Mammalian telomeres have evolved safeguards to prevent their recognition as DNA double‐stranded breaks by suppressing the activation of various DNA sensing and repair proteins. We have shown that the telomere‐binding proteins TRF2 and RAP1 cooperate to prevent telomeres from undergoing aberrant homology‐directed recombination by mediating t‐loop protection. Our recent findings also suggest that mammalian telomere‐binding proteins interact with the nuclear envelope to maintain chromosome stability. RAP1 interacts with nuclear lamins through KU70/KU80, and disruption of RAP1 and TRF2 function (...) result in nuclear envelope rupture, promoting telomere‐telomere recombination to form structures termed ultrabright telomeres. In this review, we discuss the importance of the interactions between shelterin components and the nuclear envelope to maintain telomere homeostasis and genome stability. (shrink)

In this study a combination of computer tools for coupling and virtual screening is detailed, in 108 active molecules and 3620 decoys to find stabilizers for G quadruplex. To have more precise results, combinations of coupling programs with fifteen energy scoring functions were applied. The validation and evaluation of the metrics was done with the CompScore genetic algorithm. The results showed an increase in BEDROC and EF of 50% compared to other strategies, as well as reflecting early recognition of active (...) molecules. From these results it is possible to work with the molecules that showed a good early recognition and evaluate their effect as G4 stabilizers. This ensures more efficient and accurate results in the preclinical stage for the development of anticancer drugs. Keywords: Enrichment metrics; telomere; G quadruplex ; CompScore. References [1]M. Porru, P. Zizza, M. Franceschin, C. Leonetti and A. Biroccio. «EMICORON: A multi-targeting G4 ligand with a promising preclinical profile» 2017. Biochimica et Biophysica Acta - General Subjects, 1861, 1362–1370. [Online]. Available: https://doi.org/10.1007/s00294-018-0836-6. [2]K. Tomita. «How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis». Current Genetics, 64, 1177–1181. 2018. [Online]. Available: https://doi.org/10.1016/j.bbagen. 2016.11.010. [3]M. Jafri, S. Ansari, M. Alqahtani and J. Shay. «Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine., 2016. [Online]. Available: https://doi.org/10.3390/ijms19020482. [4]J. Huppert and S. Balasubramanian. «G-quadruplexes in promoters throughout the human genome». 35, 406–413. 2007. [Online]. Available: https://doi.org/10.1016/j.bbapap.2017.06.012. [5]S. Joy, Vijayakumar, S. Choi and H. Sunhye. «Role of computer-aided drug design in modern drug discovery». Archives of Pharmacal Research. 2015. [Online]. Available: https://doi.org/10.1007/s12272-015-0640-5. [6]S. Asamitsu, S. Obata, Z. Yu, T. Bando and H. Sugiyama. «Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy». Molecules, 24, 429. 2019. [En línea]. Available: https://doi.org/10.3390/molecules24030429. [7]R. Monsen and J. Trent. «Biochimie G-quadruplex virtual drug screening : A review». Biochimie, 152, 134–148. 2018. [Online]. Available: https://doi.org/10.1039/c9cc06748e. [8]J. Beauvarlet, P. Bensadoun, E. Darbo, G. Labrunie, E. Richard, I. Draskovic and M. Djavaheri-mergny. «Modulation of the ATM / autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells». 1–18. 2019. [Online]. Available: https://doi.org/10.1093/nar/gkz095. [9].Z. Crees, J. Girard, Z. Rios, G. Botting, K. Harrington and C. Shearrow. « Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy».2014. [Online]. Available: https://doi.org/10.2174/1381612820666140630100702. [10].M. Meier, A. Moya-torres, N. Krahn, M. Mcdougall, L. Orriss, E. Mcrae and T. Patel. «Structure and hydrodynamics of a DNA Gquadruplex with a cytosine bulge»., 1–13. 2018. [Online]. Available: https://doi.org/10.1093/nar/gky307. (shrink)

Depression might be associated with accelerated cellular aging. However, does this result in an irreversible state or is the body able to slow down or recover from such a process? Telomeres are DNA‐protein complexes that protect the ends of chromosomes and generally shorten with age; and therefore index cellular aging. The majority of studies indicate that persons with depression have shorter leukocyte telomeres than similarly aged non‐depressed persons, which may contribute to the observed unfavorable somatic health outcomes in the depressed (...) population. Some small‐scale preliminary studies raise the possibility that behavioral or pharmacological interventions may either slow down or else reverse this accelerated telomere shortening, possibly through increasing the activity of the telomere‐lengthening enzyme telomerase. This paper covers the current state of evidence in the relationship between depression and the telomere‐telomerase system and debates whether depression‐related cellular aging should be considered a reversible process or permanent damage. (shrink)

Telomeres are short repetitive DNA sequences capping the ends of chromosomes. Telomere shortening occurs during cell division and may be accelerated by oxidative damage or ameliorated by telomere maintenance mechanisms. Consequently, telomere length changes with age, which was recently confirmed in a large meta‐analysis across vertebrates. However, based on the correlation between telomere length and age, it was concluded that telomere length can be used as a tool for chronological age estimation in animals. Correlation should (...) not be confused with predictability, and the current data and studies suggest that telomeres cannot be used to reliably predict individual chronological age. There are biological reasons for why there is large individual variation in telomere dynamics, which is mainly due to high susceptibility to a wide range of environmental, but also genetic factors, rendering telomeres unfeasible as a tool for age estimation. The use of telomeres for chronological age estimation is largely a misguided effort, but its occasional reappearance in the literature raises concerns that it will mislead resources in wildlife conservation. (shrink)

Hunger is a psychological state that serves physiological energy homeostasis. I argue that it is a pure underived desire to eat and examine its role in homeostasis. After scene-setting explanations of homeostasis and desire, I argue that hunger is a close phenomenological match with underived desire. Then, I show why desire is an apt instrument for energy homeostasis. Finally, I argue that energy homeostasis is a multi-factorial future-regarding behavioural strategy. Hunger is a special purpose sensory (...) state that serves only to implement the strategy. Thus, it is a sensory desire. I conclude by reflecting on the credibility of this desire. (shrink)

Linear chromosomes shorten in every round of replication. In Drosophila, telomere‐specialized long interspersed retrotransposable elements (LINEs) belonging to the jockey clade offset this shortening by forming head‐to‐tail arrays at Drosophila telomere ends. As such, these telomeric LINEs have been considered adaptive symbionts of the genome, protecting it from premature decay, particularly as Drosophila lacks a conventional telomerase holoenzyme. However, as reviewed here, recent work reveals a high degree of variation and turnover in the telomere‐specialized LINE lineages across (...) Drosophila. There appears to be no absolute requirement for LINE activity to maintain telomeres in flies, hence the suggestion that the telomere‐specialized LINEs may instead be neutral or in conflict with the host, rather than adaptive. (shrink)

Whereas telomeres protect terminal ends of linear chromosomes, telomerases identify natural chromosome ends, which differ from broken DNA and replicate telomeres. Although telomeres play a crucial role in the linear chromosome organization of eukaryotic cells, their molecular syntax most probably descended from an ancient retroviral competence. This indicates an early retroviral colonization of large double-stranded DNA viruses, which are putative ancestors of the eukaryotic nucleus. This contribution demonstrates an advantage of the biosemiotic approach towards our evolutionary understanding of telomeres, telomerases, (...) other reverse transcriptases and mobile elements. Their role in genetic/genomic content organization and maintenance is no longer viewed as an object of randomly derived alterations (mutations) but as a highly sophisticated hierarchy of regulatory networks organized and coordinated by natural genome-editing competences of viruses. (shrink)

Transcription in organisms as diverse as yeast and mammals is subject to chromosomal position effects that result in heritable and variegated patterns of gene expression. Two recent studies have employed a reversible protein‐DNA crosslinking method to identify the structural components of heterochromatin in budding yeast(1,2). The results show that a complex containing the proteins Rap1, Sir2p, Sir3p and Sir4p is physically associated with nucleosomes at telomere proximal regions, but that the repressive chromatin structure extended by Sir3p overexpression has a (...) different composition. (shrink)

Drosophila telomeres comprise DNA sequences that differ dramatically from those of other eukaryotes. Telomere functions, however, are similar to those found in telomerase‐based telomeres, even though the underlying mechanisms may differ. Drosophila telomeres use arrays of retrotransposons to maintain chromosome length, while nearly all other eukaryotes rely on telomerase‐generated short repeats. Regardless of the DNA sequence, several end‐binding proteins are evolutionarily conserved. Away from the end, the Drosophila telomeric and subtelomeric DNA sequences are complexed with unique combinations of proteins (...) that also modulate chromatin structure elsewhere in the genome. Maintaining and regulating the transcriptional activity of the telomeric retrotransposons in Drosophila requires specific chromatin structures and, while telomeric silencing spreads from the terminal repeats in yeast, the source of telomeric silencing in Drosophila is the subterminal arrays. However, the subterminal arrays in both species may be involved in telomere–telomere associations and/or communication. BioEssays 30:25–37, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Christopher Boorse’s Biostatistical Theory of Health has been the main contender among naturalistic accounts of health for the last 40 years. Yet, a recent criticism of this theory, presented by Elselijn Kingma, identifies a dilemma resulting from the BST’s conceptual linking of health and statistical typicality. Kingma argues that the BST either cannot accommodate the situation- specificity of many normal functions or cannot account for many situation-specific diseases. In this article, we expand upon with Daniel Hausman’s response to Kingma’s dilemma. (...) We propose that recalling Boorse’s specification that health is an intrinsic property of its bearers and explicating this intrinsic property in relation to the concept of homeostasis can illuminate how proponents of naturalistic accounts of health should deal with the situation- specificity of normal functions. We argue that beyond what Boorse and Hausman have delineated, the situation- specificity of normal function cannot be fully captured in a simple dichotomy between normal and abnormal environment or between relevant and irrelevant situations. By bringing homeostasis to the fore of the analysis of health, we set out a richer picture of what the various situations that affect living organisms’ functional performance can be. Accordingly, we provide a broader classification of these various situations which, we contend, better accounts for the main intuitions that philosophers of medicine have sought to accommodate than previous naturalistic theories of health. (shrink)

DNA damage repair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms to repair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNA repair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also affect subtelomeric regions (...) that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long‐read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature. (shrink)

The complexity of the physiological phenotype currently prevents us from identifying an integrative measure to assess how the internal state and environmental conditions modify life‐history strategies. In this article, it is proposed that shorter telomeres should lead to a faster pace‐of‐life where investment in self‐maintenance is decreased as a means of saving energy for reproduction, but at the cost of somatic durability. Inversely, longer telomeres would favor an increased investment in soma maintenance and thus a longer reproductive lifespan (i.e., slower (...) pace‐of‐life). Under this hypothesis, telomere dynamics could be such an integrative mediator, which will assemble the information about oxidative stress levels, inflammation status and stress reactivity, and relate this information to the potential lifespan of the organism and its pace‐of‐life strategy. The signaling function of telomere dynamics can also reach over generations, a phenomenon in which the telomere lengths of gametes would provide a channel through which offspring would receive information about their environment early in their development, hence increasing the possibilities for developmental plasticity. -/- . (shrink)

In search of a potential problem with cloning, I investigate the phenomenon of telomere shortening which is caused by cell replication; clones created from somatic cells will have shortened telomeres and therefore reach a state of senescence more rapidly. While genetic intervention might fix this problem at some point in the future, I ask whether, absent technological advances, this biological phenomenon undermines the moral permissibility of cloning.

Reproduction, a basic property of biological life, entails costs for an organism, ultimately detectable as reduction in survival prospects. Telomeres are an excellent candidate biomarker for explaining these reproductive costs, because their shortening correlates with increased mortality risk. For similar reasons, telomeres are perceived as biomarkers of individual “quality.” The relationship between reproduction and telomere dynamics is reviewed, emphasizing that cost and quality perspectives, commonly presented in isolation, should be integrated. While a majority of correlative studies have confirmed the (...) relationship between telomere dynamics and various reproductive outputs, only limited experimental support exists showing that reproduction causes telomeres to shorten. A shift of focus to experimental manipulations of reproductive effort/telomere dynamics is crucial. However, the observation of survival reduction in response to these manipulations is essential for establishing telomeres as genuine biomarkers, allowing to unravel trade‐offs related to reproduction. (shrink)

Several authors have argued that higher taxa are monophyletic homeostatic property cluster natural kinds. On the traditional definition of monophyly, this will not work: the emergence of taxon-defining homeostatic property clusters would not always correspond to unique speciation events. An alternative conception of monophyly is developed and advocated, which can accommodate the homeostatic property cluster proposal. Recent work in philosophy of science shows that it meets appropriate standards of objectivity and precision.

Human individuals often exhibit important differences in their sensitivity to ionising radiation. Extensive literature links radiation sensitivity with impaired DNA repair which is due to a lack of correct functioning in many proteins involved in DNA‐repair pathways and/or in DNA‐damage checkpoint responses. Given that ionising radiation is an important and widespread diagnostic and therapeutic tool, it is important to investigate further those factors and mechanisms that underlie individual radiosensitivity. Recently, evidence is accumulating that telomere function may well be involved (...) in cellular and organism responses to ionising radiation, broadening still further the currently complex and challenging scenario. BioEssays. BioEssays 28: 1172–1180, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Eukaryotic chromosomes end with tandem repeats of simple sequences. These GC rich repeats allow telomere replication and stabilize chromosome ends. Telomere replication involves an equilibrium of sequence loss and addition at the ends of chromosomes. Repeats are added de novo by telomerase, an unusual DNA polymerase. Telomerase is an RNP in which an essential RNA component provides the template for the added telomere repeats. Telomere length maintenance plays an essential role in cell viability.

Antonio Damasio elabora una teoría de la mente humana y de la conducta moral a partir de su hipótesis sobre la evolución de los mecanismos de autorregulación biológicos. En ella, a la capacidad para representar relaciones organismo-mundo se le confiere un importante papel en los cambios organizacionales que emergen de los sistemas con un sistema nervioso central. Concretamente, en nuestro artículo analizamos, en primer lugar, la tesis acerca de la doble homeostasis biológica- mental que caracteriza a los agentes racionales. (...) Desde su perspectiva, la conciencia es producto y manifestación de complejos procesos del procesamiento de representaciones, los cuales favorecen la regulación no consciente. Además, para entender los procesos conscientes también es clave, según Damasio, conocer cómo la evolución de tales mecanismos está asociada con el desarrollo de áreas neuronales próximas al córtex emocional, especialmente, el giro cingulado. Los argumentos que Damasio utiliza para vincular los procesos representacionales con la particular preocupación humana por los sentimientos de los otros es la segunda cuestión que evaluamos. (shrink)

How can adverse experiences in early life, such as maltreatment, exert such powerful negative effects on health decades later? The answer may lie in changes to DNA. New research suggests that exposure to stress can accelerate the erosion of DNA segments called telomeres. Shorter telomere length correlates with chronological age and also disease morbidity and mortality. Thus, telomere erosion is a potential mechanism linking childhood stress to health problems later in life. However, an array of mechanistic, methodological, and (...) basic biological questions must be addressed in order to translate telomere discoveries into clinical applications for monitoring health and predicting disease risk. This paper covers the current state of the science and lays out new research directions. (shrink)

The concept of a G‐quartet, a unique structural arrangement intrinsic to guanine‐rich DNA, was first introduced by Gellert and colleagues1 over 40 years ago. For decades, it has been uncertain whether the G‐quartet and the structure that it gives rise to, the G‐quadruplex, are purely in vitro phenomena. Nevertheless, the presence of signature G‐rich motifs in the eukaryotic genome, and the plethora of proteins that bind to, modify or resolve this nucleic acid structure in vitro have provided circumstantial evidence for (...) its physiological relevance. More recently, direct visualisation of G‐quadruplex DNA at native telomeres was achieved, bolstering the evidence for its existence in the cell. Furthermore, G‐quadruplex folded telomeric DNA has been found to perturb telomere function and to impede the action of telomerase, an enzyme overexpressed in >85% of human cancers, hence opening up a novel avenue for cancer therapy in the form of G‐quadruplex stabilising agents. BioEssays 29: 155–165, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Telomeres play a vital role in protecting the ends of chromosomes and preventing chromosome fusion. The failure of cancer cells to properly maintain telomeres can be an important source of the chromosome instability involved in cancer cell progression. Telomere loss results in sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/B) cycles, leading to extensive DNA amplification and large deletions. These B/F/B cycles end primarily when the unstable chromosome acquires a new telomere by translocation of the ends of other chromosomes. (...) Many of these translocations are nonreciprocal, resulting in the loss of the telomere from the donor chromosome, providing a mechanism for transfer of instability from one chromosome to another until a chromosome acquires a telomere by a mechanism other than nonreciprocal translocation. B/F/B cycles can also result in other forms of chromosome rearrangements, including double‐minute chromosomes and large duplications. Thus, the loss of a single telomere can result in instability in multiple chromosomes, and generate many of the types of rearrangements commonly associated with human cancer. BioEssays 26:1164–1174, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Hunger is a psychological state that serves physiological energy homeostasis. I argue that it is a pure underived desire to eat and examine its role in homeostasis. After scene‐setting explanations of homeostasis and desire, I argue that hunger is a close phenomenological match with underived desire. Then, I show why desire is an apt instrument for energy homeostasis. Finally, I argue that energy homeostasis is a multi‐factorial future‐regarding behavioural strategy. Hunger is a special purpose sensory (...) state that serves only to implement the strategy. Thus, it is a sensory desire. I conclude by reflecting on the credibility of this desire. (shrink)

The formal properties of orbits in a plane are explored by elementary topology. The notions developed from first principles include: convex and polygonal orbits; convexity; orientation, winding number and interior; convex and star-shaped regions. It is shown that an orbit that is convex with respect to each of its interior points bounds a convex region. Also, an orbit that is convex with respect to a fixed point bounds a star-shaped region.Biological considerations that directed interest to these patterns are indicated, and (...) the implications of the prospect of higher orders of star-shapedness mentioned. (shrink)

Fritz Allhoff has recently offered an extremely compelling challenge to the morality of human cloning. He argues that a biological phenomenon, that of telomere shortening, undermines the moral permissibility of human cloning. Telomere shortening is caused by cell replication, and appears to be one of the central reasons that cells and organisms age and die. Allhoff considers a thirty-year-old woman who wishes to create a genetic clone. He notes that the DNA from her cell that would be used (...) to create the clone would have shortened telomeres—as it would have gone through many generations of cell replication. As a result, the clone would begin its existence with shortened telomeres; the clone’s telomeres would be the same length as the woman’s telomeres at the time of cloning. The moral problem lies in the fact that because of shortened telomeres, the clone will senesce more rapidly as compared with noncloned organisms, and would have increased susceptibility to degenerative conditions and diseases. Allhoff then goes on to argue that earlier senescence and disease susceptibility constitute a moral ground for rejecting cloning because “the life of a clone would be worse than that of a non-clone”. This line of argument is rooted in Parfit’s The Same Number Quality Claim : “If in either of two outcomes the same number of people would ever live, it would be bad if those who live are worse off, or have a lower quality of life, than those who would have lived”. Applying Parfit’s Q principle to cases of cloning, it could be argued that parents ought to produce children that would be maximally well off, and since clones would be worse off than children produced “normally,” it follows that parents should avoid cloning. As Allhoff puts it, “obviously sexual reproduction would not transfer shortened telomeres to offspring so, all else being equal, sexual reproduction is better than cloning ”. For this sort of line to pack any moral punch, Q must be interpreted rather strongly. (shrink)

Some properties are discussed of regular polygons that may result from angular homeostatic processes in stable orbit. To characterize these homeostatic polygons we need to discuss the winding number, the sidedness (integer, fractional and irrational), multiplicity, envelopes, and density. A regular (i.e., equilateral, equiangular) polygon may be closed in one revolution about its unique center, in multiple revolutions, or not at all. A homeostatic polygon can be generated only if all vertices are included in a single polygon, which occurs if (...) and only if the number of vertices and the number of revolutions required to complete the polygon are relatively prime. For the homeostatic polygon to have a finite number of sides (without repeating itself) the angle subtended by any two successive vertices at the center must be a rational multiple of 2. Biological implications of these properties are illustrated. (shrink)

Yan Xin Life Science Technology-Optimized Caloric Restriction (YXLST-CR) is a unique food abstinence, which suppresses appetite and sensation of hunger while maintaining physiological homeostasis. The authors review the first clinical case study on YXLST-CR, or YXLST-bigu, a 15-day, 24-hour observation in 1987 on a 21-year-old female undergoing YXLST-bigu for several months. The participant took no food or water and conducted normal physical activities. The daily records of body weight, temperature, pulse rate, blood pressure, and daily urine test results showed (...) no abnormalities. Homeostasis was maintained during YXLST-CR. The authors also report serum leptin levels in a group of individuals undergoing YXLST-CR and a control group before and after a 24-hour water-only period. The leptin level prior to the observation for the YXLST-CR group was lower than that for the control group and remained unchanged during the observation, suggesting the possibilities of an established metabolic adaptation. (shrink)

It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved. Replication stress at telomeres promotes the formation of so‐called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of factors is required (...) to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions. (shrink)

"Exhalation," a 2008 science fiction short story by Ted Chiang, virtuoso of the genre and the form, begins with a truism, refuted: "It has long been said that air (which others call argon) is the source of life. This is not in fact the case, and I engrave these words to describe how I came to understand the true source of life and, as a corollary, the means by which life will one day end" (37). The narrator's promise is so (...) alluring—knowledge of life's origin, knowledge of its expiration, and knowledge of the relation between the two—that we may be forgiven for overlooking the parenthetical. Argon amounts to less than one percent of the air breathed within Earth's atmosphere. The narrator specifies that "others call... Read More. (shrink)