the role of uncertainties in these parameters. Present paper investigates this aspect by combining the concept of interval uncertainties in transport parameters such as soil diffusivity, advection velocity etc, occurring in the radon transport equation as applied to soil matrix. The predictions made with interval arithmetic have been compared and discussed with the results of classical deterministic model. The practical applicability of the model is demonstrated through a case study involving radon flux measurements at the soil surface with an accumulator deployed in steady-state mode. It is possible to detect the presence of very low levels of advection processes by applying uncertainty bounds on the variations in the observed concentration data in the accumulator. The results are further discussed.

Graphical abstract

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Omission P3 after voluntary action indexes the formation of action-driven prediction

Publication date: Available online 17 December 2017
Source:International Journal of Psychophysiology
Author(s): Motohiro Kimura, Yuji Takeda
When humans frequently experience a certain sensory effect after a certain action, a bidirectional association between neural representations of the action and the sensory effect is rapidly acquired, which enables action-driven prediction of the sensory effect. The present study aimed to test whether or not omission P3, an event-related brain potential (ERP) elicited by the sudden omission of a sensory effect, is sensitive to the formation of action-driven prediction. For this purpose, we examined how omission P3 is affected by the number of possible visual effects. In four separate blocks (1-, 2-, 4-, and 8-stimulus blocks), participants successively pressed a right button at an interval of about 1s. In all blocks, each button press triggered a bar on a display (a bar with square edges, 85%; a bar with round edges, 5%), but occasionally did not (sudden omission of a visual effect, 10%). Participants were required to press a left button when a bar with round edges appeared. In the 1-stimulus block, the orientation of the bar was fixed throughout the block; in the 2-, 4-, and 8-stimulus blocks, the orientation was randomly varied among two, four, and eight possibilities, respectively. Omission P3 in the 1-stimulus block was greater than those in the 2-, 4-, and 8-stimulus blocks; there were no significant differences among the 2-, 4-, and 8-stimulus blocks. This binary pattern nicely fits the limitation in the acquisition of action-effect association; although an association between an action and one visual effect is easily acquired, associations between an action and two or more visual effects cannot be acquired concurrently. Taken together, the present results suggest that omission P3 is highly sensitive to the formation of action-driven prediction.



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Use of photodynamic therapy in the treatment of bovine subclinical mastitis

Publication date: Available online 16 December 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Lívia Helena Moreira, José Carlos Pereira de Souza, Carlos José de Lima, Miguel Angel Castillo Salgado, Adriana Barrinha Fernandes, Dora Inés Kozusny Andreani, Antonio Balbin Villaverde, Renato Amaro Zângaro
BackgroundBovine mastitis is a disease that causes a severe drawback in dairy production. Conventional treatments with antibiotic could leave antibiotic residues in the milk. The aim of this study was to evaluate the effect of photodynamic therapy in the treatment of bovine subclinical mastitis to develop an in vivo therapeutic protocol that could be used in routine farm practice, favoring the early return to production.MethodsForty cows with subclinical mastitis (n = 40) were divided into 4 groups (control, photodynamic therapy – PDT, light irradiation – LED, and photosensitizer – PS). Control group received no treatment, PDT group received application of 1.0 mL of 2.5% toluidine blue photosensitizer followed by LED irradiation at λ = 635 nm, the LED group was treated with LED irradiation alone, and the PS group received only 2.5% toluidine blue dye. LED irradiation was applied to the mammary gland by means of an acrylic light guide coupled to the LED equipment. The PDT and LED groups were irradiated with 200 J/cm² at three different positions inside the mammary gland. Milk samples were collected at 0 h, 12 h, 24 h after treatment for microbial identification and total bacterial count.ResultsThe treatment of the PDT group showed significant difference p <0.05, characterizing the efficiency of this technique with the reduction of the microorganisms Streptococcus dysgalactiae and coagulase-negative Staphylococcus.ConclusionPhotodynamic therapy was effective when applied in vivo for subclinical bovine mastitis. There was no need to separate the animal from production.



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5-Aminolevulinic acid photodynamic therapy in refractory vulvar lichen sclerosus et atrophicus: series of ten cases

Publication date: Available online 16 December 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Ting Lan, Yongzhen Zou, Michael R. Hamblin, Rui Yin
BackgroundVulvar lichen sclerosus et atrophicus (VLSA) is a chronic inflammatory skin disease of unknown etiology that mainly affects postmenopausal and perimenopausal women. The primary clinical symptoms of VLSA are itching, burning pain, and dyspareunia that can results in decreased quality of life. Existing therapies including topical corticosteroid ointment, topical calcineurin inhibitors, estrogens, are not very effective for treatment of VLSA.ObjectiveTo evaluate the effectiveness and safety of 5-aminolevulinic acid mediated photodynamic therapy (ALA-PDT) in the treatment of VLSA.Materials and MethodsTen patients with VLSA who had failed conventional treatment received ALA-PDT. 10% 5-ALA in an oil-in-water emulsion was applied to the lesions and occluded with plastic film for 3 h, when the lesions were irradiated with 100 mW/cm², 635 ± 15 nm red light for 20 minutes. Treatments were repeated three times at 2-week intervals. Objective and subjective symptoms and signs of the vulvar lesions based on horizontal visual analogue scales were recorded at each treatment and 1, 3, and 6 months after the last session. The quality of life was assessed using dermatology life quality index (DLQI) questionnaire.ResultsAll patients completed three ALA-PDT treatments and the follow-up visits. Clinical symptoms of itching disappeared completely in nine patients, one patient had itching decreased from severe to mild. All subjects showed objective improvement in lesions. The DLQI of all cases improved after treatment. The main side-effects of ALA-PDT were pain, erythema, and swelling. Side-effects were transient and tolerable. All patients reported being "satisfied" or "very satisfied" with their outcomes.ConclusionsALA-PDT is an effective and safe approach for the treatment of VLSA



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Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers

Publication date: Available online 16 December 2017
Source:Seminars in Cancer Biology
Author(s): Claire Lhuillier, Claire Vanpouille-Box, Lorenzo Galluzzi, Silvia Chiara Formenti, Sandra Demaria
Over the past few years, multiple immune checkpoint blockers (ICBs) have achieved unprecedented clinical success and have been approved by regulatory agencies for the treatment of an increasing number of malignancies. However, only a limited fraction of patients responds to ICBs employed as a standalone intervention, calling for the development of combinatorial regimens. Radiation therapy (RT) stands out as a very promising candidate for this purpose. Indeed, RT mediates antineoplastic effects not only by cytotoxic and cytostatic mechanisms, but also by modulating immunological functions, both locally (within the irradiated field) and systemically. As combinatorial regimens involving RT and ICBs are being developed and clinically tested at an accelerating pace, it is paramount to identify biomarkers that reliably predict the likelihood of individual patients to respond. Here, we discuss emerging biomarkers that may potentially predict the response of cancer patients to RT plus ICBs.



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Emerging biomarkers for immunomodulatory cancer treatment of upper gastrointestinal, pancreatic and hepatic cancers

Publication date: Available online 16 December 2017
Source:Seminars in Cancer Biology
Author(s): Belinda Lee, Ryan Hutchinson, Hui-Li Wong, Jeanne Tie, Tracy Putoczki, Ben Tran, Peter Gibbs, Michael Christie
Carcinomas of the oesophagus, stomach, pancreas and liver are common and account for a disproportionately high number of cancer deaths. There is a need for new treatment options for patients with advanced disease. Immunomodulatory treatments including immune checkpoint blockade offer a promising new approach, with efficacy shown in other solid tumour types. However, only a small proportion of patients with carcinomas of the oesophagus, stomach, pancreas and liver have responded to single agent checkpoint inhibitors, and there is a need for markers that are predictive of response to guide treatment of individual patients. Predictive markers may include epidemiological factors such as ethnicity, the genomic status of the tumour, circulating markers, expression of immune checkpoint molecules, and other features of the stromal/immune response at the site of the tumour. This review will focus on predictive biomarkers for immune checkpoint blockade in oesophageal, gastric, pancreatic and hepatocellular carcinomas, including the genomic context and immune landscape in which they occur. Pancreatic carcinomas are largely resistant to immune checkpoint inhibition in trials to date, therefore emerging immunomodulatory treatments in this tumour type are also reviewed.



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Understanding Preanalytical Variables and their Effects on Clinical Biomarkers of Oncology and Immunotherapy

Publication date: Available online 16 December 2017
Source:Seminars in Cancer Biology
Author(s): Lokesh Agrawal, Kelly B. Engel, Sarah R. Greytak, Helen M. Moore
Identifying a suitable course of immunotherapy treatment for a given patient as well as monitoring treatment response is heavily reliant on biomarkers detected and quantified in blood and tissue biospecimens. Suboptimal or variable biospecimen collection, processing, and storage practices have the potential to alter clinically relevant biomarkers, including those used in cancer immunotherapy. In the present review, we summarize effects reported for immunologically relevant biomarkers and highlight preanalytical factors associated with specific analytical platforms and assays used to predict and gauge immunotherapy response. Given that many of the effects introduced by preanalytical variability are gene-, transcript-, and protein-specific, biospecimen practices should be standardized and validated for each biomarker and assay to ensure accurate results and facilitate clinical implementation of newly identified immunotherapy approaches.



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Investigation of the pulsatility of cerebrospinal fluid using cardiac-gated Intravoxel Incoherent Motion imaging

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Anton S. Becker, Andreas Boss, Markus Klarhoefer, Tim Finkenstaedt, Moritz C. Wurnig, Cristina Rossi
The quantitative and non-invasive monitoring of cerebrospinal fluid (CSF) dynamics and composition may have high clinical relevance in the management of CSF disorders. In this study, we propose the use of the Intravoxel Incoherent Motion (IVIM) MRI for obtaining simultaneous measurements of CSF self-diffusion and fluid circulation. The rationale for this study was that turbulent fluid and mesoscopic fluid fluctuations can be modeled in a first approximation as a fast diffusion process. In this case, we expect that the fast fluid circulation and slower molecular diffusion dynamics can be quantified, assuming a bi-exponential attenuation pattern of the diffusion-weighted signal in MRI.IVIM indexes of fast and slow diffusion measured at different sites of the CSF system were systematically evaluated depending on both the phase of the heart cycle and the direction of the diffusion-encoding. The IVIM measurements were compared to dynamic measurements of fluid circulation performed by phase-contrast MRI.Concerning the dependence on the diffusion/flow-encoding direction, similar patterns were found both in the fraction of fast diffusion, f, and in the fluid velocity. Generally, we observed a moderate to high correlation between the fraction of fast diffusion and the maximum fluid velocity along the high-flow directions. Exploratory data analysis detected similarities in the dependency of the fraction of fast diffusion and of the velocity from the phase of the cardiac cycle. However, no significant differences were found between parameters measured during different phases of the cardiac cycle.Our results suggest that the fraction of fast diffusion may reflect CSF circulation. The bi-exponential IVIM model potentially allows us to disentangle the two diffusion components of the CSF dynamics by providing measurements of fluid cellularity (via the slow-diffusion coefficient) and circulation (via the fraction of fast-diffusion index).

Graphical abstract

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An unbiased data-driven age-related structural brain parcellation for the identification of intrinsic brain volume changes over the adult lifespan

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Epifanio Bagarinao, Hirohisa Watanabe, Satoshi Maesawa, Daisuke Mori, Kazuhiro Hara, Kazuya Kawabata, Noritaka Yoneyama, Reiko Ohdake, Kazunori Imai, Michihito Masuda, Takamasa Yokoi, Aya Ogura, Toshihiko Wakabayashi, Masafumi Kuzuya, Norio Ozaki, Minoru Hoshiyama, Haruo Isoda, Shinji Naganawa, Gen Sobue
This study aims to elucidate age-related intrinsic brain volume changes over the adult lifespan using an unbiased data-driven structural brain parcellation. Anatomical brain images from a cohort of 293 healthy volunteers ranging in age from 21 to 86 years were analyzed using independent component analysis (ICA). ICA-based parcellation identified 192 component images, of which 174 (90.6%) showed a significant negative correlation with age and with some components being more vulnerable to aging effects than others. Seven components demonstrated a convex slope with aging; 3 components had an inverted U-shaped trajectory, and 4 had a U-shaped trajectory. Linear combination of 86 components provided reliable prediction of chronological age with a mean absolute prediction error of approximately 7.2 years. Structural co-variation analysis showed strong interhemispheric, short-distance positive correlations and long-distance, inter-lobar negative correlations. Estimated network measures either exhibited a U- or an inverted U-shaped relationship with age, with the vertex occurring at approximately 45–50 years. Overall, these findings could contribute to our knowledge about healthy brain aging and could help provide a framework to distinguish the normal aging processes from that associated with age-related neurodegenerative diseases.



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Drosophila active zones: from molecules to behaviour

Publication date: Available online 16 December 2017
Source:Neuroscience Research
Author(s): Nadine Ehmann, David Owald, Robert J. Kittel
In a constantly changing environment, neuronal circuits need to be updated and adjusted to elicit directed actions. Synaptic plasticity plays an important role in modulating such globally and locally acting networks. The active zone (AZ) is a protein-rich compartment of chemical synapses, where precisely orchestrated molecular interactions control synaptic vesicle (SV) fusion with the presynaptic membrane. The subsequent release of neurotransmitter substances onto postsynaptic receptor fields forms the basis of neuronal communication. Structural, functional and molecular features of AZs can differ significantly between systems, within one and the same neuron and at an individual site over time. Moreover, the properties of an AZ can be altered by changes in cellular activity. While it is recognized that such AZ plasticity modulates synaptic communication, our mechanistic understanding of its impact on neural network function and animal behaviour is far from complete. Research on Drosophila melanogaster has created an advantageous situation for investigating molecular mechanisms of AZ physiology in a behavioural context. The sophisticated genetic tools and excellent experimental accessibility of the fruit fly can now be combined with detailed anatomical information on the nervous system and quantifiable readouts of various behaviours at high resolution. Here, we review molecular studies of AZ structure and function at the neuromuscular junction (NMJ) and consider how mechanisms identified in the periphery may relate to the operation of central AZs. Our discussion emphasizes that the location of AZs in central networks defines sites of plasticity which shape animal behaviour.



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Loss of inhibition in ipsilateral somatosensory areas following altered afferent nerve signaling from the hand

Publication date: Available online 16 December 2017
Source:Neuroscience Research
Author(s): Anders Björkman, Andreas Weibull
Cutaneous stimulation of the hand results in increased neural activity in the contralateral primary somatosensory cortex (S1) in humans, whereas an inhibition of neurons is seen in the ipsilateral S1.The aim of this study was to assess changes in neural activity in the S1 bilaterally, with a focus on the ipsilateral hemisphere, following altered afferent nerve signaling from the hand. Three cohorts, all with altered afferent nerve signaling from the hand, participated in the study. There were: 18 patients with traumatic median nerve injury, 10 patients with vibration induced neuropathy and 11 healthy subjects who had their dominant hand and wrist immobilized for 72 hours. In addition, 36 healthy subjects were included as controls. Each subject was examined using functional magnetic resonance imaging at 3 Tesla. All three study cohorts showed enlarged activation in the contralateral S1 during tactile stimulation compared to healthy controls. Moreover, inhibition of the ipsilateral S1 was significantly decreased or completely lost. Thus, somatosensory areas of both hemispheres respond to changed afferent nerve signaling from the hand. The loss of inhibition of neurons in the ipsilateral S1 suggests an important role of the ipsilateral hemisphere in the cerebral adaptation following a change in afferent nerve signaling.



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A nephron model for study of drug-induced acute kidney injury and assessment of drug-induced nephrotoxicity

Publication date: February 2018
Source:Biomaterials, Volume 155
Author(s): Yueyang Qu, Fan An, Yong Luo, Yao Lu, Tingjiao Liu, Weijie Zhao, Bingcheng Lin
In this study, we developed a multilayer microfluidic device to simulate nephron, which was formed by "glomerulus", "Bowman's capsule", "proximal tubular lumen" and "peritubular capillary". In this microdevice, artificial renal blood flow was circulating and glomerular filtrate flow was single passing through, mimicking the behavior of a nephron. In this dynamic artificial nephron, we observed typical renal physiology, including the glomerular size-selective barrier, glomerular basement membrane charge-selective barrier, glucose reabsorption and para-aminohippuric acid secretion. To demonstrate the capability of our microdevice, we used it to investigate the pathophysiology of drug-induced acute kidney injury (AKI) and give assessment of drug-induced nephrotoxicity, with cisplatin and doxorubicin as model drugs. In the experiment, we loaded the doxorubicin or cisplatin in the "renal blood flow", recorded the injury of primary glomerular endothelial cells, podocytes, tubular epithelial cells and peritubular endothelial cells by fluorescence imaging, and identified the time-dependence, dose-dependence and the death order of four types of renal cells. Then by measuring multiple biomarkers, including E-cadherin, VEGF, VCAM-1, Nephrin, and ZO-1, we studied the mechanism of cell injuries caused by doxorubicin or cisplatin. Also, we investigated the effect of BSA in the "renal blood flow" on doxorubicin-or-cisplatin-induced nephrotoxicity, and found that BSA enhanced the tight junctions between cells and eased cisplatin-induced nephrotoxicity. In addition, we compared the nephron model and traditional tubule models for assessment of drug-induced nephrotoxicity. And it can be inferred that our biomimetic microdevice simulated the complex, dynamic microenvironment of nephron, yielded abundant information about drug-induced-AKI at the preclinical stage, boosted the drug safety evaluation, and provided a reliable reference for clinical therapy.



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Theranostic 2D ultrathin MnO2 nanosheets with fast responsibility to endogenous tumor microenvironment and exogenous NIR irradiation

Publication date: February 2018
Source:Biomaterials, Volume 155
Author(s): Zhuang Liu, Shengjian Zhang, Han Lin, Menglong Zhao, Heliang Yao, Linlin Zhang, Weijun Peng, Yu Chen
The fabrication of functional nanoparticles with unique ultra-sensitivity to endogenous tumor microenvironment (TME) is of great significance for their improved theranostic performance and easy excretion out of the body, which has not been realized among diverse nano-sized photothermal agents for photothermal therapy (PTT) of tumor. In this work, we report on the synthesis of 2D ultrathin MnO2 nanosheets for highly efficient PTT against tumor with ultra-sensitivity to endogenous TME. These ultrathin 2D MnO2 nanosheets show the intriguing characteristic of disintegration and releasing of Mn²⁺ in response to the mild acidic condition and elevated reducing microenvironment of TME, which has successfully realized the pH- and reducing-responsive T1-weighted magnetic resonance imaging of tumor. Importantly, the high PTT efficiency of 2D MnO2 nanosheets responsive to exogenous NIR irradiation has been systematically demonstrated both in vitro and in vivo for suppressing the tumor growth. This first report on the exploring of TME-sensitive photothermal agents with concurrent diagnostic and therapeutic (theranostic) functions significantly broadens the biomedical application of 2D functional biomaterials, which also promotes the further potential clinical translations of nano-sized photothermal agents.

Graphical abstract

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DNA nanoparticles for ophthalmic drug delivery

Publication date: March 2018
Source:Biomaterials, Volume 157
Author(s): Jan Willem de Vries, Sven Schnichels, José Hurst, Lisa Strudel, Agnieszka Gruszka, Minseok Kwak, Karl-U. Bartz-Schmidt, Martin S. Spitzer, Andreas Herrmann
Nucleic acids represent very appealing building blocks for the construction of nano-scaled objects with great potential applications in the field of drug delivery where multifunctional nanoparticles (NPs) play a pivotal role. One opportunity for DNA nanotechnology lies in the treatment of ophthalmic diseases as the efficacy of eye drops is impaired by the short survival time of the drug on the eye surface. As a consequence, topical administration of ocular therapeutics requires high drug doses and frequent administration, still rarely providing high bioavailability. To overcome these shortcomings we introduce a novel and general carrier system that is based on DNA nanotechnology. Non-toxic, lipid-modified DNA strands (12mers with 4 lipid modified thymines at the 5′ end) form uniform NPs (micelles), which adhere to the corneal surface for extended periods of time. In a single self-assembly step they can be equipped with different drugs by hybridization with an aptamer. The long survival times of DNA NPs can be translated into improved efficacy. Their functionality was demonstrated in several ex-vivo experiments and in an in-vivo animal model. Finally, the NPs were confirmed to be applicable even for human tissue.

Graphical abstract

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Editorial Board

Publication date: February 2018
Source:Biomaterials, Volume 155





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Air Versus Ground Transportation in Isolated Severe Head Trauma: A National Trauma Data Bank Study

Publication date: Available online 16 December 2017
Source:The Journal of Emergency Medicine
Author(s): Alberto Aiolfi, Elizabeth Benjamin, Gustavo Recinos, Alejandro De Leon Castro, Kenji Inaba, Demetrios Demetriades
BackgroundThe effect of prehospital helicopter emergency medical services (HEMS) on mortality has been analyzed previously in polytrauma patients with discordant results.ObjectiveOur aim was to compare outcomes in patients with isolated severe blunt traumatic brain injuries (TBIs) transported by HEMS or ground emergency medical services (GEMS).MethodsWe conducted a National Trauma Data Bank study (2007–2014). All adult patients (≥16 years old) who sustained an isolated severe blunt TBI and were transported by HEMS or GEMS were included in the study.ResultsThere were 145,559 patients who met the inclusion criteria. Overall, 116,391 (80%) patients were transported via GEMS and 29,168 (20%) via HEMS. Median transportation time was longer for HEMS patients (41 vs. 25 min; p < 0.001). HEMS patients were more likely to have hypotension (2.7% vs. 1.5%; p < 0.001), Glasgow Coma Scale (GCS) score < 9 (38.2% vs. 10.9%; p < 0.001), and head Abbreviation Injury Scale (AIS) score of 5 (20.1% vs. 9.7%; p < 0.001). Stepwise logistic regression analysis identified age ≥ 65 years old, male sex, hypotension, GCS score < 9, prehospital intubation, and head AIS scores 4 and 5 as independent predictors of mortality. Helicopter transportation was independently associated with improved survival (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.47–0.67; p < 0.001). Admission to a Level I trauma center was an independent predictor of survival (OR 0.64; 95% CI 0.53–0.82; p = 0.001). Regardless of head AIS, helicopter transport was an independent predictor of survival (AIS 3: OR 0.35; p < 0.001; AIS 4: OR 0.44; p < 0.001; AIS 5: OR 0.76; p < 0.001). A prolonged transport time was not an independent predictor of mortality.ConclusionsHelicopter transport, in adult patients with isolated severe TBI, is associated with improved survival.



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Piezoresistive response of extruded polyaniline/(styrene-butadiene-styrene) polymer blends for force and deformation sensors

Publication date: 5 March 2018
Source:Materials & Design, Volume 141
Author(s): J. Teixeira, L. Horta-Romarís, M.-J. Abad, P. Costa, S. Lanceros-Méndez
Smart materials for sensor applications are increasingly being used in a wide variety of applications ranging from engineering to medical devices. This work reports on piezoresistive sensors based on conductive polyaniline and thermoplastic elastomer processed by conventional polymer extrusion. The material presents excellent processability and piezoresistive performance offering an alternative to traditional composites with conductive nanofillers for sensor applications.The polyaniline/styrene-butadiene-styrene (PANI/SBS) conductive polymer blends present good mechanical properties, high electrical conductivity and piezoresistive response. The maximum strain reaches ≈60% for 30 weight percentage (wt%) PANI content and the electrical conductivity is σ≈0.1S/m for blends with 40wt% PANI content. Further, the sample with 40wt% PANI content shows a piezoresistive gauge factor GF≈1 for deformation measurements between 0.1 and 3mm in bending cycles.

Graphical abstract

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Antioxidant Functionalized Polymer Capsules to Prevent Oxidative Stress

Publication date: Available online 16 December 2017
Source:Acta Biomaterialia
Author(s): Aitor Larrañaga, Isma Liza Mohd Isa, Vaibhav Patil, Sagana Thamboo, Mihai Lomora, Marc A. Fernández-Yague, Jose-Ramon Sarasua, Cornelia G. Palivan, Abhay Pandit
Polymeric capsules exhibit significant potential for therapeutic applications as microreactors, where the bio-chemical reactions of interest are efficiently performed in a spatial and time defined manner due to the encapsulation of an active biomolecule (e.g., enzyme) and control over the transfer of reagents and products through the capsular membrane. In this work, catalase loaded polymer capsules functionalized with an external layer of tannic acid (TA) are fabricated via a layer-by-layer approach using calcium carbonate as a sacrificial template. The capsules functionalised with TA exhibit a higher scavenging capacity for hydrogen peroxide and hydroxyl radicals, suggesting that the external layer of TA shows intrinsic antioxidant properties, and represents a valid strategy to increase the overall antioxidant potential of the developed capsules. Additionally, the hydrogen peroxide scavenging capacity of the capsules is enhanced in the presence of the encapsulated catalase. The capsules prevent oxidative stress in an in vitro inflammation model of degenerative disc disease. Moreover, the expression of matrix metalloproteinase-3 (MMP-3), and disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5), which represents the major proteolytic enzymes in intervertebral disc, are attenuated in the presence of the polymer capsules. This platform technology exhibits potential to reduce oxidative stress, a key modulator in the pathology of a broad range of inflammatory diseases.Statement of significanceOxidative stress damages important cell structures leading to cellular apoptosis and senescence, for numerous disease pathologies including cancer, neurodegeneration or osteoarthritis. Thus, the development of biomaterials-based systems to control oxidative stress has gained an increasing interest. Herein, polymer capsules loaded with catalase and functionalized with an external layer of tannic acid are fabricated, which can efficiently scavenge important reactive oxygen species (i.e., hydroxyl radicals and hydrogen peroxide) and modulate extracellular matrix activity in an in vitro inflammation model of nucleus pulposus. The present work represents accordingly, an important advance in the development and application of polymer capsules with antioxidant properties for the treatment of oxidative stress, which is applicable for multiple inflammatory disease targets.

Graphical abstract

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Editors, Issue sections

Publication date: October 2017
Source:Current Opinion in Immunology, Volume 48





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Control of innate-like B cell location for compartmentalised IgM production

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Lucy H Jackson-Jones, Cécile Bénézech
Natural IgM are crucial for early protection against infection and play an important homeostatic function by clearing dead cells. The production of IgM is ensured by a population of B cells with innate-like properties: their response is rapidly activated by innate signals early during the onset of infection. The main reservoir of innate-like B cells (IBCs) are the serous cavities, but their maintenance and activation depends on their relocation to a variety of lymphoid tissues. Recent advances indicate that fat-associated lymphoid clusters (FALCs) and milky spots contribute to local IgM secretion and play a central role in the localisation and regulation of IBC function.

Graphical abstract

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Insights into immune tolerance from AIRE deficiency

Publication date: December 2017
Source:Current Opinion in Immunology, Volume 49
Author(s): Irina Proekt, Corey N Miller, Michail S Lionakis, Mark S Anderson
AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or absent AIRE function have markedly variable phenotypes that include a range of autoimmune manifestations. Recent evidence suggests that this variability stems from cooperation of autoimmune susceptibilities involving both central and peripheral tolerance checkpoints. Here we discuss the broadening understanding of the factors that influence Aire expression, modify AIRE function, and the impact and intersection of AIRE with peripheral immunity. This rapidly expanding body of knowledge will force a reexamination of the definition and clinical management of APS-1 patients as well as provide a foundation for the development of immunomodulatory strategies targeting central tolerance.



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Heme and hemolysis in innate immunity: adding insult to injury

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Rui Martins, Sylvia Knapp
Heme is a vital, iron-containing prosthetic molecule present in a variety of proteins, of which hemoglobin is the most abundant. While the reactivity afforded by its central iron ion is essential for many cellular processes, it renders heme a potentially damaging molecule upon its release from hemeproteins, as it can catalyze the generation of reactive oxygen species. Severe intravascular hemolysis results in the leakage of vast amounts of hemoglobin, and subsequently, heme into the plasma. As such, heme is increasingly recognized as a major driving force for hemolysis-associated pathology including an increased risk for bacterial infections, due to its pro-oxidant, cytotoxic and immunomodulatory effects. Here, we provide a succinct review of recent, significant developments on how heme can influence innate immune functions, ranging from the maintenance of iron homeostasis by macrophages, the modulation of inflammatory responses, to its role in altering resistance mechanisms against bacterial infections.



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A ravenous defense: canonical and non-canonical autophagy in immunity

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Payel Sil, Ginger Muse, Jennifer Martinez
While classically considered a survival mechanism employed during nutrient scarcity, the autophagy pathway operates in multiple scenarios wherein a return to homeostasis or degradative removal of an invader is required. Now recognized as a pathway with vast immunoregulatory power, autophagy can no longer serve as a 'one size fits all' term, as its machinery can be recruited to different pathogens, at different times, with different outcomes. Both canonical autophagy and the molecularly related, yet divergent pathways non-canonical autophagy are key players in proper host defense and allow us an opportunity to tailor infectious disease intervention and treatment to its specific pathway.



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Editorial overview: Offence is the best defense: host–pathogen interactions driving evolution of human immunity and the germs we live with

Publication date: October 2017
Source:Current Opinion in Immunology, Volume 48
Author(s): Marc Pellegrini, Elizabeth Hartland




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Recent advances in inflammasome biology

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): David E Place, Thirumala-Devi Kanneganti
The inflammasome is a complex of proteins that through the activity of caspase-1 and the downstream substrates gasdermin D, IL-1β, and IL-18 execute an inflammatory form of cell death termed pyroptosis. Activation of this complex often involves the adaptor protein ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. Here we discuss new regulatory mechanisms that have been identified for the canonical inflammasomes, the most recently identified NLRP9b inflammasome, and the new gasdermin family of proteins that mediate pyroptosis and other forms of regulated cell death.



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Reinterpreting recent thymic emigrant function: defective or adaptive?

Publication date: April 2018
Source:Current Opinion in Immunology, Volume 51
Author(s): Cody A Cunningham, Eric Y Helm, Pamela J Fink
Recent thymic emigrants (RTEs) are those peripheral T cells that have most recently completed thymic development and egress. Over the past decade, significant advances have been made in understanding the cell-extrinsic and cell-intrinsic requirements for RTE maturation to mature naïve (MN) T cells and in detailing the functional differences that characterize these two T cell populations. Much of this work has suggested that RTEs are hypo-functional versions of more mature T cells. However, recent evidence has indicated that rather than being defective T cells, RTEs are exquisitely adapted to their cellular niche. In this review, we argue that RTEs are not flawed mature T cells but are adapted to fill an underpopulated T cell compartment, while maintaining self tolerance and possessing the capacity to mount robust immune responses.



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New roles and controls of mast cells

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Eric Espinosa, Salvatore Valitutti
Mast cells are innate immune cells implicated in immune surveillance and defense. They are filled with secretory granules where a vast array of molecules endowed with multiple biological activities are stored. The process of granule secretion, named degranulation, is a tightly controlled biological phenomenon that allows mast cells to rapidly and efficiently release bioactive mediators in response to extracellular stimuli. MC degranulation allows fighting pathogens, limiting envenomation and contributes to tissue homeostasis. However, it is also a potentially harmful response that plays a key role in the development of allergy and inflammatory diseases.Recent findings revealed that MC degranulation is a complex modular process that can be controlled at multiple levels. First, mast cells can decode different activation stimuli into two main patterns of degranulation that differently impact inflammatory responses. Second, mast cells in contact with antibody-opsonized cells or parasites form antibody-dependent degranulatory synapse for dedicated secretion and defense. Third, IL-33 fine-tunes FcR-mediated degranulation at the single cell level.Together these recent findings show how mast cells adapt their degranulation responses to environmental cues and highlight the remarkable functional plasticity of these cells.



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Monogenic lupus: it's all new!

Publication date: December 2017
Source:Current Opinion in Immunology, Volume 49
Author(s): Patricia Costa-Reis, Kathleen E Sullivan
Monogenic lupus is rare, but its study has contributed immensely to a better understanding of the pathogenesis of systemic lupus erythematosus. The first forms identified were inherited complement deficiencies, which predisposed to lupus due to impaired tolerance, and aberrant clearance of apoptotic bodies and immune complexes. In recent years, several new monogenic disorders with a lupus-like phenotype have been described. These include forms that affect nucleic acid repair, degradation and sensing (TREX1, DNASE1L3), the type I interferon (IFN) pathway (SAMHD1, RNASEH2ABC, ADAR1, IFIH1, ISG15, ACP5, TMEM173) and B cell development checkpoints (PRKCD; RAG2). Pathways informed by these newly described disorders have continued to improve our understanding of systemic lupus erythematosus.

Graphical abstract

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Immunoresolvents signaling molecules at intersection between the brain and immune system

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Jesmond Dalli, Charles N Serhan
Understanding mechanisms that control immunity is central in the quest to gain insights into the etiopathology of many of the diseases that afflict modern societies. New results implicate the nervous system as a central player in controlling many aspects of both the innate and adaptive arms of the immune response. Furthermore it is now well appreciated that a novel group of autacoids termed as specialized proresolving mediators, which are enzymatically produced from essential fatty acids, orchestrate the immune response promoting the termination of inflammation as well as tissue repair and regeneration. The present brief review discusses evidence for the crosstalk between the nervous system and leukocytes in regulating SPM production. We will also discuss the impact that this has on controlling tissue resolution tone and the resolution of both infectious and sterile inflammation.



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Highlights in immune response, microbiome and precision medicine in allergic disease and asthma

Publication date: October 2017
Source:Current Opinion in Immunology, Volume 48
Author(s): Milena Sokolowska, Cezmi A. Akdis
Several recent key findings in immunology of allergic diseases that have led to a need of reassessment of our current thinking are reviewed in this issue of the journal. Recently developed strong evidence on the role of hygiene hypothesis in protection from allergic disease and its immune mechanisms is reviewed by Ober et al. The authors pointed out immunologic mechanisms of lower prevalence of asthma and allergic sensitization observed among Amish children living on traditional farms with higher endotoxin levels as compared to Hutterite children living on industrialized farms. Barcik et al. reviewed that biologically active histamine in humans is produced by certain bacteria in the gut in addition to several cells, and has broad immunoregulatory functions. Turcanu et al. reviewed immune mechanisms of a revolutionary change to protect from food allergy. The immunologic window of opportunity in the infants can be used to enable oral tolerance in severe allergy predisposed children. Accordingly, van de Veen et al. reviewed general mechanisms of allergen tolerance highlighting recent findings. Extensive usage of precision medicine due to emerging biologics is knocking the doors of allergic diseases and asthma. Boyd et al. reviewed the existing and future "immune monitoring" approaches in the multiple omics perspective with the hope of identifying better correlates of disease status, predictors of therapeutic outcomes, and potential side-effects of treatment. Paul et al. reviewed newly uncovered innate and adaptive immunologic mechanisms that contribute to the pathogenesis of eosinophilic esophagitis. Further highlighting newly developing disease subgroups and precision medicine, Guttman-Yassky & Kruger reviewed clinical subtypes of atopic dermatitis and psoriasis, which may potentially benefit from newly developing highly efficient biologicals. Complementing this paper, Kabashima & Nomura reviewed similarities and distinctions in mouse models of atopic dermatitis and psoriasis.



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DNA damage signaling and polyploid macrophages in chronic inflammation

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Veronika Horn, Antigoni Triantafyllopoulou
Whole genome duplications, an important step in cancer development, also occur in the macrophage lineage in disease: large multinucleated macrophages found within compact, ordered aggregates of immune cells, called granulomas, are a well-known histologic entity. Very recent work suggests that granuloma macrophages remarkably acquire epithelial cell features and the genotoxic stress response instructs granuloma macrophage genome duplications, suggesting that granuloma macrophages and pre-malignant epithelial cells may share common mechanisms of adaptation to chronic genotoxic stress. Exploring these mechanisms is key for a better understanding of the pathogenesis of chronic inflammatory diseases. Here we review the mechanisms of macrophage polyploidization, the role of DNA damage signaling in this process and the function of polyploid macrophages, with a focus on chronic inflammation.



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Regulation of MAVS activation through post-translational modifications

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Bingyu Liu, Chengjiang Gao
RLRs (including RIG-I and MDA5) are the main receptors that recognize cytoplasmic viral RNA. Upon binding of viral RNA, RIG-I and MDA5 recruit mitochondria-localized MAVS to activate the downstream antiviral signaling. MAVS forms prion-like aggregates on the mitochondria after virus infection. The regulatory mechanisms for MAVS activation have been defined in various studies. Here, we summarize the recent advances about MAVS roles in antiviral immunity, discuss the regulation of MAVS activation, and suggest interesting areas for future research.



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Developmental control of macrophage function

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Johnny Bonnardel, Martin Guilliams
The combination between novel fate-mapping tools and single-cell RNA-sequencing technology has revealed the presence of multiple macrophage progenitors. This raises the fascinating possibility that what was once perceived as immense functional plasticity of macrophages could in fact come down to separate macrophage subsets performing distinct functions because of their differential cellular origin. The question of macrophage plasticity versus macrophage heterogeneity is broader than the difference between macrophages of embryonic or adult hematopoietic origin and is particularly relevant in the context of inflammation. In this manuscript, we review the potential impact of cellular origin on the function of macrophages. We also highlight the need for novel 'functional fate-mapping' tools that would reveal the history of the functional state of macrophages, rather than their cellular origin, in order to finally study their true plasticity in vivo.



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Cytosolic sensing of immuno-stimulatory DNA, the enemy within

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Rekha Dhanwani, Mariko Takahashi, Sonia Sharma
In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2′–5′-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS–STING–IRF3 response is triggered by direct recognition of the DNA genomes of bacteria and viruses, but also during RNA virus infection, neoplastic transformation, tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno-stimulatory DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived DNA substrates, including endogenous retroviral elements, mitochondrial DNA (mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults.



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Disease tolerance: concept and mechanisms

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): JL McCarville, JS Ayres
Two distinct defense strategies provide a host with survival to infectious diseases: resistance and tolerance. Resistance is dependent on the ability of the host to kill pathogens. Tolerance promotes host health while having a neutral to positive impact of pathogen fitness. Immune responses are almost inevitably defined in terms of pathogen resistance. Recent evidence has shown, however, that several effects attributed to activation of innate and adaptive immune mechanisms, cannot be readily explained with the paradigm of immunity as effectors of microbial destruction. This review focuses on integrating the concept of disease tolerance into recent studies of immune system function related to the regulation and resolution of tissue damage, T cell exhaustion, and tolerance to innocuous antigen.



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Molecular control of regulatory T cell development and function

Publication date: December 2017
Source:Current Opinion in Immunology, Volume 49
Author(s): Yohko Kitagawa, Shimon Sakaguchi
Treg cells expressing the transcription factor Foxp3 are essential for immunological tolerance and homeostasis. Recent genome-wide studies have revealed that Foxp3⁺ natural Treg cells possess a number of unique transcriptional and epigenetic features, which appear to be acquired along the course of Treg cell development and maintained throughout their lifespan. These studies also provide novel insights into how genomic variations contribute to genetic susceptibility to human autoimmune diseases by affecting Treg cell development and function.



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Editors, Issue sections

Publication date: December 2017
Source:Current Opinion in Immunology, Volume 49





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What's up in the ALPS

Publication date: December 2017
Source:Current Opinion in Immunology, Volume 49
Author(s): Frédéric Rieux-Laucat
The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia. This clinical entity was recognized in the mid 60s and its genetic etiology was described in 1995 by the discovery of the FAS gene mutations. This was the first description of a monogenic cause of autoimmunity but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients. The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic causes of ALPS such as somatic mutations of RAS or the recently described CTLA-4 insufficiency. The recognition of these genetic diseases brought new information on the regulation of the adaptive immune responses and uncovered new therapeutical targets. Finally, the deciphering the role of somatic mutations may pave the way to the understanding of more common autoimmune diseases.



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