mRNA synthesis in all organisms is performed by RNA polymerases, which work as nanomachines on DNA templates. The rate at which their product is made is an important parameter in gene expression. Transcription rate encompasses two related, yet different, concepts: the nascent transcription rate, which measures the in situ mRNA production by RNA polymerase, and the rate of synthesis of mature mRNA, which measures the contribution of transcription to the mRNA concentration. Both parameters (...) are useful for molecular biologists, but they are not interchangeable and they are expressed in different units. It is important to distinguish when and where each one should be used. We propose that for functional genomics the use of nascent transcription rates should be restricted to the evaluation of the transcriptional process itself, whereas mature mRNA synthesis rates should be employed to address the transcriptional input to mRNA concentration balance leading to variation of gene expression. (shrink)

Transcriptional enhancer sequences have been shown to play a pivotal role in the regulation of some highly expressed genes. First described in eukaryotic viruses, the discovery of enhancers has augmented the previously defined control‐sequence motifs to give a more complete understanding of eukaryotic transcriptional regulatory mechanisms. Some properties of enhancers that distinguish them from other regulatory sequences include their ability to function in a position‐ and orientation‐independent manner. Furthermore, the observation that some enhancers and transcriptional promoters exhibit tissue specificity in (...) their activity has generated considerable interest. Enhancer activation is thought to involve sequence‐specific DNA‐binding proteins but the process by which this leads to an increase in the initiation of transcription remains obscure. Although viral enhancers are more fully characterized, several cellular enhancers have recently been identified. One such enhancer sequence has been detected in a 3′ flanking region of a highly expressed human placental lactogen gene. This enhancer can increase the transcriptional rate of an adjacent gene by at least 50‐fold. (shrink)

As cells approach S phase, many changes occur to create an environment conducive for DNA synthesis and commitment to cell division. The transcription rate of many genes encoding enzymes involved in DNA synthesis, including the dihydrofolate reductase (dhfr) gene, increases at the G1/S boundary of the cell cycle. Although a number of transcription factors interact to finely tune the levels of dhfr RNA produced, two families of transcription factors, Sp1 and E2F, play central roles in modulating (...) dhfr levels. A region containing several Sp1‐binding sites is required for both regulated and basal transcription levels. In contrast, the E2F‐binding sites near the transcription start site are required only for regulated transcription. A model is presented for the regulation of the dhfr gene which may also pertain to other cell cycle‐associated genes. (shrink)

Recently discovered transcription‐independent features of p53 involve the choice of DNA damage repair pathway after PARylation, and p53's complex formation with phosphoinositide lipids, PI(4,5)P2. PARylation‐mediated rapid accumulation of p53 at DNA damage sites is linked to the recruitment of downstream repair factors and tumor suppression. This links p53's capability to sense damaged DNA in vitro and its relevant functions in cells. Further, PI(4,5)P2 rapidly accumulates at damage sites like p53 and complexes with p53, while it is required for ATR (...) recruitment. These findings help explain how p53 and PI(4,5)P2 maintain genome stability by directing DNA repair pathway choice. Additionally, there is a strong correlation between p53 sequence homology, genome mutation rates as well as lifespans across various mammalian species. Further investigation is required to better understand the connections between genome stability, tumor suppression, longevity and the transcriptional‐independent function of p53. (shrink)

The major challenge in complex disease genetics is to understand the fundamental features of this complexity and why functional alterations at multiple independent genes conspire to lead to an abnormal phenotype. We hypothesize that the various genes involved are all functionally united through gene regulatory networks (GRN), and that mutant phenotypes arise from the consequent perturbation of one or more rate‐limiting steps that affect the function of the entire GRN. Understanding a complex phenotype thus entails unraveling the details of (...) each GRN, namely, the transcription factors that bind to cis regulatory elements affected by sequence variants altering transcription of specific genes, and their mutual feedback relationships. These GRNs can be identified through their rate‐limiting steps and are best uncovered by genomic analyses of rare, extreme phenotype families, thus providing a coherent molecular basis to complex traits and disorders. (shrink)

A gene's “expression profile” denotes the number of transcripts present relative to all other transcripts. The overall rate of transcript production is determined by transcription and RNA processing rates. While the speed of elongating RNA polymerase II has been characterized for many different genes and organisms, gene‐architectural features – primarily the number and length of exons and introns – have recently emerged as important regulatory players. Several new studies indicate that rapidly cycling cells constrain gene‐architecture toward short genes (...) with a few introns, allowing efficient expression during short cell cycles. In contrast, longer genes with long introns exhibit delayed expression, which can serve as timing mechanisms for patterning processes. These findings indicate that cell cycle constraints drive the evolution of gene‐architecture and shape the transcriptome of a given cell type. Furthermore, a tendency for short genes to be evolutionarily young hints at links between cellular constraints and the evolution of animal ontogeny. (shrink)

BackgroundCervical cancer disproportionately burdens disadvantaged women. Organised cervical screening aims to make cancer prevention available to all women in a population, yet screening uptake and cancer incidence and mortality are strongly correlated with socioeconomic status. Reaching underscreened populations is a stated priority in many screening programs, usually with an emphasis on something like ‘equity’. Equity is a poorly defined and understood concept. We aimed to explain experts’ perspectives on how cervical screening programs might justifiably respond to ‘the underscreened’.MethodsThis paper reports (...) on a grounded theory study of cervical screening experts involved in program organisation. Participants were 23 experts from several countries and a range of backgrounds: gynecology; epidemiology; public health; pathology; general practice; policy making. Data were gathered via semi-structured interview and concepts developed through transcript coding and memo writing.ResultsMost experts expressed an intuitive commitment to reducing systematic differences in screening participation or cancer outcomes. They took three different implicit positions, however, on what made organised programs justifiable with respect to underscreened populations. These were: 1) accepting that population screening is likely to miss certain disenfranchised groups for practical and cultural reasons, and focusing on maximising mainstream reach; 2) identifying and removing barriers to screening; and 3) providing parallel tailored screening services that attended to different cultural needs. Positions tended to fall along country of practice lines.ConclusionsExperts emphasised the provision of opportunity for underscreened populations to take up screening. A focus on opportunity appeared to rely on tacit premises not supported by evidence: that provision of meaningful opportunity leads to increased uptake, and that increased uptake of an initial screening test by disadvantaged populations would decrease cervical cancer incidence and mortality. There was little attention to anything other than the point of testing, or the difficulties disadvantaged women can have in accessing follow up care. The different approaches to ‘improving equity’ taken by participants are differently justified, and differently justifiable, but none attend directly to the broader conditions of disadvantage. (shrink)

The transcription factor NF‐κB (p65/p50) plays a central role in the coordination of cellular responses by activating the transcription of numerous target genes. The precise role of the dynamics of NF‐κB signalling in regulating gene expression is still an open question. Here, we show that besides external stimulation intracellular parameters can influence the dynamics of NF‐κB. By applying mathematical modelling and bifurcation analyses, we show that NF‐κB is capable of exhibiting different types of dynamics in response to the (...) same stimulus. We identified the total NF‐κB concentration and the IκBα transcription rate constant as two critical parameters that modulate the dynamics and the fold change of NF‐κB. Both parameters might vary as a result of cell‐to‐cell variability. The regulation of the IκBα transcription rate constant, e.g. by co‐factors, provides the possibility of regulating the NF‐κB dynamics by crosstalk. (shrink)

Auxin, a class of plant hormones which affects a wide array of growth and developmental processes including cell elongation and cell division, alters gene expression in a very rapid, selective, and dramatic way. The relative level of some mRNAs decreases several fold, while that of other mRNAs increases many fold. These changes are mediated, at least in some cases, by very fast (within 5–10 min) modulation by auxin of transcription as measured by run‐off transcription assays using nuclei isolated (...) from control and auxin‐treated tissues. Rapid turnover of mRNAs following auxin treatment also contributes to large changes in steady state concentration in some cases. The data are suggestive of multiple and complex mechanisms of regulation of expression of those genes which have been studied, using cloned cDNAs for direct quantitation of mRNA steady state levels and relative transcription rates. While there is no definitive evidence that auxin‐regulated gene expression mediates any of the growth responses effected by auxin, several lines of evidence are supportive of a very close relationship between these processes. The working hypothesis is that there is a causal relationship between the effects of auxin on gene expression and at least some of the physiological and growth responses to auxin. (shrink)

Somatic mutations arising in human skin cancers are heterogeneously distributed across the genome, meaning that certain genomic regions (e.g., heterochromatin or transcription factor binding sites) have much higher mutation densities than others. Regional variations in mutation rates are typically not a consequence of selection, as the vast majority of somatic mutations in skin cancers are passenger mutations that do not promote cell growth or transformation. Instead, variations in DNA repair activity, due to chromatin organization and transcription factor binding, (...) have been proposed to be a primary driver of mutational heterogeneity in melanoma. However, as discussed in this review here, recent studies indicate that chromatin organization and transcription factor binding also significantly modulate the rate at which UV lesions form in DNA. The authors propose that local variations in lesion susceptibility may be an important driver of mutational hotspots in melanoma and other skin cancers, particularly at binding sites for ETS transcription factors. (shrink)

Post‐transcriptional tRNA modifications contribute to the decoding efficiency of tRNAs by supporting codon recognition and tRNA stability. Recent work shows that the molecular and cellular functions of tRNA modifications and tRNA‐modifying‐enzymes are linked to brain development and neurological disorders. Lack of these modifications affects codon recognition and decoding rate, promoting protein aggregation and translational stress response pathways with toxic consequences to the cell. In this review, we discuss the peculiarity of local translation in neurons, suggesting a role for fine‐tuning (...) of translation performed by tRNA modifications. We provide several examples of tRNA modifications involved in physiology and pathology of the nervous system, highlighting their effects on protein translation and discussing underlying mechanisms, like the unfolded protein response (UPR), ribosome quality control (RQC), and no‐go mRNA decay (NGD), which could affect neuronal functions. We aim to deepen the understanding of the roles of tRNA modifications and the coordination of these modifications with the protein translation machinery in the nervous system. (shrink)

Through their transcript products genes regulate the rates at which an immense variety of transcripts and subsequent proteins occur. Understanding the mechanisms that determine which genes are expressed, and when they are expressed, is one of the keys to genetic manipulation for many purposes, including the development of new treatments for disease. Viewing each gene in a genome as a distinct variable that is either on or off, or more realistically as a continuous variable, the values of some of these (...) variables influence the values of others through the regulatory proteins they express, including, of course, the possibility that the rate of expression of a gene at one time may, in various circumstances, influence the rate of expression of that same gene at a later time. If we imagine an arrow drawn from each gene expression variable at a given time to a gene variable whose expression it influences a short while after, the result is a network, technically a directed acyclic graph. For example, the DAG in Figure 1 is a representation of a system in which the expression level of gene G1 at time 1 ) causes the expression level of G2, which in turn causes the expression level of G3. The arrows in Figure 1 which do not have a variable at their tails are “error terms” which represent all of the causes of a variable other than the ones explicitly represented in the DAG. The DAG describes more than associations—it describes causal connections among gene expression rates. A shock to a cell—by mutation, heating, chemical treatment, etc. may alter the DAG describing the relations among gene expressions, for example by activating a gene that was otherwise not expressed, producing a cascade of new expression effects. Although “knockout” experiments can reveal some of the underlying causal network of gene expression levels, unless guided by information from other sources, such experiments are limited in how much of the network structure they can reveal, due to the sheer number of possible combinations of experimental manipulations of genes necessary to reveal the complete causal network. Recent developments have made it possible to compare quantitatively the expression of tens of thousands of genes in cells from different sources in a single experiment, and to trace gene expression over time in thousands of genes simultaneously. cDNA microarrays are already producing extensive data, much of it available on the web. Thus there are calls for analytic software that can be applied to microarray and other data to help infer regulatory networks. In this paper we will review current techniques that are available for searching for the causal relations between variables, describe algorithmic and data gathering obstacles to applying these techniques to gene expression levels, and describe the prospects for overcoming these obstacles. (shrink)

Extraordinary extended lampbrush chromosomes with thousands of transcription loops are favorable objects in chromosome biology. Chromosomes become lampbrushy due to unusually high rate of transcription during oogenesis. However, until recently, the information on the spectrum of transcribed sequences as well as genomic context of individual chromomeres was mainly limited to tandemly repetitive elements. Here we briefly outline novel findings and future directions in lampbrush chromosome studies in the post‐genomic era. We emphasize the fruitfulness of combining genome‐wide approaches (...) with microscopy imaging techniques using lampbrush chromosomes as a remarkable model object. We believe that new data on the spectrum of sequences transcribed on the lateral loops of lampbrush chromosomes and their structural organization push the boundaries in the discussion of their biological role. Also see the video abstract here: https://youtu.be/zexoHfzX9rM. (shrink)

When rates of transcription from specific genes change, delays of variable length intervene before the corresponding mRNAs and proteins attain new levels. For most mammalian genes, the time required to complete transcription, processing, and transport of mRNA is much shorter than the period needed to achieve a new, steady‐state level of protein. Studies of inducible genes have shown that the period required to attain new levels of individual mRNAs and proteins is related to their unique half‐lives. The basis (...) for this is a physical principle that predicts rates of accumulation of particles in compartmental systems. The minimum period required to achieve a new level is directly proportional to product half‐lives because rates of decay control the ratio between the rate of synthesis and the concentration of gene products at steady state. This kinetic model suggests that sensitivity of gene products to degradation by ribonucleases and proteinases is an important determinant of the time scale of gene expression. (shrink)

A widely accepted tenet of evolutionary biology is that spontaneous mutations occur randomly with regard to their fitness effect. However, since the mutation rate varies along a genome and this variation can be subject to selection, organisms might evolve lower mutation rates at loci where mutations are most deleterious or increased rates where mutations are most needed. In fact, mechanisms of targeted hypermutation are known in organisms ranging from bacteria to humans. Here we review the main forces driving the (...) evolution of local mutation rates and identify the main limiting factors. Both targeted hyper‐ and hypomutation can evolve, although the former is restricted to loci under very frequent positive selection and the latter is severely limited by genetic drift. Nevertheless, we show how an association of repair with transcription or chromatin‐associated proteins could overcome the drift limit and lead to non‐random hypomutation along the genome in most organisms.Editor's suggested further reading in BioEssays Stress‐induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine Abstract. (shrink)

Next SectionBackground: Physicians face ethical difficulties daily, yet they seek ethics consultation infrequently. To date, no systematic data have been collected on the strategies they use to resolve such difficulties when they do so without the help of ethics consultation. Thus, our understanding of ethical decision making in day to day medical practice is poor. We report findings from the qualitative analysis of 310 ethically difficult situations described to us by physicians who encountered them in their practice. When facing such (...) situations, the physicians sought to avoid conflict, obtain assistance, and protect the integrity of their conscience and reputation, as well as the integrity of the group of people who participated in the decisions. These goals could conflict with each other, or with ethical goals, in problematic ways. Being aware of these potentially conflicting goals may help physicians to resolve ethical difficulties more effectively. This awareness should also contribute to informing the practice of ethics consultation. Objective: To identify strategies used by physicians in dealing with ethical difficulties in their practice. Design, setting, and participants: National survey of internists, oncologists, and intensive care specialists by computer assisted telephone interviews (n = 344, response rate = 64%). As part of this survey, we asked physicians to tell us about a recent ethical dilemma they had encountered in their medical practice. Transcripts of their open-ended responses were analysed using coding and analytical elements of the grounded theory approach. Main measurements: Strategies and approaches reported by respondents as part of their account of a recent ethical difficulty they had encountered in their practice. Results: When faced with ethical difficulties, the physicians avoided conflict and looked for assistance, which contributed to protecting, or attempting to protect, the integrity of their conscience and reputation, as well as the integrity of the group of people who participated in the decisions. These efforts sometimes reinforced ethical goals, such as following patients’ wishes or their best interests, but they sometimes competed with them. The goals of avoiding conflict, obtaining assistance, and protecting the respondent’s integrity and that of the group of decision makers could also compete with each other. Conclusion: In resolving ethical difficulties in medical practice, internists entertained competing goals that they did not always successfully achieve. Additionally, the means employed were not always the most likely to achieve those aims. Understanding these aspects of ethical decision making in medical practice is important both for physicians themselves as they struggle with ethical difficulties and for the ethics consultants who wish to help them in this process. (shrink)

In a work that appeared in 1967 but which has lost none of its interest today, P. Alexandre gave a list of the 51 languages of Black Africa (or homogeneous dialectical and linguistic groups) that approached or surpassed a million speakers. For each of them he evaluated available documentation, on a scale of from 1 to 6. He gave the rating 1 to languages for which the documentation was poor (outdated grammars and dictionaries, incomplete or absurd systems of unscientific (...) class='Hi'>transcription) and the rating 6 to languages for which works conforming to modern requirements were available (correctly noted sound systems, phonological and phonetic descriptions, annotated texts, dictionaries, stylistic and dialectological studies, audio material). Only three languages merited the rating 6 and only four were rated 5. This means that only seven languages out of about 1200 could be considered as accurately described, that is, offering all the necessary guarantees to the specialist. (shrink)

Ribonucleotide reductase (RNR) catalyzes the rate limiting step in the production of deoxyribonucleotides needed for DNA synthesis. In addition to the well documented allosteric regulation, the synthesis of the enzyme is also tightly regulated at the level of transcription. mRNAs for both subunits are cell cycle regulated and inducible by DNA damage in all organisms examined, including E. coli, S. cerevisiae and H. sapiens. This DNA damage regulation is thought to provide a metabolic state that facilitates DNA replicational (...) repair processes. S. cerevisiae also encodes a second large subunit gene, RNR3, that is expressed only in the presence of DNA damage. Genetic analysis of the DNA damage response in S. cerevisiae has shown that RNR expression is under both positive and negative control. Among mutants constitutive for RNR expression are the general transcriptional repression genes, SSN6 and TUP1. Mutations in POL1 and POL3 also activate RNR expression, indicating that the DNA damage sensory network may respond directly to blocks in DNA synthesis. A protein kinase, Dun1, has been identified that controls inducibility of RNR1, RNR2 and RNR3 in response to DNA damage and replication blocks. This result suggests that the RNR genes in S. cerevisiae form a regulon that is coordinately regulated by protein phosphorylation in response to DNA damage. (shrink)

Of the many genes mutated on the road to tumor formation, few have received as much attention as p53. The gene has come to occupy center stage for the simple reason that it is more frequently altered in human tumors than any other known gene, undergoing mutation at a significant rate in almost every tumor type in which it has been studied. This association between p53 mutation and tumorigenesis has spurred a flurry of research attempting to delineate the normal (...) function of p53 and, by extension, the role of p53 mutation in tumor formation. At the cellular level, p53 has been shown to suppress growth. Recent efforts to further discern the function of p53 have centered on the underlying molecular basis for this growth suppression. In particular, research has focused on the identification of cellular molecules (specifically DNA and proteins) with which the p53 protein associates. p53 has now been shown to bind DNA in a sequence‐specific manner, and mounting evidence suggests that p53 acts as a transcription factor, perhaps regulating the expression levels of genes involved in the inhibition of cell growth. The logical next step in understanding p53 function involves the resolution of two questions: (1) what are the physiological transcriptional targets of p53, and (2) what cellular proteins regulate or mediate the ability of p53 to modulate transcription? Some initial clues to these puzzles are now emerging, and these form the subject of this review. (shrink)

The new developments in our social context, the recent pandemic outbreak, caused a series of changes in everyday practices. The student population represents a particular case, both their safety and future education were under duress during this period. However, their views over the situation have not been present in the scientific literature. The present qualitative research aimed to explore students' perceptions, attitudes, views, and representations on the Covid-19 pandemic. Three focus groups, each containing twelve participants, were organised to explore these (...) aspects and students’ particular experiences. Focus group sessions were audio-recorded and the transcripts were analysed. The results revealed four dimensions of the students' representations: change – as a constant of the present, prospective scenarios, the pulse of the moment, and surrounding risks. The limitations and the importance of the study are discussed. The consequences of these representations are particularly important due to the influence they can have on people’s practices during the crisis and the extent of measures’ acceptance. The results offer precious insights on why some communication strategies used by the authorities had a low compliance rate, what should be done differently, and what should be considered in order to promote adaptive health behaviors during the latter phases of the pandemic. (shrink)

Response to Floridi et al, 2008/2009. Based on insufficient evidence, and inadequate research, Floridi and his students report inaccuracies and draw false conclusions in their Minds and Machines evaluation, which this paper aims to clarify. Acting as invited judges, Floridi et al. participated in nine, of the ninety-six, Turing tests staged in the finals of the 18th Loebner Prize for Artificial Intelligence in October 2008. From the transcripts it appears that they used power over solidarity as an interrogation technique. As (...) a result, they were fooled on several occasions into believing that a machine was a human and that a human was a machine. Worse still, they did not realise their mistake. This resulted in a combined correct identification rate of less than 56%. In their paper they assumed that they had made correct identifications when they in fact had been incorrect. (shrink)

In the course of an immune response, antibodies undergo affinity maturation in order to increase their efficiency in neutralizing foreign invaders. Affinity maturation occurs by the introduction of multiple point mutations in the variable region gene that encodes the antigen binding site. This somatic hypermutation is restricted to immunoglobulin genes and occurs at very high rates. The precise molecular basis of this process remains obscure. However, recent studies using a variety of in vivo and in vitro systems have revealed important (...) regulatory regions, base motifs that are preferred targets of mutation and evidence that transcription may play an active role in hypermutation. BioEssays 20:227–234, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the (...) biogenesis of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. Are randomly generated mutations the only source of genetic variation during evolution? This paper describes the molecular mechanisms by which co-transcriptional and co-translational biophysical constraints trigger genetic variations in targeted-genomic sequences in an RNA-depending manner. This directed-mutational process that drives genome evolution is related to antiparasite genome defence systems. (shrink)

High-dose chemotherapy and autologous stem cell transplantation is used to treat some advanced malignancies. It is a traumatic procedure, with a high complication rate and significant mortality. ASCT patients and their carers draw on many sources of information as they seek to understand the procedure and its consequences. Some seek information from beyond orthodox medicine. Alternative beliefs and practices may conflict with conventional understanding of the theory and practice of ASCT, and ‘contested understandings’ might interfere with patient adherence to (...) the strict and demanding protocols required for successful ASCT.The present study, conducted in Sydney, Australia, examines narrative-style interviews with 10 sequentially recruited ASCT patients and nine of their carers conducted at the time of transplant and three months later. Transcripts were read for instances of mention of alternative advice, and for instances of contested understanding of information relevant to the transplant.Patients and carer pairs expressed closely concordant views about alternative advice. Five pairs were consulting alternative practitioners. Contested understanding was expressed in four domains—understandings of the transplant itself and its underlying theory, of the relationship between the components of the ‘transplant’, of the nature and role of stem cells, and of beliefs about bodily function and life-style. Contested understandings of the transplant treatment were expressed as predominantly personal interpretations of orthodox informationPatients and carers seemed to recognise that alternative and conventional systems were discordant, yet they were able to separate the two, and adhere to each practice without prejudicing their medical treatment. A single case of late, post-transplant repudiation of Western medicine is discussed to emphasise some of the possible determinants of dissonance when it does occur. (shrink)

One of the main challenges in group therapy with drug-addicted patients is collective pseudomentalization, i.e., a group discourse consisting of words and clichés that are decoupled from any inner emotional life and are poorly related to external reality. In this study, we aimed to explore the phenomenology of pseudomentalization and how it was addressed by the therapist in an outpatient group for drug-addicted patients. The group was composed of seven members, and the transcripts of eight audio-recorded sessions were rated and (...) studied. The interventions of the therapist were measured with the mentalization-based group therapy adherence and quality scale by independent raters. Two sessions, one with the highest and one with the lowest adherence, were selected, and the clinical sequences of pseudomentalization were analyzed in a comparative way. The findings revealed that pseudomentalization does occur as a collective phenomenon, akin to “basic assumptions” of Wilfred Bion, which we reconceptualized in this study. Any pseudomentalization seemed to be reinforced by the therapist when she was presenting frequent and long interventions, when abstaining from the management of group boundaries, when providing questions focused more on content than on the mental states of the group members, and when not focusing on emotions. However, the ultimate source of collective pseudomentalization seemed to be the fear of the group members of being overwhelmed by painful emotions, mental confusion, and a loss of identity. The findings also indicated that the principles of MBT-G may be a good antidote to pseudomentalization. (shrink)

Ethical decision making is of concern to researchers across all fields. However, researchers typically focus on the biases that may act to undermine ethical decision making. Taking a new approach, this study focused on identifying the most common compensatory strategies that counteract those biases. These strategies were identified using a series of interviews with university researchers in a variety of areas, including biological, physical, social, and health as well as scholarship and the performing arts. Interview transcripts were assessed with two (...) scoring procedures, an expert rating system and computer-assisted qualitative analysis. Although the expert rating system identified Understanding Guidelines, Recognition of Insufficient Information, and Recognizing Boundaries as the most frequently used compensatory strategies across fields, other strategies, Striving for Transparency, Value/norm Assessment, and Following Appropriate Role Models, were identified as most common by the computer-assisted qualitative analyses. Potential reasons for these findings and implications for training and practice are identified and discussed. (shrink)

Transposable elements (TEs) are mobile genomic elements constituting a big fraction of eukaryotic genomes. They ignite an evolutionary arms race with host genomes, which in turn evolve strategies to restrict their activity. Despite being tightly repressed, TEs display precisely regulated expression patterns during specific stages of mammalian development, suggesting potential benefits for the host. Among TEs, the long interspersed nuclear element (LINE‐1 or L1) has been found to be active in neurons. This activity prompted extensive research into its possible role (...) in cognition. So far, no specific cause‐effect relationship between L1 retrotransposition and brain functions has been conclusively identified. Nevertheless, accumulating evidence suggests that interactions between L1 RNAs and RNA/DNA binding proteins encode specific messages that cells utilize to activate or repress entire transcriptional programs. We summarize recent findings highlighting the activity of L1 RNAs at the non‐coding level during early embryonic and brain development. We propose a hypothesis suggesting a mutualistic relationship between L1 mRNAs and the host cell. In this scenario, cells tolerate a certain rate of retrotransposition to leverage the regulatory effects of L1s as non‐coding RNAs on potentiating their mitotic potential. In turn, L1s benefit from the cell's proliferative state to increase their chance to mobilize. (shrink)

Recent advances in DNA sequencing have revolutionized the field of genomics, making it possible for even single research groups to generate large amounts of sequence data very rapidly and at a substantially lower cost. These high‐throughput sequencing technologies make deep transcriptome sequencing and transcript quantification, whole genome sequencing and resequencing available to many more researchers and projects. However, while the cost and time have been greatly reduced, the error profiles and limitations of the new platforms differ significantly from those of (...) previous sequencing technologies. The selection of an appropriate sequencing platform for particular types of experiments is an important consideration, and requires a detailed understanding of the technologies available; including sources of error, error rate, as well as the speed and cost of sequencing. We review the relevant concepts and compare the issues raised by the current high‐throughput DNA sequencing technologies. We analyze how future developments may overcome these limitations and what challenges remain. (shrink)

An exploration of our fall from the pinnacle of human evolution 200,000 years ago and how we can begin our return. Explores recent neurological and psychological research on the brain and the role of plant biochemistry in human brain expansion. Explains how humanity's prehistoric diet change led to a neurodegenerative condition characterized by aggression and a fearful perception of the world. Outlines a strategy of raw foods, tantric sexuality, shamanic practices, and entheogens to reverse our mental degeneration and restore our (...) advanced abilities. Over a period of a million years the human brain expanded at an increasingly rapid rate, and then, 200,000 years ago, the expansion abruptly stopped. Modern science has overlooked this in order to maintain that we are at the pinnacle of our evolution. However, the halt in brain expansion explains not only recently uncovered anomalies within the human brain but also the global traditions of an earthly paradise lost and of humanity's degeneration from our original state of perpetual wonder and joy. Drawing on more than 20 years of research, authors Tony Wright and Graham Gynn explore how our modern brains are performing far below their potential and how we can unlock our higher abilities and return to the euphoria of Eden. They explain how for millions of years early forest-dwelling humans were primarily consuming the hormone-rich sex organs of plants--fruit--each containing a highly complex biochemical cocktail evolved to influence DNA transcription, rapid brain development, and elevated neural and pineal gland activity. Citing recent neurological and psychological studies, the authors explain how the loss of our symbiotic fruit-based diet led to a progressive neurodegenerative condition characterized by aggressive behaviors, a fearful perception of the world, and the suppression of higher artistic, mathematical, and spiritual abilities. The authors show how many shamanic and spiritual traditions were developed to counteract our decline. They outline a strategy of raw foods, tantric sexuality, shamanic practices, and entheogen use to reverse our degeneration, restore our connection with the plant world, and regain the bliss and peace of the brain of Eden"--Provided by publisher. (shrink)

This article reports on developing and evaluating a generic Handwritten Text Recognition (HTR) model created for the automatic computer-assisted transcription of Ukrainian handwriting publicly available via the HTR platform Transkribus. The model’s training process encompasses diverse datasets, including historical manuscripts by renowned poets Taras Shevchenko and Lesya Ukrainka, along with private correspondence used for the General Regionally Annotated Corpus of Ukrainian (GRAC) and a diary procured at the Holodomor Museum collection. We evaluate the model’s performance by comparing its theoretical (...) accuracy, with a character error rate (CER) of 4.2%, against its practical efficacy when augmented with an AI-based language model for Ukrainian and a Large Language Model. The model is versatile and functional and can thus be applied for mass-digitization of Ukrainian cultural heritage. In our outlook section, we identify possibilities for further improving the model. (shrink)

In the course of an immune response, antibodies undergo affinity maturation in order to increase their efficiency in neutralizing foreign invaders. Affinity maturation occurs by the introduction of multiple point mutations in the variable region gene that encodes the antigen binding site. This somatic hypermutation is restricted to immunoglobulin genes and occurs at very high rates. The precise molecular basis of this process remains obscure. However, recent studies using a variety of in vivo and in vitro systems have revealed important (...) regulatory regions, base motifs that are preferred targets of mutation and evidence that transcription may play an active role in hypermutation. BioEssays 20:227–234, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

This study investigated the impact of maternal reflective functioning (RF) and attachment security on children’s mentalization. The Adult Attachment Interview (AAI) was administered to mothers in a sample of 41 mother–preadolescent dyads. AAI transcripts were rated in terms of the Berkeley AAI System ( Main and Goldwyn, 1998 ) and the Reflective Functioning Scale (RFS; Fonagy et al., 1998 ). Preadolescent mentalization was assessed using a semi-structured interview adapted from O’Connor and Hirsch (1999) and also by analyzing mental-state talk produced (...) during an autobiographical interview. Relationships between maternal RF and children’s mentalization were analyzed, with consideration given to the different RFS markers and references to positive, negative, and mixed-ambivalent mental states. Children’s mentalization was positively correlated with the mother’s RF, particularly the mother’s ability to mentalize negative or mixed-ambivalent mental states. No significant differences in mentalization were observed between children of secure and insecure mothers. (shrink)

We propose that interaction rules derived from polyamine exchange in connected cells may explain the spatio‐temporal organization of gap junctions observed during tissue regeneration and tumorigenesis. We also hypothesize that polyamine exchange can be considered as signal that allows cells to sense the proliferation status of their neighbors. Polyamines (putrescine, spermidine, and spermine) are indeed small aliphatic polycations that serve as fuels to sustain elevated proliferation rates of the order observed in cancer cells. Based on recent reports, we consider here (...) that polyamines can be exchanged through gap junction channels between mammalian cells. Such intercellular exchange of polyamines has critical consequences on the local control of growth. In line with this hypothesis, the complex protein network that keeps polyamine levels finely tuned in mammalian cells can translate polyamine efflux or influx into integrated signals controlling transcription, translation, and cell communications. (shrink)

Understanding aging and how it affects an organism's lifespan is a fundamental problem in biology. A hallmark of aging is stem cell senescence, the decline of functionality, and number of somatic stem cells, resulting in an impaired regenerative capacity and reduced tissue function. In addition, aging is characterized by profound remodeling of the immune system and a quantitative decline of adequate immune responses, a phenomenon referred to as immune‐senescence. Yet, what is causing stem cell and immune‐senescence? This review discusses experimental (...) studies of potentially immortal Hydra which have made contributions to answering this question. Hydra transcription factor FoxO has been shown to modulate both stem cell proliferation and innate immunity, lending strong support to a role of FoxO as critical rate‐of‐aging regulator from Hydra to human. Constructing a model of how FoxO responds to diverse environmental factors provides a framework for how stem cell factors might contribute to aging. (shrink)

In the course of an immune response, antibodies undergo affinity maturation in order to increase their efficiency in neutralizing foreign invaders. Affinity maturation occurs by the introduction of multiple point mutations in the variable region gene that encodes the antigen binding site. This somatic hypermutation is restricted to immunoglobulin genes and occurs at very high rates. The precise molecular basis of this process remains obscure. However, recent studies using a variety of in vivo and in vitro systems have revealed important (...) regulatory regions, base motifs that are preferred targets of mutation and evidence that transcription may play an active role in hypermutation. BioEssays 20:227–234, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

The unfertilized sea urchin egg is a metabolically quiescent cell. Fertilization results in the activation of a variety of metabolic and biosynthetic pathways, including a 20‐ to 40‐fold increase in the rate of protein synthesis by 2 h after fertilization. This increase is regulated at a purely translational level without the need for new transcription. The greatest part of this increase is due to the translation of stored maternal mRNAs which were not translated in the egg. There is (...) also a 2‐to 3‐fold increase in the peptide elongation rate. The molecular and physiological mechanisms responsible for this activation process are beginning to be understood, and turn out to be much more complex than was anticipated. (shrink)

The fate of root epidermal cells is controlled by a complex interplay of transcriptional regulators, generating a genetically determined, position‐biased arrangement of root hair cells. This pattern is altered during postembryonic development and in response to environmental signals to confer developmental plasticity that acclimates the plant to the prevailing conditions. Based on the hypothesis that events downstream of this initial mechanism can modulate the pattern installed during embryogenesis, we have developed a reaction diffusion model that reproduces the root hair patterning (...) previously observed experimentally. Under all growth conditions, an almost equal spacing between root hair forming cells was observed both in vitro and in silico, indicating that long‐range intercellular communication is crucial for the trichoblasts' decision to form a root hair. We assume that a hair growth promoter (HGP) is upregulated in root‐hair‐forming cells by a trichoblast‐specific component. Once established, HGP production is self‐enhancing. The autocatalytic regulation of HGP is antagonized by an HGP‐produced hair growth inhibitor (HGI). HGI is exported from trichoblasts and diffuses to neighboring cells, where it inhibits further HGP production and promotes the non‐hair cell fate. Under conditions of phosphate deficiency, we hypothesise that HGP production is increased and HGI diffusion rate is reduced, leading to a position‐independent formation of extra root hairs. BioEssays 30:75–81, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Low mean fundamental frequency (F 0) in men’s voices has been found to positively influence perceptions of dominance by men and attractiveness by women using standardized speech. Using natural speech obtained during an ecologically valid social interaction, we examined relationships between multiple vocal parameters and dominance and attractiveness judgments. Male voices from an unscripted dating game were judged by men for physical and social dominance and by women in fertile and non-fertile menstrual cycle phases for desirability in short-term and long-term (...) relationships. Five vocal parameters were analyzed: mean F 0 (an acoustic correlate of vocal fold size), F 0 variation, intensity (loudness), utterance duration, and formant dispersion (D f , an acoustic correlate of vocal tract length). Parallel but separate ratings of speech transcripts served as controls for content. Multiple regression analyses were used to examine the independent contributions of each of the predictors. Physical dominance was predicted by low F 0 variation and physically dominant word content. Social dominance was predicted only by socially dominant word content. Ratings of attractiveness by women were predicted by low mean F 0, low D f , high intensity, and attractive word content across cycle phase and mating context. Low D f was perceived as attractive by fertile-phase women only. We hypothesize that competitors and potential mates may attend more strongly to different components of men’s voices because of the different types of information these vocal parameters provide. (shrink)

Telepsychotherapy is an increasingly common way of conducting psychotherapy. Previous research has shown that patients usually have positive experiences of online therapy, however, with large individual differences. The aim of this study was to explore patients’ experiences of transition from in-person psychotherapy sessions to telepsychotherapy during the COVID-19 pandemic, as well as variation in the experiences with regard to the patients’ personality orientation. Seven psychotherapy patients in Sweden were interviewed and the transcripts were analyzed using thematic analysis. Additionally, the participants (...) were asked to rate their dissatisfaction/satisfaction with the transition, how hindering/helpful the transition was, and how unsafe/safe they felt after the transition in comparison to before. Personality orientation on relatedness or self-definition was assessed applying a self-assessment instrument. The participants experienced telepsychotherapy as qualitatively different from in-person psychotherapy. They reported several essential losses: the rituals surrounding therapy sessions were lost, including the transitional time and space between their every-day life and the therapy sessions, less therapeutic work was done, the therapists could lose their therapeutic stance, the sense of rapport was impaired, and the patients felt less open and emotionally available. On the other hand, some patients could feel freer online. As six of the participants had an anaclitic personality orientation, the present study could especially contribute to the understanding of how patients with strong affiliative needs and fear of abandonment experience the transition to meeting their therapists via communication technology. The participants’ self-ratings showed that they were only marginally dissatisfied with the transition and experienced the transition as slightly hindering, whereas they felt rather safe after the transition, indicating low concordance between qualitative and quantitative evaluations. New studies are needed to explore the introjective patients’ experiences of the transition. An essential topic is also to collect evidence and to test how the impaired sense of rapport when using communication technology can be remedied by adequate, patient-tailored interventions, a topic that has to be included in psychotherapy education and training. (shrink)

May discovered Diderot's copiously annotated copy of this anti-materialist tract by Hemsterhuis, known to many contemporaries as "the Dutch Plato"; this edition contains May's interesting introduction, a facsimile of the original text, and a transcription of all of Diderot's comments. The comments bear on infelicities of style as well as of thought, though the latter preponderate: the Lettre is not, alas, the product of a first-rate philosophical intellect. Diderot's strong objections to Hemsterhuis' crude theory of a moral organ (...) can be taken as complementing his Refutation of Helvetius, which dates from the same period.—W. L. M. (shrink)

The multistep pathway of eukaryotic gene expression involves a series of highly regulated events in the nucleus and cytoplasm. In the nucleus, genes are transcribed into pre‐messenger RNAs which undergo a series of nuclear processing steps. Mature mRNAs are then transported to the cytoplasm, where they are translated into protein and degraded at a rate dictated by transcript‐ and cell‐type‐specific cues. Until recently, these individual nuclear and cytoplasmic events were thought to be primarily regulated by different RNA‐ and DNA‐binding (...) proteins that are localized either only in the nucleus or only the cytoplasm. Here, we describe multifunctional proteins that control both nuclear and cytoplasmic steps of gene expression. One such class of multifunctional proteins (e.g., Bicoid and Y‐box proteins) regulates both transcription and translation whereas another class (e.g., Sex‐lethal) regulates both nuclear RNA processing and translation. Other events controlled by multifunctional proteins include assembly of spliceosome components, spliceosome recycling, RNA editing, cytoplasmic mRNA localization, and cytoplasmic RNA stability. The existence of multifunctional proteins may explain the paradoxical involvement of the nucleus in an RNA surveillance pathway (nonsense‐mediated decay) that detects cytoplasmic signals (premature termination codons). We speculate that shuttling multifunctional proteins serve to efficiently link RNA metabolism in the cytoplasmic and nuclear compartments. BioEssays 23:775–787, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Nuclear speckles are eukaryotic nuclear bodies enriched in splicing factors. Their exact purpose has been a matter of debate. The different proposed roles of nuclear speckles are reviewed and an additional layer of function is put forward, suggesting that by accumulating splicing factors within them, nuclear speckles can buffer the nucleoplasmic levels of splicing factors available for splicing and thereby modulate splicing rates. These findings build on the already established model that nuclear speckles function as a storage/recycling site for splicing (...) factors. Many studies have demonstrated proximity between nuclear speckles and sites of active transcription, suggesting that this juxtaposition can enhance the rates of gene expression. It is found that nuclear speckle disassembly increases splicing factor availability in the nucleoplasm, leading to an increase in splicing rates and faster release of nascent transcripts from the gene after transcription. Altogether, this era in which genomic and imaging approaches are applied to study nuclear organization has expanded the outlook on the possible roles of nuclear speckles. (shrink)

Protein synthesis inhibitors prolong the half‐lives of most mRNAs at least fourfold in the somatic cells of higher eukaryotes and in yeast cells. Some mRNAs are stabilized because the inhibitors affect mRNA‐specific regulatory factors; however, hundreds or thousands of other mRNAs are probably stabilized by a common mechanism. We propose that mRNA stabilization in cells treated with a translation inhibitor reflects a physiological process that occurs during each mitosis and is important for cell survival. Transcription and translation rates decline (...) drastically during a 1–2 hour interval of mitosis. We hypothesize that translational repression during this interval somehow inactivates a critical component of the mRNA degradation machinery. As a result, mRNA half‐lives are prolonged during the interval when transcription is repressed. If labile mRNAs were not stabilized during mitosis they, and perhaps also the labile proteins they encode, would be depleted as the cell entered G1 phase, with deleterious consequences. Stabilization during mitosis, or in response to translation inhibitors, thus preserves the capacity of the cell to synthesize essential proteins as it enters G1 or recovers from inhibitor treatment. mRNA stabilization might serve a similar purpose during starvation or any stress negatively affecting translation. (shrink)

Previous research has shown that inconsistencies across repeated interviews do not indicate deception because liars deliberately tend to repeat the same story. However, when a strategic interview approach that makes it difficult for liars to use the repeat strategy is used, both consistency and evasive answers differ significantly between truth tellers and liars, and statistical software (binary logistic regression analyses) can reach high classification rates (Masip et al., 2016b ). Yet, if the interview procedure is to be used in applied (...) settings the decision process will be made by humans, not statistical software. To address this issue, in the current study, 475 college students (Experiment 1) and 142 police officers (Experiment 2) were instructed to code and use consistency, evasive answers, or a combination or both before judging the veracity of Masip et al.'s ( 2016b ) interview transcripts. Accuracy rates were high (60% to over 90%). Evasive answers yielded higher rates than consistency, and the combination of both these cues produced the highest accuracy rates in identifying both truthful and deceptive statements. Uninstructed participants performed fairly well (around 75% accuracy), apparently because they spontaneously used consistency and evasive answers. The pattern of results was the same among students, all officers, and veteran officers only, and shows that inconsistencies between interviews and evasive answers reveal deception when a strategic interview approach that hinders the repeat strategy is used. (shrink)

The function of meiotic recombination has remained controversial, despite recent inroads into mechanisms. Ideas concerning a possible role of recombination in the elimination or efficient incorporation of mutations have been backed by theoretical studies but have lacked empirical support. Recent investigations into the basis for local variations in recombination frequency in yeast have uncovered a strong association between recombination initiation sites and transcriptional regulatory sequences. Other recent studies indicate a strong correlation between transcription and mutation rates in yeast genes. (...) Taken together, these data imply that distributions of recombination and mutation frequencies may be strongly correlated. This suggests that recombination may be targeted to genomic sites of high mutation frequency; such a ‘mutation‐tracking’ function would clearly aid in the shuffling of mutations to break up unfavorable and create favorable allelic combinations. Moreover, recent insights into the mechanism of gene conversion in yeast reveal a very strong inherent bias in favor of alleles on the non‐initiating homolog. Combined with mutation tracking, these findings suggest a novel and general mechanism by which allelic gene conversion may act to eliminate mutations. (shrink)