Alexei Sharov

• Ph.D.
• Vice President at Elixirgen Scientific

Topoisomerases are required to release topological stress generated by RNA polymerase II (RNAPII) during transcription. Here, we show that in response to starvation, the complex of topoisomerase 3b (TOP3B) and TDRD3 can enhance not only transcriptional activation, but also repression, which mimics other topoisomerases that can also alter transcript...

Bloomsbury Semiotics offers a state-of-the-art overview of the entire field of semiotics by revealing its influence on a wide range of disciplinary perspectives. With four volumes spanning theory, method and practice across the disciplines, this definitive reference work emphasizes and strengthens common bonds shared across intellectual cultures, a...

Background Cytomegalovirus (CMV) infection leads to effector memory CD8⁺ T cell expansion and is associated with immune dysfunction in older adults. However, the molecular alterations of CMV-specific CD8⁺ T cells in CMV infected healthy young and middle-aged adults has not been fully characterized. Results We compared CD8⁺ T cells specific for a C...

Background Transcription factors (TFs) play central roles in maintaining “stemness” of embryonic stem (ES) cells and their differentiation into several hundreds of adult cell types. The regulatory competence of TFs is routinely assessed by detecting target genes to which they bind. However, these data do not indicate which target genes are activate...

Topoisomerase 3β (TOP3B) and TDRD3 form a dual-activity topoisomerase complex that interacts with FMRP and can change the topology of both DNA and RNA. Here, we investigated the post-transcriptional influence of TOP3B and associated proteins on mRNA translation and turnover. First, we discovered that in human HCT116 colon cancer cells, knock-out (K...

Semiogenesis is the emergence of new or modified sign relations in agents. New sign relations emerge by way of the interpretive activities of agents and subagents in adaptive evolution, development , physiology, and behavior . The gene-centric concept of evolution needs to be replaced by an agency-centric concept . The genome may change passively a...

Background Transcription factors (TFs) play central roles in maintaining “stemness” of ES cells and their differentiation into several hundreds of adult cell types. Their regulatory competence is routinely assessed by detecting target genes to which they bind. However, these data do not indicate which target genes are activated, repressed, or not a...

What is ‘translation’? Even as the scholarly viewpoint of translation studies has expanded over recent years, the notion of ‘translation’ has remained fixedly defined by its interlinguistic element. However, there are many different contexts and disciplines in which translation takes place for which this definition is entirely unsuitable. Exploring...

Topoisomerases solve topological problems for DNA, but whether they function similarly for RNA remains unclear. Here we show that the Topoisomerase 3b (TOP3B)-TDRD3 complex acts on both DNA and RNA. On DNA, TOP3B-TDRD3 binds transcription start or termination regions; and inactivation of TOP3B topoisomerase activity decreases expression of some tho...

Topoisomerase 3b (TOP3B)-TDRD3 is a dual-activity topoisomerase complex in animals that can change topology for both DNA and RNA. A current hypothesis proposes that this complex interacts with Fragile X mental retardation protein, FMRP, to regulate mRNA translation. Here we examined this hypothesis by identifying TOP3B-TDRD3-bound mRNAs in human HC...

The assumption that life originated on Earth has dominated science since the emergence of the theory of evolution. It became the cornerstone of all major scenarios of the origin of life. Presumed habitats of primordial life on Earth include Darwin’s “warm little pond”, clays, and hydrothermal vents. Thus, challenging the dogma of the origin of life...

The target article by Denis Noble is an excellent overview of the illusions of the Modern Synthesis that still remains in textbooks despite of the recent criticism. Overcoming these illusions shows the active role of organisms in the evolutionary process and accounts for additional mechanisms such as plasticity of embryo development, epigenetic her...

Here we explore the development of the notion of agency within natural philosophy, modern philosophy and science. Ancient philosophy is represented by Aristotle’s theories on causation, the soul, and ethics. Enlightenment philosophy was inspired by the Cartesian mind-body dualism and includes the a priori knowledge conceptualized by Kant. Evolution...

Sign is a semiotic tool, whose form is meaningful for certain agents. Agents use signs to regulate their activities, communicate with others, and accumulate knowledge in the form of heredity, memory , perception , representation , and cognition. Sign processes, collectively known as semiosis, vary in their complexity and function , and their types...

We call the science on semiotic agency in all its forms ‘agentology’, adopting the term coined by Tomáš Šalamon. The establishment of this new discipline is justified by the fact that the class of all agents is easily distinguishable from other things in the universe by empirical studies. In our perspective, agentology is inspired by and can draw f...

A precondition for understanding current ecology is to understand how human agency influences ecology . In this chapter we describe the world-changing effects of human agency. A key notion in this context is the ‘Anthropocene’, the geological epoch in which human agency predominates as a causal factor. Drawing on Umwelt theory, we explain how human...

In this chapter we discuss the phenomenological tradition within philosophy with emphasis on representative phenomenological positions on subjectivity, sentience, consciousness and self-consciousness, and make the argument that giving phenomenology a biosemiotic grounding will make it more comprehensive. Even though both Husserl and Heidegger, two...

The origin of life involves a transition from a merely physical world into the world of semiotic agency . Attempts to explain the origin of life by synthesis of such organic molecules as peptides or nucleic acids is baseless, because amino acids and nucleotides are products of the evolving life rather than parts from which the first living system w...

This chapter opens the discussion of agency in organisms by starting with human agency, which is a bundle of adaptive processes with different time and spatial scales that integrate the past and future of Homo sapiens organisms via autonomy and goal-directedness. Despite of the common belief that each human being is a singular decision-making unit,...

Semiotic agency is not restricted to humans; it is a natural phenomenon that is found in all living organisms. However, there are many levels of semiotic competence, and these are typically separated by qualitative evolutionary transitions, such as the origin of the eukaryotic cell, multicellular eukaryotes, the nervous system, learning, thinking,...

In this chapter we argue that the multiplicity of subagents is a typical feature of agency which is necessary for a higher-level agent’s reliable self-construction, robustness, and adaptability. The composite organization allows for a dialectic balance between interests and functions of the whole and its parts. We argue that subagents are semi-auto...

Here we present a systematic analysis of the phenomenon of semiotic agency : a capacity for acting purposefully and using signs to make informed choices. Semiotic agents have an extended ontological status because their existence depends on past purposeful activity of their own and/or ancestral agents, and also supports future purposeful activities...

This book invites readers to embark on a journey into the world of agency encompassing humans, other organisms, cells, intracellular molecular agents, colonies, populations, ecological systems, and artificial autonomous systems. We combine mechanistic and non-mechanistic approaches in the analysis of the function and evolution of organisms, their s...

Topoisomerase 3β (Top3β) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3β mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3β knockout mice exhibit behavioural phenotypes r...

Transcription factors (TFs) play a pivotal role in determining cell states, yet our understanding of the causative relationship between TFs and cell states is limited. Here, we systematically examine the state changes of human pluripotent embryonic stem cells (hESCs) by the large-scale manipulation of single TFs. We establish 2,135 hESC lines, repr...

The retina is a specialized neural tissue that senses light and initiates image processing. Although the functional organization of specific retina cells has been well studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile the human retina, we performed single-cell RNA sequencing on 20,009 cells from...

Aging of immune system is characterized by progressive decline of physiological and cellular function of T cells, leading to a reduced immune function in the old. Recent studies of naïve T cells from young and old mice have identified age-related altered gene expressions, but the mechanisms underlying age associated changes of naïve T cells remain...

Topoisomerases solve topological problems during DNA metabolism, but whether they participate in RNA metabolism remains unclear. Top3β represents a family of topoisomerases carrying activities for both DNA and RNA. Here we show that in Drosophila, Top3β interacts biochemically and genetically with the RNAi-induced silencing complex (RISC) containin...

The retina is a highly specialized neural tissue that senses light and initiates image processing. Although the functional organisation of specific cells within the retina has been well-studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile cell types in the human retina, we performed single cell RNA...

Development of artificial cognition, one of the major challenges of contemporary science, requires better understanding of the nature and function of mind. This paper follows the idea of Searle that mind is more than computation, and explores the notion that mind has to be embodied in agency that actively interacts with the outside world. To avoid...

Aging of immune system is characterized by progressive decline of physiological and cellular function of T cells. Recent studies of naïve T cells from young and old mice have identified age-related altered gene expressions but the mechanisms underlying age associated changes of naïve T cells remain poorly understood. Here we compared the transcript...

The origin of life means the emergence of heritable and evolvable self-reproduction. However the mechanisms of primordial heredity were different from those in contemporary cells. Here I argue that primordial life had no nucleic acids; instead heritable signs were represented by isolated catalytically active self-reproducing molecules, similar to e...

Statistical analysis of gene expression data. Free online program

Principles of constructivism are used here to explore how organisms develop tools, subagents, scaffolds, signs, and adaptations. Here I discuss reasons why organisms have composite nature and include diverse subagents that interact in partially cooperating and partially conflicting ways. Such modularity is necessary for efficient and robust functio...

Some long noncoding RNAs (lncRNAs) can regulate gene expression programs, in turn affecting specific cellular processes. We sought to identify the mechanism through which the lncRNA OIP5-AS1, which is abundant in the cytoplasm, suppressed cell proliferation. Silencing of OIP5-AS1 in human cervical carcinoma HeLa cells triggered the appearance of ma...

The integrity of living cells is maintained via regular communication between cell components. Membrane receptors provide information on the environment and launch signals to modify cellular functions accordingly. Gene regulatory networks coordinate the work of genes to keep the homeostasis of the cell and optimize its functions. Ribosomes are mini...

In contrast to the traditional relational semiotics, biosemiotics decisively deviates towards dynamical aspects of signs at the evolutionary and developmental time scales. The analysis of sign dynamics requires constructivism (in a broad sense) to explain how new components such as subagents, sensors, effectors, and interpretation networks are prod...

Optic neuropathies are characterised by a loss of retinal ganglion cells (RGCs) that lead to vision impairment. Development of cell therapy requires a better understanding of the signals that direct stem cells into RGCs. Human embryonic stem cells (hESCs) represent an unlimited cellular source for generation of human RGCs in vitro. In this study, w...

Specific neuronal types derived from embryonic stem cells (ESCs) can facilitate mechanistic studies and potentially aid in regenerative medicine. Existing induction methods, however, mostly rely on the effects of the combined action of multiple added growth factors, which generally tend to result in mixed populations of neurons. Here, we report tha...

Mouse embryonic stem cells (ESCs) can differentiate into a wide range – and possibly all cell types in vitro, and thus provide an ideal platform to study systematically the action of transcription factors (TFs) in cell differentiation. Previously, we have generated and analyzed 137 TF-inducible mouse ESC lines. As an extension of this “NIA Mouse ES...

Retinoic acid (RA) is one of the most potent inducers of differentiation of mouse embryonic stem cells (ESCs). However, previous studies show that RA treatment of cells cultured in the presence of a leukemia inhibitory factor (LIF) also result in the upregulation of a gene called Zscan4, whose transient expression is a marker for undifferentiated E...

Biological evolution is often viewed narrowly as a change of morphology or allele frequency in a sequence of generations. Here I pursue an alternative informational concept of evolution, as preservation, advance, and emergence of functional information in natural agents. Functional information is a network of signs (e.g., memory, transient messenge...

The origin of life means the emergence of heritable and evolvable self-reproduction. However the mechanisms of primordial heredity were different from those in contemporary cells. Here I argue that primordial life had no nucleic acids; instead heritable signs were represented by isolated catalytically active self-reproducing molecules, similar to e...

A key feature of biosemiotics is, in contrast with traditional semiotics, that it considers the dynamics of semiosis at multiple time scales, and emphasizes the active role organisms have in reshaping sign relations.

The TCR repertoire serves as a reservoir of TCRs for recognizing all potential pathogens. Two major types of T cells, CD4(+) and CD8(+), that use the same genetic elements and process to generate a functional TCR differ in their recognition of peptide bound to MHC class II and I, respectively. However, it is currently unclear to what extent the TCR...

Mouse embryonic stem cells (mESCs) have a remarkable capacity to maintain normal genome stability and karyotype in culture. We previously showed that infrequent bursts of Zscan4 expression (Z4 events) are important for the maintenance of telomere length and genome stability in mESCs. However, the molecular details of Z4 events remain unclear. Here...

We have developed ExAtlas, an on-line software tool for meta-analysis and visualization of gene expression data. In contrast to existing software tools, ExAtlas compares multi-component data sets and generates results for all combinations (e.g. all gene expression profiles versus all Gene Ontology annotations). ExAtlas handles both users' own data...

This paper presents the results of the study conducted in summers of 2002, 2005 and 2006 to evaluate Shin-Etsu sprayable formulation for its ability to disrupt mating in low-density gypsy moth populations.

The journal Biosemiotics was envisioned by its founding editor, Marcello Barbieri, as a major periodical for interdisciplinary papers that integrate biology and semiotics. Since 2008 the journal has published 21 issues, including special issues on crucial problems such as the semiotics of perception, origins of mind, code biology, biohermeneutics,...

Life has semiotic nature; and as life forms differ in their complexity, functionality, and adaptability, we assume that forms of semiosis also vary accordingly. Here we propose a criterion to distinguish between the primitive kind of semiosis, which we call "protosemiosis" (following Prodi) from the advanced kind of semiosis, or "eusemiosis". In pr...

In the era of the extended evolutionary synthesis, which no longer considers natural selection as the only leading factor of evolution, it is meaningful to revisit the legacy of biologists who discussed the role of alternative factors. Here we analyze the evolutionary views of Sergei Meyen (1935–1987), a paleobotanist who argued that the theory of...

Abstract Transcription factors (TFs) bind to DNA and regulate the transcription of nearby genes. However, only a small fraction of TF binding sites have such regulatory effects. Here we search for the predictors of functional binding sites by carrying out a systematic computational screening of a variety of contextual factors (histone modifications...

Natural selection is traditionally viewed as a leading factor of evolution, whereas variation is assumed to be random and non-directional. Any order in variation is attributed to epigenetic or developmental constraints that can hinder the action of natural selection. In contrast I consider the positive role of epigenetic mechanisms in evolution bec...

A network of transcription factors (TFs) determines cell identity, but identity can be altered by overexpressing a combination of TFs. However, choosing and verifying combinations of TFs for specific cell differentiation have been daunting due to the large number of possible combinations of ∼2,000 TFs. Here, we report the identification of individu...

The class V POU domain transcription factor Oct4 (Pou5f1) is a pivotal regulator of embryonic stem cell (ESC) self-renewal and reprogramming of somatic cells to induced pluripotent stem (iPS) cells. Oct4 is also an important evolutionarily conserved regulator of progenitor cell differentiation during embryonic development. Here we examine the funct...

Topoisomerases are crucial for solving DNA topological problems, but they have not been linked to RNA metabolism. Here we show that human topoisomerase 3β (Top3β) is an RNA topoisomerase that biochemically and genetically interacts with FMRP, a protein that is deficient in fragile X syndrome and is known to regulate the translation of mRNAs that ar...

Pair-wise comparisons (FDR < 0.05, >2-fold expression difference) were performed between HV− and HV+ populations to reveal significant changes in gene expression; 47 genes upregulated and 31 downregulated.

Pair-wise comparisons (FDR < 0.05, >2-fold expression difference) were performed between HV- and HV+ populations to reveal significant changes in gene expression; 60 genes upregulated and 272 downregulated.

Embryonic stem cells (ESCs) are derived from mammalian embryos during the transition from totipotency, when individual blastomeres can make all lineages, to pluripotency, when they are competent to make only embryonic lineages. ESCs maintained with inhibitors of MEK and GSK3 (2i) are thought to represent an embryonically restricted ground state. Ho...

Mouse embryonic stem (ES) cells are prototypical stem cells that remain undifferentiated in culture for long periods, yet maintain the ability to differentiate into essentially all cell types. Previously, we have reported that ES cells oscillate between two distinct states, which can be distinguished by the transient expression of Zscan4 genes orig...

Networks of transcription factors (TFs) are thought to determine and maintain the identity of cells. Here we systematically repressed each of 100 TFs with shRNA and carried out global gene expression profiling in mouse embryonic stem (ES) cells. Unexpectedly, only the repression of a handful of TFs significantly affected transcriptomes, which chang...

An extrapolation of the genetic complexity of organisms to earlier times suggests that life began before the Earth was formed. Life may have started from systems with single heritable elements that are functionally equivalent to a nucleotide. The genetic complexity, roughly measured by the number of non-redundant functional nucleotides, is expected...

In contrast to the human standard for mind established by Alan Turing, I search for a “minimal mind,” which is present in animals and even lower-level organisms. Mind is a tool for the classification and modeling of objects. Its origin marks an evolutionary transition from protosemiotic agents, whose signs directly control actions, to eusemiotic ag...

Oct4 is an essential regulator of pluripotency in vivo and in vitro in embryonic stem cells, as well as a key mediator of the reprogramming of somatic cells into induced pluripotent stem cells. It is not known whether activation and/or repression of specific genes by Oct4 is relevant to these functions. Here, we show that fusion proteins containing...

B-type lamins, the major components of the nuclear lamina, are believed to be essential for cell proliferation and survival. We found that mouse embryonic stem cells (ESCs) do not need any lamins for self-renewal and pluripotency. Although genome-wide lamin-B binding profiles correlate with reduced gene expression, such binding is not directly requ...

Here we report the generation and characterization of 84 mouse ES cell lines with doxycycline-controllable transcription factors (TFs) which, together with the previous 53 lines, cover 7-10% of all TFs encoded in the mouse genome. Global gene expression profiles of all 137 lines after the induction of TFs for 48 hrs can associate each TF with the d...