Diversity-oriented synthesis encoded by deoxyoligonucleotides.

Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs.

Machine Learning on DNA-Encoded Library Count Data Using an Uncertainty-Aware Probabilistic Loss Function.

DNA-encoded library (DEL) screening and quantitative structure-activity relationship (QSAR) modeling are two techniques used in drug discovery to find novel small molecules that bind a protein target. Applying QSAR modeling to DEL selection data can facilitate the selection of compounds for off-DNA synthesis and evaluation. Such a combined approach has been done recently by training binary classifiers to learn DEL enrichments of aggregated "disynthons" in order to accommodate the sparse and noisy nature of DEL data.

First population norms for the EQ-5D-3L in the Russian Federation.

Purpose: The EQ-5D survey instrument is routinely applied to general and patient specific populations in many countries, as a means of measuring Health Related Quality of Life (HRQOL) and/or informing Health Technology Assessment. The instrument is the subject of growing interest in the Russian Federation, as too is Health Technology Assessment. This research is the first to systematically present the EQ-5D-3L nationally representative population norms and to examine the socioeconomic and socio-demographic characteristics of the instrument among a representative sample of the Russian population.

Labour market status and depression in Russia: A longitudinal study, 2011-2017.

Aims: This is the first longitudinal study to examine the relationship between depression and the labour market in Russia. Using data from 2011 to 2017, we identify the impact that not being in employment has on mental distress, and we explore the mechanism underlying the observed association.

Methods: Using data from the Russia Longitudinal Monitoring Survey - Higher School of Economics, we employ random-effects regression models to estimate the impact of employment conditions on the likelihood of reporting mental distress in Russia.

Voluntary private health insurance, health-related behaviours and health outcomes: evidence from Russia.

This paper contributes to the discussion around ex-post (increased utilisation of health care) and ex-ante (changes in health behaviours) moral hazard in supplemental private health insurance. Applying a range of methodologies to data from the Russian Longitudinal Monitoring Survey-Higher School of Economics we exploit a selection mechanism in the data to compare the impact of workplace provided and individually purchased supplemental health insurance on the utilisation of health care, on a range of health behaviours and on self-assessed health. We find compelling policy-relevant evidence of ex-post moral hazard that confirms a theoretical prediction and empirical regularity found in other settings.

Unifying principles of bifunctional, proximity-inducing small molecules.

Nature uses a variety of tools to mediate the flow of information in cells, many of which control distances between key biomacromolecules. Researchers have thus generated compounds whose activities stem from interactions with two (or more) proteins simultaneously. In this Perspective, we describe how these 'bifunctional' small molecules facilitate the study of an increasingly wide range of complex biological phenomena and enable the drugging of otherwise challenging therapeutic targets and processes.

Recent achievements and current trajectories of diversity-oriented synthesis.

For two decades, diversity-oriented synthesis (DOS) has facilitated the assembly of small-molecule libraries comprising a variety of complex molecular architectures. Here, we describe some of the recent achievements in this field, many of which promise to contribute to the development of new chemical probes and drug leads. In particular, we report progress along several avenues of bioactive discovery that leverage topographically complex compounds generated using DOS and other methods.

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules.

It is challenging to incorporate stereochemical diversity and topographic complexity into DNA-encoded libraries (DELs) because DEL syntheses cannot fully exploit the capabilities of modern synthetic organic chemistry. Here, we describe the design, construction, and validation of DOS-DEL-1, a library of 107 616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C-H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality.

Valuing Health States in Russia: A First Feasibility Study.

Objective: The aim of this study was to explore the feasibility of different health-related quality-of-life valuation methods in a new setting. Based on a small feasibility study of 100 young Russians, we trialed different methodologies and identified key differences that have implications for the development of health technology assessment in Russia.

Methods: In face-to-face interviews, respondents completed a series of health self-assessments based on a modified version of the EQ-5D-3L, visual analogue scale, time tradeoff, standard gamble, and best-worst scaling methodologies, covering actual and hypothetical health states.

DNA-Compatible [3 + 2] Nitrone-Olefin Cycloaddition Suitable for DEL Syntheses.

The limited scope of DNA-compatible chemistry restricts the types of chemical features that can be incorporated into DNA-encoded libraries (DELs). Here, a method to synthesize DNA-conjugated polycyclic isoxazolidines via a [3 + 2] nitrone-olefin cycloaddition is described. The reaction is compatible with many olefin-containing substrates and diverse N-alkylhydroxylamines.

Attitudes to reform: Could a cooperative health insurance scheme work in Russia?

As for all health systems, in Russia, the demand for medical care is greater than its health system is able to guarantee the supply of. In this context, removing services from the state guaranteed package is an option that is receiving serious consideration. In this paper, we examine the attitudes of the Russian population to such a reform.

Convergence or Divergence? Life Expectancy Patterns in Post-communist Countries, 1959-2010.

In the 1960s and 1970s, the countries of Central and Eastern Europe and the Soviet Union experienced an unanticipated stagnation in the process of mortality reduction that was accelerating in the west. This was followed by even starker fluctuations and overall declines in life expectancy during the 1980s and 1990s. We identify statistically the extent to which, since the 1990s, the countries of the post-communist region have converged as a group towards other regional or cross-regional geopolitical blocks, or whether there are now multiple steady-states ('convergence clubs') emerging among these countries.

Chemical probes and drug leads from advances in synthetic planning and methodology.

Screening of small-molecule libraries is a productive method for identifying both chemical probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chemical space efficiently by populating small-molecule libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chemistry, and we illustrate the impact of the resultant chemical probes and drug leads in a wide range of diseases.

The effect of chronic conditions and multi-morbidity on self-assessed health in Russia.

Aims: Chronic disorders, such as cardiovascular disease, cancer, respiratory diseases and diabetes, are the leading cause of mortality globally, representing 68% of all recorded deaths. The incidence of chronic disease and multiple chronic disease is rising across the world, but relatively little is known about the impact of multi-morbidities on the life experiences of those individuals who encounter them. In this paper, we examine and quantify the relationship between chronic illness, multi-morbidity and the individual self-assessed health of the Russian population using individual-level Russian data and a novel quantitative technique.

Too many and too few: The paradoxical case of physicians in the Russian Federation.

There is a paradox characterising the Russian health workforce. By international standards, Russia has a very high number of physicians per capita but at the same time is confronted by chronic real shortages of qualified physicians. This paper explores the reasons for this paradox by examining the structural characteristics of health workforce development in the context of the Soviet legacy and the comparative performance of other European countries.

Reforming voluntary drug insurance in Russian healthcare: does social solidarity matter?

With low take-up of both private health insurance and the existing public drug reimbursement scheme, it is thought that less than 5% of the Russian population have access to free outpatient drug treatment. This represents a major policy challenge for a country grappling with reforms of its healthcare system and experiencing low or no economic growth and significant associated reductions in spending on social services. In this paper, we draw on data from a 2011 Levada-Center survey to examine the attitudes and social solidarity of the Russian population towards drug policies in general and towards the introduction of a proposed voluntary drug insurance system in particular.

Real-Time Biological Annotation of Synthetic Compounds.

Organic chemists are able to synthesize molecules in greater number and chemical complexity than ever before. Yet, a majority of these compounds go untested in biological systems, and those that do are often tested long after the chemist can incorporate the results into synthetic planning. We propose the use of high-dimensional "multiplex" assays, which are capable of measuring thousands of cellular features in one experiment, to annotate rapidly and inexpensively the biological activities of newly synthesized compounds.

Gender, education and Russia's tobacco epidemic: A life-course approach.

While a number of studies, based on cross-sectional data for Russia, have documented strong increases in female smoking during the past two decades, the analysis of longer-term trends in smoking prevalence is hampered by the lack of representative data for the Soviet era. In this paper we create life-course smoking histories based on retrospective data from the Russia Longitudinal Monitoring Survey of HSE (RLMS-HSE) and the Global Adult Tobacco Survey (GATS) which allow us to examine the dynamics of smoking patterns over the past 7 decades. We find that smoking rates differ most strongly by gender within all cohorts, but that this differential has decreased over time, driven by increases in female smoking and more recently by decreases in smoking among men.

Social inequalities in self-rated health in Ukraine in 2007: the role of psychosocial, material and behavioural factors.

Background: Despite Ukraine's large population, few studies have examined social inequalities in health. This study describes Ukrainian educational inequalities in self-rated health and assesses how far psychosocial, material and behavioural factors account for the education gradient in health.

Methods: Data were analyzed from the 2007 wave of the Ukrainian Longitudinal Monitoring Survey.

General platform for systematic quantitative evaluation of small-molecule permeability in bacteria.

The chemical features that impact small-molecule permeability across bacterial membranes are poorly understood, and the resulting lack of tools to predict permeability presents a major obstacle to the discovery and development of novel antibiotics. Antibacterials are known to have vastly different structural and physicochemical properties compared to nonantiinfective drugs, as illustrated herein by principal component analysis (PCA). To understand how these properties influence bacterial permeability, we have developed a systematic approach to evaluate the penetration of diverse compounds into bacteria with distinct cellular envelopes.

The impact of migration on the sexual health, behaviours and attitudes of Central and East European gay/bisexual men in London.

Background: Building on an earlier quantitative study which found that gay/bisexual men from Central and Eastern Europe were at greater risk of sexual ill health following migration to the UK, the aim of this qualitative study is to explore how the process of migration itself may have influenced the migrants' sexual behaviour and attitudes.

Methods: To address these questions, we conducted 17 in-depth interviews in London with gay/bisexual male migrants from Central and Eastern Europe, drawing on Fisher and Fisher's Information-Motivation-Behavioral Skills model as an interpretive framework.

Results: We find that the sexual behaviours of our respondents have been significantly influenced by the process of migration itself.

The journals are full of great studies but can we believe the statistics? Revisiting the mass privatisation - mortality debate.

Cross-national statistical analyses based on country-level panel data are increasingly popular in social epidemiology. To provide reliable results on the societal determinants of health, analysts must give very careful consideration to conceptual and methodological issues: aggregate (historical) data are typically compatible with multiple alternative stories of the data-generating process. Studies in this field which fail to relate their empirical approach to the true underlying data-generating process are likely to produce misleading results if, for example, they misspecify their models by failing to explore the statistical properties of the longitudinal aspect of their data or by ignoring endogeneity issues.