We developed the synthesis of a series of furan-fused tetracyclic analogues of the antitumor agent ametantrone. The reactions included nucleophilic substitution of propoxy groups in 4,11-dipropoxyanthra[2,3-b]furan-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b] furan-5,10-dione in good yields. Studies of anti-proliferative activity on a panel of mammalian tumor cell lines demonstrated that anthra[2,3-b]furan-5,10- diones were the most potent derivatives among heteroarene-fused ametantrone analogues with one heteroatom. We identified several compounds that evoked a growth inhibitory effect at submicromolar concentrations. The anthra[2,3-b]furan-5,10-dione 9 with distal methylamino groups was markedly potent against drug-resistant cell lines with P-glycoprotein overexpression or p53 gene deletion. Furthermore, this derivative attenuated in vitro topoisomerase I-mediated DNA uncoiling at low micromolar concentrations. These results demonstrate that anthrafurandiones are a new class of heterocyclic anthraquinone derivatives with the properties potentially valuable for anticancer therapy.
The article problematises the role of real estate in geopolitical circulations. The internationalisation of real estate increases mutual dependencies and vulnerabilities between nation states and, therefore, calls for a better appreciation of the geopolitical externalities and exteriorities of real estate. The article brings together disjoint bodies of literature on real estate globalisation, assemblage theory, and international relations to show how real estate is a case of the geopolitics of the multiple – geopolitics that is being assembled by diverse and distributed actors, discourses, and materialities representing the contingent and emergent formation of connections and considerations, which affect the ways how foreign relations are negotiated today. The argument is substantiated by considering several dimensions of the real estate/geopolitics nexus: (1) external influences over domestic real estate markets; (2) the implications of outward real estate investment; and (3) state-led mega-projects conveying externally the power of the state. These dimensions are considered empirically in the context of the renewed geopolitical tensions between a resurgent Russia and the West. Overall, the article calls for a better positioning of real estate in the conceptualisations of soft power, state power, and geopolitics.
Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies.
To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013.
The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs.
In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100,000 and age-standardized death rates (ASDRs) per 100,000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10% in 113 countries and decreased by more than 10% in 12 of 188 countries.
CONCLUSIONS AND RELEVANCE
Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990. The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments. The annual update on the global burden of cancer will provide all stakeholders with timely estimates to guide policy efforts in cancer prevention, screening, treatment, and palliation.
With recent improvements in vaccines and treatments against viral hepatitis, an improved understanding of the burden of viral hepatitis is needed to inform global intervention strategies. We used data from the Global Burden of Disease (GBD) Study to estimate morbidity and mortality for acute viral hepatitis, and for cirrhosis and liver cancer caused by viral hepatitis, by age, sex, and country from 1990 to 2013.
We estimated mortality using natural history models for acute hepatitis infections and GBD's cause-of-death ensemble model for cirrhosis and liver cancer. We used meta-regression to estimate total cirrhosis and total liver cancer prevalence, as well as the proportion of cirrhosis and liver cancer attributable to each cause. We then estimated cause-specific prevalence as the product of the total prevalence and the proportion attributable to a specific cause. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs).
Between 1990 and 2013, global viral hepatitis deaths increased from 0·89 million (95% uncertainty interval [UI] 0·86–0·94) to 1·45 million (1·38–1·54); YLLs from 31·0 million (29·6–32·6) to 41·6 million (39·1–44·7); YLDs from 0·65 million (0·45–0·89) to 0·87 million (0·61–1·18); and DALYs from 31·7 million (30·2–33·3) to 42·5 million (39·9–45·6). In 2013, viral hepatitis was the seventh (95% UI seventh to eighth) leading cause of death worldwide, compared with tenth (tenth to 12th) in 1990.
Viral hepatitis is a leading cause of death and disability worldwide. Unlike most communicable diseases, the absolute burden and relative rank of viral hepatitis increased between 1990 and 2013. The enormous health loss attributable to viral hepatitis, and the availability of effective vaccines and treatments, suggests an important opportunity to improve public health.
The Great Acceleration of the anthropogenic impact on the Earth system is marked by the ubiquitous distribution of anthropogenic materials throughout the global environment, including technofossils, radionuclides and the exponential increases of methane and carbon dioxide concentrations. However, personal care products as direct tracers of human domestic habits are often overlooked. Here, we present the first research combining fragrances, as novel personal care products, and polycyclic aromatic hydrocarbons (PAHs) as combustion and industrial markers, across the onset of the Great Acceleration in the Elbrus, Caucasus, ice core. This archive extends from the 1930s to 2005, spanning the profound changes in the relationship between humans and the environment during the twentieth century. Concentrations of both fragrances and PAHs rose throughout the considered period, reflecting the development of the Anthropocene. However, within this rising trend, remarkable decreases of the tracers track the major socioeconomic crises that occurred in Eastern Europe during the second half of the twentieth century.
This paper conceptualises post-socialist urban economic geographies through the notion of hybrid spatialities that emerge from the mutual embeddedness of neoliberalism and socialist legacies. While the dismantling of state socialism was a massive moment towards the exacerbation of uneven development, ironically it is the socialist-era spatial legacy that has become the single major differentiating factor for the economic status of cities. This superficial overdetermination, however, masks the root causes of uneven development that must be seen in the logic of capitalism and its attendant practices which subsume legacy, recode its meaning, and recast the formerly equalitarian spaces as an uneven spatial order. The authors argue that the socialist legacy, rather than being an independent carrier of history, has been alienated from its history to become an infrastructure of neoliberalisation, conducive to capitalist process. The paper draws specifically on the experiences of Russia, although its reflections should reverberate much more broadly.
Despite the burgeoning literature on creative cities, seldom explored is the context of cities rich in cultural capital but more orthodox in their approach to preserving the autonomy of culture. This article discusses the status of artistic spaces occupying abandoned industrial premises (‘creative brownfields') in historic cities that traditionally shape their policies around prestigious cultural institutions (‘cities of high culture'). Based on comparative insights from St Petersburg and Lausanne, the article explores the relations and tensions between mainstream cultural governance and creative brownfields. While there is no lack of creative brownfields in these cities, their wider urban impact is found to be marginal; moreover, these sites represent dispersed instances of temporary occupations rather than situated clusters of creative actors. More than coincidental, this (lack of) spatialization is argued to result from a particular governmentality—that of high culture—which disregards, rather than promotes, spaces of alternative cultural governance. The article conceptualizes creative brownfields in cities of high culture as the ‘soft infrastructure' of cultural production, in contrast with those in ‘creative cities' as the ‘hard infrastructure' of urban production. The article also calls for a recognition of the local context of regulation and accumulation in understanding the cultural/urban interplay.
Sir Boris Uvarov (1886 [sic]–1970), FRS, KCMG, a Russian-born British entomologist was during his lifetime a recognised leader of the discipline of Orthopterology. He is widely known for his numerous descriptions of new taxa as well as for his locust phase theory which was important for rationalising locust control. Until recently, his date of birth remained uncertain, for at different times it was reported as November 5, 1888 or 1889. Archival research reveals the true date of his birth (October 22 / November 3, 1886) and allows to correct some oher key facts and dates on his early biography.
Russia is one of the largest carbon emitters in the world, possessing huge resources of both fossil fuels and zero-carbon energy sources. The Paris Agreement targets require substantial efforts to limit global warming to “well below 2 °C”. Energy-economic modeling provides sound conclusions that continuation of existing energy and climate policy will lead to stabilization of energy carbon emissions in Russia at the current level in 2010–2050 (about 30% below 1990). Stronger mitigation policies could gradually reduce domestic energy CO2 emissions by 61% from 2010 to 2050 (75% below 1990). Deep decarbonization policies with even more ambitious commitments could ensure an 83% reduction in energy CO2 emissions from 2010 levels (88% below 1990) by 2050. All key sectors (energy, industries, transport, and buildings) can play a substantial role in decarbonizing the national economy. However Russia’s historical reliance on domestic consumption and exports of fossil fuels creates strong barriers to decarbonization. Emission reduction costs are expected to be below 29 USD/tCO2 by 2030, 55 USD/ tCO2 by 2040, and 82 USD/tCO2 by 2050 in the most ambitious decarbonization scenario. The results of this study provide insights into how Russia can enhance its ambitions to implement the Paris Agreement and contribute to global efforts toward building a climate-neutral economy by 2050.
We tested whether mirror visual feedback (MVF) from a moving hand induced high gamma oscillation (HGO) response in the hemisphere contralateral to the mirror and ipsilateral to the self-paced movement. MEG was recorded in 14 subjects under three conditions: bilateral synchronous movements of both index fingers (BILATERAL), movements of the right hand index fingerwhile observing the immobile left index finger (NOMIRROR), and movements of the right hand index fingerwhile observing its mirror reflection (MIRROR). The right hemispheric spatiospectral regions of interests (ROIs) in the sensor space, sensitive to bilateral movements, were found by statistical comparison of the BILATERAL spectral responses to baseline. For these ROIs, the post-movement HGO responses were compared between the MIRROR and NOMIRROR conditions. We found that MVF from the moving hand, similarly to the real movements of the opposite hand, induced HGOs (55–85 Hz) in the sensorimotor cortex. This MVF effect was frequency-specific and did not spread to oscillations in other frequency bands. This is the first study demonstrating movement-related HGO induced by MVF from the moving hand in the absence of proprioceptive feedback signaling. Our findings support the hypothesis that MVF can trigger the feedback-based control processes specifically associated with perception of one's own movements.
Observation data on the September 5, 1971, earthquake that occurred near the Moneron Island (Sakhalin) have been analyzed and a numerical simulation of the tsunami induced by this earthquake is conducted. The tsunami source identified in this study indicates that the observational data are in good agreement with the results of calculations performed on the basis of shallow-water equations
The question of the environmental risks of social and economic infrastructure has recently become apparent due to an increase in the number of extreme weather events. Extreme runoff events include floods and droughts. In water engineering, extreme runoff is described in terms of probability and uses methods of frequency analysis to evaluate an exceedance probability curve (EPC) for runoff. It is assumed that historical observations of runoff are representative of the future; however, trends in the observed time series show doubt in this assumption. The paper describes a probabilistic hydrological MARCSHYDRO (the MARkov Chain System) model that can be applied to predict future runoff extremes. The MARCSHYDRO model simulates statistical estimators of multi-year runoff in order to perform future projections in a probabilistic form. Projected statistics of the meteorological variables available in climate scenarios force the model. This study introduces the new model’s core version and provides a user guide together with an example of the model set-up in a single case study. In this case study, the model simulates the projected EPCs of annual runoff under three climate scenarios. The scope of applicability and limitations of the model’s core version 0.2 are discussed.
The migration balance of urban municipal areas (hereinafter, okrugs — Russ.) and municipal dis¬tricts in Russia in 2012-2014 is analyzed from the standpoint of its impact on the concentration and decon-centration of the population. The paper reviews the distribution of urban okrugs and municipal districts by population density and the current ratio of sparsely and densely populated areas across the country. Calcula¬tions show that the conditions in Russia today contribute to concentration of the population and, hence, the polarization of space between densely populated major cities and deserted poorly developed areas. Unlike in many European countries and the United States, where concentration and deconcentration processes have been alternating for decades, concentration of the population is an ongoing process in Russia. Two directions of migration are analyzed: (1) from the intraregional periphery to regional centers: the farther from the center, the more intense the outflow; (2) from low-populated municipalities to densely populated territorial units, primarily, large cities. The contributions of individual migration flows (intraregional, interregional, and international) to the concentration and deconcentration of the population are evaluated.
The base excision repair (BER) pathway consists of sequential action of DNA glycosylase and apurinic/apyrimidinic (AP) endonuclease necessary to remove a damaged base and generate a single-strand break in duplex DNA. Human multifunctional AP endonuclease 1 (APE1, a.k.a. APEX1, HAP-1, or Ref-1) plays essential roles in BER by acting downstream of DNA glycosylases to incise a DNA duplex at AP sites and remove 3′-blocking sugar moieties at DNA strand breaks. Human 8-oxoguanine-DNA glycosylase (OGG1), methyl-CpG-binding domain 4 (MBD4, a.k.a. MED1), and alkyl-N-purine-DNA glycosylase (ANPG, a.k.a. Aag or MPG) excise a variety of damaged bases from DNA. Here we demonstrated that the redox-deficient truncated APE1 protein lacking the first N-terminal 61 amino acid residues (APE1-NΔ61) cannot stimulate DNA glycosylase activities of OGG1, MBD4, and ANPG on duplex DNA substrates. Electron microscopy imaging of APE1–DNA complexes revealed oligomerization of APE1 along the DNA duplex and APE1-mediated DNA bridging followed by DNA aggregation. APE1 polymerizes on both undamaged and damaged DNA in cooperative mode. Association of APE1 with undamaged DNA may enable scanning for damage; however, this event reduces effective concentration of the enzyme and subsequently decreases APE1-catalyzed cleavage rates on long DNA substrates. We propose that APE1 oligomers on DNA induce helix distortions thereby enhancing molecular recognition of DNA lesions by DNA glycosylases via a conformational proofreading/selection mechanism. Thus, APE1-mediated structural deformations of the DNA helix stabilize the enzyme–substrate complex and promote dissociation of human DNA glycosylases from the AP site with a subsequent increase in their turnover rate.
Significance Statement: The major human apurinic/apyrimidinic (AP) endonuclease, APE1, stimulates DNA glycosylases by increasing their turnover rate on duplex DNA substrates. At present, the mechanism of the stimulation remains unclear. We report that the redox domain of APE1 is necessary for the active mode of stimulation of DNA glycosylases. Electron microscopy revealed that full-length APE1 oligomerizes on DNA possibly via cooperative binding to DNA. Consequently, APE1 shows DNA length dependence with preferential repair of short DNA duplexes. We propose that APE1-catalyzed oligomerization along DNA induces helix distortions, which in turn enable conformational selection and stimulation of DNA glycosylases. This new biochemical property of APE1 sheds light on the mechanism of redox function and its role in DNA repair.
This work discusses bioinformatics and experimental approaches to explore the human proteome, a constellation of proteins expressed in different tissues and organs. As the human proteome is not a static entity, it seems necessary to estimate the number of different protein species (proteoforms) and measure the number of copies of the same protein in a specific tissue. Here, meta-analysis of neXtProt knowledge base is proposed for theoretical prediction of the number of different proteoforms that arise from alternative splicing (AS), single amino acid polymorphisms (SAPs), and posttranslational modifications (PTMs). Three possible cases are considered: (1) PTMs and SAPs appear exclusively in the canonical sequences of proteins, but not in splice variants; (2) PTMs and SAPs can occur in both proteins encoded by canonical sequences and in splice variants; (3) all modification types (AS, SAP, and PTM) occur as independent events. Experimental validation of proteoforms is limited by the analytical sensitivity of proteomic technology. A bell-shaped distribution histogram was generated for proteins encoded by a single chromosome, with the estimation of copy numbers in plasma, liver, and HepG2 cell line. The proposed metabioinformatics approaches can be used for estimation of the number of different proteoforms for any group of protein-coding genes.
The archives of measurements at a network of stations of Roshydromet stocks of available water capacity and satellite measurements of relative soil moisture topsoil according with the instrument ASCAT (MetOp satellites) were used. The estimation of the statistical structure of the fields of available water capacity in the upper 10- and 20-cm soil layers, correlations were found between the data of remote sensing (RS) data and agrometeorological stations. Developed procedure for automated pre-control ground-based measurements. The algorithm is statistically optimal transform of remote sensing data in estimating the amount of moisture in the upper soil layer.
The efficiency of the hydrocarbon deposits development is determined by recovery factor of oil or gas and the amount of material costs for the development of mineral resources and their exploitation - profitability of the project. Today, science and technology allows to develop economically feasible deposits with hard to recover reserves by applying methods of stimulation to the well, one of the most popular is the construction of wells with horizontal profiles. Drilling of directional and horizontal wells require the use of special drilling equipment - rotary-steerable systems (RSS) to control the trajectory of the wellbore in real time. Today the market offers a large number of equipment for directional drilling the main is a foreign proceeding. Work with such systems need to attract highly qualified personnel, and often foreign experts. In this regard, the development of a remote monitoring and control system of the trajectory of the wellbore hardware and software while drilling wells using RSS is an actual scientific and practical task. The paper presents the set-theoretic model of the synthesis of the structure of remote monitoring and control system of the trajectory of the wellbore hardware and software while drilling wells using the rotary steerable systems. Approach to systematize the creation of software and hardware systems structure for monitoring and control provides qualitative information and algorithmic environment that meets all the requirements of modern standards. On the basis of the proposed model the structure of the complex is designed, which includes a set of submersible units, executive and implementing measurement and control system, communication system, scheduling system. The structure of hardware and software has a modular principle of organization, it involves building up features, including the introduction of additional telemetry parameters, has the mainstream and alternative information channels, advanced power system components, including redundant power supplies.
The research aimed at testing the combination of GAM/M-GAM models (Geosite Assessment Model/Modified Geosite Assessment Model) on selected geoheritage sites (geosites) of great scientific significance and geotourism potential. Testing was done on eight sites in the City of Belgrade (Serbian capital), an area which has significant potential for geotourism development in typical urban conditions. For this purpose, an assessment scale was used to highlight differences and similarities between main and additional values of the observed geosites. The modification of the original GAM model is based on the inclusion of visitors’ opinions regarding the importance of indicators in the assessment process. The assessment was done by using both GAM/M-GAM and its results were analyzed and compared afterwards. The analysis has successfully identified locations and features of geosites that require action for maintaining or increasing their overall value and function. Moreover, the principal aim of the paper was to analyze the relevance of each sub-indicator for the assessment process by introducing the importance factor in the modified model. The authors were able to point out those values of principal importance for geosite visitors, as well as to attach a different relevance to sub-indicators, which can influence the position of the geosites in the GAM/M-GAM matrices.
especially impaired on regular past-tense forms like played, whether the task requires production, comprehension or even the judgement that "play" and "played" sound different. Within a dual-mechanism account of inflectional morphology, these deficits reflect disruption to the rule-based process that adds (or strips) the suffix -ed to regular verb stems; but the fact that the patients are also impaired at detecting the difference between word pairs like "tray" and "trade" (the latter being a phonological but not a morphological twin to "played") suggests an important role for phonological characteristics of the regular past tense. The present study examined MEG brain responses in healthy participants evoked by spoken regular past-tense forms and phonological twin words (plus twin pseudowords and a non-speech control) presented in a passive oddball paradigm. Deviant forms (played, trade, kwade/kwayed) relative to their standards (play, tray, kway) elicited a pronounced neuromagnetic response at approximately 130 ms after the onset of the affix; this response was maximal at sensors over temporal areas of both hemispheres but stronger on the left, especially for played and kwayed. Relative to the same standards, a different set of deviants ending in /t/--plate, trait and kwate--produced stronger difference responses especially over the right hemisphere. Results are discussed with regard to dual- and single-mechanism theories of past tense processing and the need to consider neurobiological evidence in attempts to understand inflectional morphology.
One of the problems in proteogenomic research aimed at identification of variant peptides is the presence of peptides with amino acid isomers of different origin in the analyzed samples. Among the most challenging examples are peptides with threonine and isothreonine (homoserine) in their sequences. Indeed, the latter residue may appear in vitro as a methionine substitution during sample preparation for shotgun proteome analysis. Yet, this substitution of Met to isoThr is not encoded genetically and should be unambiguously distinguished from, e.g., point mutations in proteins that result in Met conversion to Thr.
In this work we compared tandem mass (MS/MS) spectra produced by an Orbitrap mass spectrometer of Thr- and isoThr-containing tryptic peptides and found a distinctive feature in their collisionally activated fragmentation patterns.
Up to 84% of MS/MS spectra for peptides containing isoThr residues have been positively specified. We also studied the differences in retention times for peptides containing Thr isoforms that can be further used for their distinction.
Threonine can be distinguished from isothreonine by its retention time and HCD fragmentation pattern, specifically relative intensity of the bn - product ion, which can be further used in proteomic research