Репозиторий Университета

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Main conclusion: The LysM receptor-like kinase K1 is involved in regulation of pea-rhizobial symbiosis development. The ability of the crop legume Pisum sativum L. to perceive the Nod factor rhizobial signals may depend on several receptors that differ in ligand structure specificity. Identification of pea mutants defective in two types of LysM receptor-like kinases (LysM-RLKs), SYM10 and SYM37, featuring different phenotypic manifestations and impaired at various stages of symbiosis development, corresponds well to this assumption. There is evidence that one of the receptor proteins involved in symbiosis initiation, SYM10, has an inactive kinase domain. This implies the presence of an additional component in the receptor complex, together with SYM10, that remains unknown. Here, we describe a new LysM-RLK, K1, which may serve as an additional component of the receptor complex in pea. To verify the function of K1 in symbiosis, several P. sativum non-nodulating mutants in the k1 gene were identified using the TILLING approach. Phenotyping revealed the blocking of symbiosis development at an appropriately early stage, strongly suggesting the importance of LysM-RLK K1 for symbiosis initiation. Moreover, the analysis of pea mutants with weaker phenotypes provides evidence for the additional role of K1 in infection thread distribution in the cortex and rhizobia penetration. The interaction between K1 and SYM10 was detected using transient leaf expression in Nicotiana benthamiana and in the yeast two-hybrid system. Since the possibility of SYM10/SYM37 complex formation was also shown, we tested whether the SYM37 and K1 receptors are functionally interchangeable using a complementation test. The interaction between K1 and other receptors is discussed.

© 2018 Elsevier Ltd In this review, we describe dielectric properties of biological tissues and liquids in the context of terahertz (THz) biophotonics. We discuss a model of the THz dielectric permittivity of water and water-containing media, which yields analysis of the relaxation and damped resonant molecules modes. We briefly describe modern techniques of THz spectroscopy and imaging employed in biophotonics with a strong emphasize on a THz time-domain spectroscopy. Furthermore, we consider the methods of sub-wavelength resolution THz imaging and the problem of THz wave delivery to hard to access tissues and internal organs. We consider the THz dielectric properties of biological solutions and liquids. Although strong absorption by water molecules prevents THz-waves from penetration of hydrated tissues and probing biological molecules in aqueous solutions, we discuss approaches for overcoming these drawbacks – novel techniques of freezing and temporal dehydration by application of hyperosmotic agents which have a potential for cancer detection. We review recent applications of THz technology in diagnosis of malignancies and aiding histology paying particular attention to the origin of contrast observed between healthy and pathological tissues. We consider recent applications of THz reflectometry in sensing the thinning dynamics of human pre-corneal tear film. Modern modalities of THz imaging, which relies on the concepts of multi-spectral and multi-temporal domains and employing the principles of color vision, phase analysis and tomography are discussed. Novel methods of THz spectra analysis based on machine learning, pattern recognition, chemical imaging and the revealing of the spatial distribution of various substances in a tissue, are analyzed. Advanced thermal model describing biological object irradiated by THz waves and phantoms mimicking the optical properties of tissues at THz frequencies are presented. Finally, application of the high-resolution THz spectroscopy in analytic chemistry, biology and medicine are described.

© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. Methods: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10–54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10–14 years and 50–54 years was estimated from data on fertility in women aged 15–19 years and 45–49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. Findings: From 1950 to 2017, TFRs decreased by 49·4% (95% uncertainty interval [UI] 46·4–52·0). The TFR decreased from 4·7 livebirths (4·5–4·9) to 2·4 livebirths (2·2–2·5), and the ASFR of mothers aged 10–19 years decreased from 37 livebirths (34–40) to 22 livebirths (19–24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83·8 million people per year since 1985. The global population increased by 197·2% (193·3–200·8) since 1950, from 2·6 billion (2·5–2·6) to 7·6 billion (7·4–7·9) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2·0%; this rate then remained nearly constant until 1970 and then decreased to 1·1% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2·5% in 1963 to 0·7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2·7%. The global average age increased from 26·6 years in 1950 to 32·1 years in 2017, and the proportion of the population that is of working age (age 15–64 years) increased from 59·9% to 65·3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1·0 livebirths (95% UI 0·9–1·2) in Cyprus to a high of 7·1 livebirths (6·8–7·4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0·08 livebirths (0·07–0·09) in South Korea to 2·4 livebirths (2·2–2·6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0·3 livebirths (0·3–0·4) in Puerto Rico to a high of 3·1 livebirths (3·0–3·2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2·0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. Interpretation: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. Funding: Bill & Melinda Gates Foundation.

© 2018 MDPI AG. All rights reserved. Soil fungi are known to contain a rich variety of defense metabolites that allow them to compete with other organisms (fungi, bacteria, nematodes, and insects) and help them occupy more preferential areas at the expense of effective antagonism. These compounds possess antibiotic activity towards a wide range of other microbes, particularly fungi that belong to different taxonomical units. These compounds include peptaibols, which are non-ribosomal synthesized polypeptides containing non-standard amino acid residues (alpha-aminoisobutyric acid mandatory) and some posttranslational modifications. We isolated a novel antibiotic peptide from the culture medium of Emericellopsis alkalina, an alkalophilic strain. This peptide, called emericellipsin A, exhibited a strong antifungal effect against the yeast Candida albicans, the mold fungus Aspergillus Niger, and human pathogen clinical isolates. It also exhibited antimicrobial activity against some Gram-positive and Gram-negative bacteria. Additionally, emericellipsin A showed a significant cytotoxic effect and was highly active against Hep G2 and HeLa tumor cell lines. We used NMR spectroscopy to reveal that this peptaibol is nine amino acid residues long and contains non-standard amino acids. The mode of molecular action of emericellipsin A is most likely associated with its effects on the membranes of cells. Emericellipsin A is rather short peptaibol and could be useful for the development of antifungal, antibacterial, or anti-tumor remedies.

© 2018 Walter de Gruyter GmbH, Berlin/Boston.  Despite intensive research, thromboembolism still accounts for significant maternal morbidity and mortality. We examined thrombophilia in patients with thromboembolism during pregnancy and evaluated the efficiency of antithrombotic prophylaxis in patients with thrombophilia for the prevention of recurrent thromboembolism. Sixty-eight women with a history of thromboembolism were managed during pregnancy, in light of their thrombotic history and the result of thrombophilia assessment. Group I (n=50) received prophylaxis with low molecular weight heparin (LMWH)±aspirin (50-100 mg/day) in preconception period or from the 1 st trimester, during pregnancy and at least 6 weeks postpartum. Group II (n=18) received LMWH±aspirin from the II to III trimester. Thromboses were associated with pregnancy in 27 patients (39.7%), with systemic diseases - in nine (13.2%), oral contraceptives use - 22 (32.3%), immobilization due to surgery and/or trauma, long flight - six (8.9%), septic complications - two (2.9%). Nevertheless, 24.5% of patients had no apparent provoking factor for the development of thrombotic complications. Thirty-seven (54%) patients with venous thromboembolism (VTE) had familial history of VTE, and 25 (36.7%) had personal history of pregnancy complications (fetal loss syndrome, preeclampsia and placental abruption) (P<0.05 vs. control). Thrombophilia was detected in 58 (85.3%). Usual thrombogenic polymorphisms [factor V (FV) Leiden and prothrombin G20210A, heterozygous forms] were revealed in 16 (23.5%) and eight (11.7%) patients, respectively. Antiphospholipid antibodies (aPL) circulation was found in 34 (50%) patients. Non-usual thrombogenic polymorphisms were identified in 44 (64.7%) of the women and hyperhomocysteinemia - in 30 (44.2%). In group I no one had severe obstetric complications. All the patients were delivered at term and all the babies were alive. In group II moderate-to-severe obstetric complications were noted: preeclampsia - in 11 (16.2%), severe preeclampsia - seven (10.3%), preterm delivery - in 18 (26.4%) patients from subgroup II (P<0.05). Women with a personal or a family history of thromboembolism and obstetric complications should be screened for thrombophilia. Beginning anticoagulant therapy early in such patients is effective not only for preventing recurring thrombosis but also preventing obstetric complications. Late prophylaxis after the completion of the trophoblast invasion therapy is much less effective.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license Blue biotechnologies implement marine bio-resources for addressing practical concerns. The isolation of biologically active molecules from marine animals is one of the main ways this field develops. Strikingly, cnidaria are considered as sustainable resources for this purpose, as they possess unique cells for attack and protection, producing an articulated cocktail of bioactive substances. The Mediterranean sea anemone Anemonia viridis has been studied extensively for years. In this short review, we summarize advances in bioprospecting of the A. viridis toxin arsenal. A. viridis RNA datasets and toxin data mining approaches are briefly described. Analysis reveals the major pool of neurotoxins of A. viridis, which are particularly active on sodium and potassium channels. This review therefore integrates progress in both RNA-Seq based and biochemical-based bioprospecting of A. viridis toxins for biotechnological exploitation.

© 2018 The Author(s). Background: To enrich the hitherto insufficient understanding regarding the mechanisms of action of transcranial direct current stimulation (tDCS) in pain disorders, we investigated its modulating effects on cerebral pain processing using functional magnetic resonance imaging (fMRI). Methods: Thirteen right-handed healthy participants received 20 min of 1.5 mA tDCS applied over the primary motor cortex thrice and under three different stimulation pattern (1.anodal-tDCS, 2.cathodal-tDCS, and 3.sham-tDCS) in a blinded cross-over design. After tDCS neural response to electric trigeminal-nociceptive stimulation was investigated using a block designed fMRI. Results: Pain stimulation showed a distinct activation pattern within well-established brain regions associated with pain processing. Following anodal tDCS increased activation was detected in the thalamus, basal ganglia, amygdala, cingulate, precentral, postcentral, and dorsolateral prefrontal cortex, while cathodal t-DCS showed decreased response in these areas (pFWE < 0.05). Interestingly the observed effect was reversed in both control conditions (visual- and motor-stimulation). Behavioral data remained unchanged irrespective of the tDCS stimulation mode. Conclusions: This study demonstrates polarity-specific modulation of cerebral pain processing, in reconfirmation of previous electrophysiological data. Anodal tDCS leads to an activation of the central pain-network while cathodal tDCS does not. Results contribute to a network-based understanding of tDCS's impact on cerebral pain-processing.

© 2018 by the authors. Recent strides in micro- and nanomanufacturing technologies have sparked the development of micro-/nanorobots with enhanced power and functionality. Due to the advantages of on-demand motion control, long lifetime, and great biocompatibility, magnetic propelled micro-/nanorobots have exhibited considerable promise in the fields of drug delivery, biosensing, bioimaging, and environmental remediation. The magnetic fields which provide energy for propulsion can be categorized into rotating and oscillating magnetic fields. In this review, recent developments in oscillating magnetic propelled micro-/nanorobot fabrication techniques (such as electrodeposition, self-assembly, electron beam evaporation, and three-dimensional (3D) direct laser writing) are summarized. The motion mechanism of oscillating magnetic propelled micro-/nanorobots are also discussed, including wagging propulsion, surface walker propulsion, and scallop propulsion. With continuous innovation, micro-/nanorobots can become a promising candidate for future applications in the biomedical field. As a step toward designing and building such micro-/nanorobots, several types of common fabrication techniques are briefly introduced. Then, we focus on three propulsion mechanisms of micro-/nanorobots in oscillation magnetic fields: (1) wagging propulsion; (2) surface walker; and (3) scallop propulsion. Finally, a summary table is provided to compare the abilities of different micro-/nanorobots driven by oscillating magnetic fields.

© Ivyspring International Publisher. Stem cells (SCs) research is one of the most promising approaches to regenerative medicine. Our understanding of SCs biology and their potential role in tissue repairing has notably increased during the last few years. Mesenchymal stem cells (MSCs) are present in almost all human tissues, including oral and dental tissues (dental-derived stem cells or DDSCs). Despite many doubts and too many pitfalls still affect regenerative dentistry; however, it represents an exciting challenge for the next generations of young dentists. Educating and training in regenerative medicine the new generation of researchers is of utmost importance, albeit often underestimated: regenerative dentistry represents a big opportunity for the next generations of researchers and clinicians, and this review report underlines that dental schools should pay more attention to teachings of strategic subjects, such as cell biology, molecular biology and tissue engineering.

© 2018 Acta Materialia Inc. Quantitative measurement of pH and metabolite gradients by microscopy is one of the challenges in the production of scaffold-grown organoids and multicellular aggregates. Herein, we used the cellulose-binding domain (CBD) of the Cellulomonas fimi CenA protein for designing biosensor scaffolds that allow measurement of pH and Ca2+ gradients by fluorescence intensity and lifetime imaging (FLIM) detection modes. By fusing CBD with pH-sensitive enhanced cyan fluorescent protein (CBD-ECFP), we achieved efficient labeling of cellulose-based scaffolds based on nanofibrillar, bacterial cellulose, and decellularized plant materials. CBD-ECFP bound to the cellulose matrices demonstrated pH sensitivity comparable to untagged ECFP (1.9–2.3 ns for pH 6–8), thus making it compatible with FLIM-based analysis of extracellular pH. By using 3D culture of human colon cancer cells (HCT116) and adult stem cell-derived mouse intestinal organoids, we evaluated the utility of the produced biosensor scaffold. CBD-ECFP was sensitive to increases in extracellular acidification: the results showed a decline in 0.2–0.4 pH units in response to membrane depolarization by the protonophore FCCP. With the intestinal organoid model, we demonstrated multiparametric imaging by combining extracellular acidification (FLIM) with phosphorescent probe-based monitoring of cell oxygenation. The described labeling strategy allows for the design of extracellular pH-sensitive scaffolds for multiparametric FLIM assays and their use in engineered live cancer and stem cell-derived tissues. Collectively, this research can help in achieving the controlled biofabrication of 3D tissue models with known metabolic characteristics. Statement of Significance: We designed biosensors consisting of a cellulose-binding domain (CBD) and pH- and Ca2+-sensitive fluorescent proteins. CBD-tagged biosensors efficiently label various types of cellulose matrices including nanofibrillar cellulose and decellularized plant materials. Hybrid biosensing cellulose scaffolds designed in this study were successfully tested by multiparameter FLIM microscopy in 3D cultures of cancer cells and mouse intestinal organoids.

© 2018 UICC The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58–1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.

© 2018 The Author(s). Background: The impact of number of endoscopic enucleation of the prostate techniques (holmium laser enucleation - HoLEP for example) on erectile function have already been investigated. However, the thulium-fiber laser, in this setting remains unstudied. In this study, we compared sexual function outcomes in patients with benign prostatic hyperplasia (BPH) treated with transurethral resection of the prostate (TURP) or thulium-fiber laser enucleation (ThuFLEP). Methods: We performed a retrospective analysis of patients who underwent transurethral resection and endoscopic enucleation of the prostate for BPH; inclusion criteria was the presence of infravesical obstruction (IPSS > 20, Qmax < 10 mL/s). Erectile function (EF) was assessed using the International Index of Erectile Function (IIEF-5) both prior to endoscopic examination, and six months after. Results: A total of 469 patients with BPH were included in the study; of these, 211 underwent to ThuFLEP, and 258 TURP. Preoperative IIEF-5 in TURP and ThuFLEP groups were 11.7 (±4.5) and 11.1 (±5.0), respectively (p = 0.17). At six month the IIEF-5 score was unchanged (p = 0.26 and p = 0.08) and comparable in both groups (p = 0.49). However, mean IIEF-5 score shown significant increase of 0.72 in ThuFLEP group, comparing to decrease of 0.24 in TURP patients (p < 0.001). Conclusions: Both TURP and ThuFLEP are effective modalities in the management of infravesical obstruction due to BPH. At six months follow-up after surgery, both techniques lead to comparable IIEF-5 score. However, our results demonstrated that the ThuFLEP is more likely to preserve the erectile function leading to increase of IIEF-5 at six months in contrast to TURP which lead to slight drop in IIEF-5 score.

© 2018 by the author. The heme in the active center of peroxidases reacts with hydrogen peroxide to form highly reactive intermediates, which then oxidize simple substances called peroxidase substrates. Human peroxidases can be divided into two groups: (1) True peroxidases are enzymes whose main function is to generate free radicals in the peroxidase cycle and (pseudo)hypohalous acids in the halogenation cycle. The major true peroxidases are myeloperoxidase, eosinophil peroxidase and lactoperoxidase. (2) Pseudo-peroxidases perform various important functions in the body, but under the influence of external conditions they can display peroxidase-like activity. As oxidative intermediates, these peroxidases produce not only active heme compounds, but also protein-based tyrosyl radicals. Hemoglobin, myoglobin, cytochrome c/cardiolipin complexes and cytoglobin are considered as pseudo-peroxidases. Peroxidases play an important role in innate immunity and in a number of physiologically important processes like apoptosis and cell signaling. Unfavorable excessive peroxidase activity is implicated in oxidative damage of cells and tissues, thereby initiating the variety of human diseases. Hence, regulation of peroxidase activity is of considerable importance. Since peroxidases differ in structure, properties and location, the mechanisms controlling peroxidase activity and the biological effects of peroxidase products are specific for each hemoprotein. This review summarizes the knowledge about the properties, activities, regulations and biological effects of true and pseudo-peroxidases in order to better understand the mechanisms underlying beneficial and adverse effects of this class of enzymes.

© 2018 by the authors. Computer-aided design (CAD) and additive manufacturing (AM) have shown promise in facilitating the fabrication of custom trays. Due to the clinical requirements, custom tray materials should achieve good bonding to the impression/adhesive systems. This study evaluated the retention of three fused deposition modeling (FDM) custom tray materials to a silicone impression/adhesive system before and after gritblasting (GB) by peel-off test. CAD-designed experimental test blocks were printed by FDM using acrylonitrile butadiene styrene (ABS), polyethylene terephthalate glycol copolyester (PETG), and high impact polystyrene (HIPS), and the reference test blocks were made of a conventional light-curing resin (n = 11). Before and after GB, the surface topography of all tray materials was analysed, and the maximum strength of the test block peeled off from a silicone impression/adhesive system was measured. After GB, the arithmetic mean height (Sa) and the valley fluid retention index (Svi) of the four material groups declined (p < 0.05). The peel-off strength of each of the four material groups significantly decreased by GB (p < 0.05), but no statistical difference could be found among them before or after GB. In all peel-off tests, adhesive failure occurred at the adhesive-impression material interface. The results indicated ABS, HIPS, and PETG could provide sufficient adhesion to the adhesive as the conventional light-curing resin, and GB could reduce the roughness generated by FDM and weaken the bonding between the adhesive and the silicone impression.

© 2018 The Royal Society of Chemistry. Tumor microenvironment is characterized by immunosuppressive mechanisms associated with the accumulation of immune regulatory cells-myeloid-derived suppressor cells (MDSC). Therapeutic depletion of MDSC has been associated with inhibition of tumor growth and therefore represents an attractive approach to cancer immunotherapy. MDSC in cancer are characterized by enhanced enzymatic capacity to generate reactive oxygen and nitrogen species (RONS) which have been shown to effectively degrade carbonaceous materials. We prepared enzymatically openable nitrogen-doped carbon nanotube cups (NCNC) corked with gold nanoparticles and loaded with paclitaxel as a therapeutic cargo. Loading and release of paclitaxel was confirmed through electron microscopy, Raman spectroscopy and LC-MS analysis. Under the assumption that RONS generated by MDSCs can be utilized as a dual targeting and oxidative degradation mechanism for NCNC, here we report that systemic administration of paclitaxel loaded NCNC delivers paclitaxel to circulating and lymphoid tissue MDSC resulting in the inhibition of growth of tumors (B16 melanoma cells inoculated into C57BL/6 mice) in vivo. Tumor growth inhibition was associated with decreased MDSC accumulation quantified by flow cytometry that correlated with bio-distribution of gold-corked NCNC resolved by ICP-MS detection of residual gold in mouse tissue. Thus, we developed a novel immunotherapeutic approach based on unique nanodelivery vehicles, which can be loaded with therapeutic agents that are released specifically in MDSC via NCNC selective enzymatic "opening" affecting change in the tumor microenvironment.

© 2018, MDPI AG. All rights reserved. Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come.

© 2018 The Author(s). Presently, many malaria-endemic countries in the world are transitioning towards malaria elimination. Out of the 105 countries with ongoing malaria transmission, 10 countries are classified as being in the pre-elimination phase of malaria control, and 9 countries are in the malaria elimination stage, whereas 7 countries are classified as being in the prevention of introduction phase. Between 2000 and 2015, 17 countries eliminated malaria (i.e., attained zero indigenous cases for 3 years or more). Seven countries were certified by the WHO as having successfully eliminated malaria. The purpose of this review was to analyse the epidemiological characteristics of vivax malaria during the various stages of malaria eradication (elimination) programmes in different countries in the past and present. Experiences of the republics of the former USSR with malaria are interesting, particularly since the data overwhelmingly were published in Russian and might not be known to western readers. Among the most important characteristics of Plasmodium vivax epidemiology at present are changes in the ratio of the short-incubation P. vivax to long-incubation P. vivax, the incidence of severe P. vivax cases, the increased numbers of asymptomatic P. vivax cases, the reduced response to anti-malarials and a few others. Various factors contributing towards the peculiarities of P. vivax epidemiology are discussed.

© 2018, © 2018 Informa UK Limited, trading as Taylor  &  Francis Group. Objective: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients. Methods: This was a post-hoc analysis of pooled individual patient data from the four large randomized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes. Results: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR = 0.66; and 95% confidence interval, CI = 0.44–0.98; p =.039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR = 0.78; 95% CI = 0.63–0.97; p =.026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR = 0.76; 95% CI = 0.61–0.94); p =.013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering. Conclusions: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1 year.

© 2018 by the authors. Objectives: Resin-modified glass ionomer cements (RMGIC) are considered excellent restorative materials with unique therapeutic and anti-cariogenic activity. However, concerns exist regarding the use of polyacrylic acid as a dentine conditioner as it may influence the bonding performance of RMGIC. The aim of this study was to evaluate the effect of different protocols for cycling mechanical stress on the bond durability and interfacial ultramorphology of a modern RMGIC applied to dentine pre-treated with/without polyacrylic acid conditioner (PAA). Methods: The RMGIC was applied onto human dentine specimens prepared with silicon-carbide (SiC) abrasive paper with or without the use of a PAA conditioner. The specimens were immersed in deionised water for 24 h then divided in 3 groups. The first group was cut into matchsticks (crosssectional area of 0.9 mm2) and tested immediately for microtensile bond strength (MTBS). The second was first subjected to load cycling (250,000 cycles; 3 Hz; 70 N) and then cut into matchsticks and tested for MTBS. The third group was subjected to load cycling (250,000 cycles; 3 Hz; 70 N), cut into matchsticks, and then immersed for 8 months storage in artificial saliva (AS); these were finally tested for MTBS. The results were analysed statistically using two-way ANOVA and the Student- Newman-Keuls test (α = 0.05). Fractographic analysis was performed using FE-SEM, while further RMCGIC-bonded dentine specimens were aged as previously described and used for interfacial ultramorphology characterisation (dye nanoleakage) using confocal microscopy. Results: The RMGIC applied onto dentine that received no pre-treatment (10% PAA gel) showed no significant reduction in MTBS after load cycling followed by 8 months of storage in AS (p > 0.05). The RMGIC- dentine interface created in PAA-conditioned SiC-abraded dentine specimens showed no sign of degradation, but with porosities within the bonding interface both after load cycling and after 8 months of storage in AS. Conversely, the RMGIC-dentine interface of the specimens with no PAA pre-treatment showed no sign of porosity within the interface after any of the aging protocols, although some bonded-dentine interfaces presented cohesive cracks within the cement after prolonged AS storage. However, the specimens of this group showed no significant reduction in bond strength (p < 0.05) after 8 months of storage in AS or load cycling (p > 0.05). After prolonged AS storage, the bond strength value attained in RMGIC-dentine specimens created in PAA pretreated dentine were significantly higher than those observed in the specimens created with no PAA pre-treatment in dentine. Conclusions: PAA conditioning of dentine prior to application of RMGIC induces no substantial effect on the bond strength after short-term storage, but its use may increase the risk of collagen degradation at the bonding interface after prolonged aging. Modern RMGIC applied without PAA dentine pre-treatment may have greater therapeutic synergy with saliva during cycle occlusal load, thereby enhancing the remineralisation and protection of the bonding interface.

© 2018, Advanced Scientific Research. All rights reserved. The composition described in current article is based on derivatives of glucosamine and acrylate polymers and is intended for treatment of various infected wounds. A semi-transparent gel demonstrates complex therapeutic activity due to several active pharmaceutical ingredients (AFIs): chitosan, chymopsin, miramistin, and lidocaine hydrochloride. Mechanism of action of the developed drug is complex and includes several therapeutic effects: enzymatic biochemical wound debridement due to lysis of denaturated proteins (without healthy tissues damaging); indirect antimicrobial activity due to chymopsin that promotes lysis of microbial growth medium; direct antimicrobial effect is provided by miramistine; and the pain is reduced by lydocaine and intrinsic cooling effect of gel dosage form. Generalizing the literature data about the products used in the infected wounds treatment, the following AFIs were chosen for the development of the topical gel: complex of proteolytic agent chymopsin and chitosan, chitosan-miramistin complex, and lidocaine anesthetic. Hydroxypropyl methylcellulose, polyacrylamide, and glycerol were utilized as excipients. Proper development of vehicles for gels used in wound treatment can be justified by the necessity of soft action on the wound, required cooling effect, good release of AFIs from the matrix, and prevention of microbial growth.