Pax6 is a transcription factor essential for the development of tissues including the eyes, central nervous system and endocrine glands of vertebrates and invertebrates. It regulates the expression of a broad range of molecules, including transcription factors, cell adhesion and short‐range cell–cell signalling molecules, hormones and structural proteins. It has been implicated in a number of key biological processes including cell proliferation, migration, adhesion and signalling both in normal development and in oncogenesis. The mechanisms by which Pax6 regulates (...) its downstream targets likely involve the use of different splice variants and interactions with multiple proteins, allowing it to generate different effects in different cells. Extrapolation to developmental transcription factors in general suggests that variation in the nature of individual factors is likely to contribute to the emergence of differences between tissues. BioEssays 24:1041–1051, 2002. © 2002 Wiley‐Periodicals, Inc. (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)

Through statistical analysis of datasets describing single cell shape following systematic gene depletion, we have found that the morphological landscapes explored by cells are composed of a small number of attractor states. We propose that the topology of these landscapes is in large part determined by cell‐intrinsic factors, such as biophysical constraints on cytoskeletal organization, and reflects different stable signaling and/or transcriptional states. Cell‐extrinsic factors act to determine how cells explore these landscapes, and the topology of the landscapes (...) themselves. Informational stimuli primarily drive transitions between stable states by engaging signaling networks, while mechanical stimuli tune, or even radically alter, the topology of these landscapes. As environments fluctuate, the topology of morphological landscapes explored by cells dynamically adapts to these fluctuations. Finally we hypothesize how complex cellular and tissue morphologies can be generated from a limited number of simple cell shapes. (shrink)

The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment (...) containing the 5'-flanking region of the human APOE gene . Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

Background COVID-19 has greatly impacted the health of incarcerated individuals in the US. The goal of this study was to examine perspectives of recently incarcerated individuals on greater restrictions on liberty to mitigate COVID-19 transmission.Methods We conducted semi-structured phone interviews from August through October 2021 with 21 people who had been incarcerated in Bureau of Prisons (BOP) facilities during the pandemic. Transcripts were coded and analyzed, using a thematic analysis approach.Results Many facilities implemented universal “lockdowns,” with time out of the (...) cell often limited to one hour per day, with participants reporting not being able to meet all essential needs such as showers and calling loved ones. Several study participants reported that repurposed spaces and tents created for quarantine and isolation provided “unlivable conditions.” Participants reported receiving no medical attention while in isolation, and staff using spaces designated for disciplinary purposes (e.g., solitary housing units) for public health isolation purposes. This resulted in the conflation of isolation and discipline, which discouraged symptom reporting. Some participants felt guilty over potentially causing another lockdown by not reporting their symptoms. Programming was frequently stopped or curtailed and communication with the outside was limited. Some participants relayed that staff threatened to punish noncompliance with masking and testing. Liberty restrictions were purportedly rationalized by staff with the idea that incarcerated people should not expect freedoms, while those incarcerated blamed staff for bringing COVID-19 into the facility.Conclusions Our results highlighted how actions by staff and administrators decreased the legitimacy of the facilities’ COVID-19 response and were sometimes counterproductive. Legitimacy is key in building trust and obtaining cooperation with otherwise unpleasant but necessary restrictive measures. To prepare for future outbreaks facilities must consider the impact of liberty-restricting decisions on residents and build legitimacy for these decisions by communicating justifications to the extent possible. (shrink)

© The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved.Cell walls of grasses, including cereal crops and biofuel grasses, comprise the majority of plant biomass and intimately influence plant growth, development and physiology. However, the functions of many cell wall synthesis genes, and the relationships among and the functions of cell wall components remain obscure. To better understand the patterns of cell wall accumulation and identify genes that act in grass (...) cell wall biosynthesis, we characterized 30 samples from aerial organs of rice at 10 developmental time points, 3-100 d post-germination. Within these samples, we measured 15 cell wall chemical components, enzymatic digestibility and 18 cell wall polysaccharide epitopes/ligands. We also used quantitative reverse transcription-PCR to measure expression of 50 glycosyltransferases, 15 acyltransferases and eight phenylpropanoid genes, many of which had previously been identified as being highly expressed in rice. Most cell wall components vary significantly during development, and correlations among them support current understanding of cell walls. We identified 92 significant correlations between cell wall components and gene expression and establish nine strong hypotheses for genes that synthesize xylans, mixed linkage glucan and pectin components. This work provides an extensive analysis of cell wall composition throughout rice development, identifies genes likely to synthesize grass cell walls, and provides a framework for development of genetically improved grasses for use in lignocellulosic biofuel production and agriculture. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

The vertebrate spleen has important functions in immunity and haematopoiesis, many of which have been well studied. In contrast, we know much less about the mechanisms governing its early embryonic development. However, as a result of work over the past decade‐mostly using knockout mice–‐significant progress has been made in unravelling the genetic processes governing the spleen's early development. Key genetic regulators, such as Tlx1 and Pbx1, have been identified, and we know some of the early transcriptional hierarchies that control the (...) early patterning and proliferation of the splenic primordium. In mouse and humans, asplenia can arise as a result of laterality defects, or the spleen can be absent with no other discernible abnormalities. Surprisingly, given the spleen's diverse functions, asplenic individuals suffer no major haematopoietic or immune defects apart from a susceptibility to infection with encapsulated bacteria. Recent evidence has shed light on a previously unknown role of the spleen in the development and maintenance of specific B cell populations that are involved in the initial response to infection caused by encapsulated bacteria. The lack of these populations in asplenic mice and humans may go some way to explaining this susceptibility. BioEssays 29: 166–177, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Establishment of cell lineage identity from multipotent progenitors is controlled by cooperative actions of lineage‐specific and stably expressed transcription factors, combined with input from environmental signals. Lineage‐specific master transcription factors activate and repress gene expression by recruiting consistently expressed transcription factors and chromatin modifiers to their target loci. Recent technical advances in genome‐wide and multi‐omics analysis have shed light on unexpected mechanisms that underlie more complicated actions of transcription factors in cell fate decisions. In this review, (...) we discuss functional dynamics of stably expressed and continuously required factors, Notch and Runx family members, throughout developmental stages of early T cell development in the thymus. Pre‐ and post‐commitment stage‐specific transcription factors induce dynamic redeployment of Notch and Runx binding genomic regions. Thus, together with stage‐specific transcription factors, shared transcription factors across distinct developmental stages regulate acquisition of T lineage identity. (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and (...) 5'-untranslated region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Cells fine‐tune their DNA repair, selecting some regions of the genome in preference to others. In the paradigm case, excision of UV‐induced pyrimidine dimers in mammalian cells, repair is concentrated in transcribed genes, especially in the transcribed strand. This is due both to chromatin structure being looser in transcribing domains, allowing more rapid repair, and to repair enzymes being coupled to RNA polymerases stalled at damage sites; possibly other factors are also involved. Some repair‐defective diseases may involve repair‐ (...) class='Hi'>transcription coupling: three candidate genes have been suggested.However, preferential excision of pyrimidine dimers is not uniformly linked to transcription. In mammals it varies with species, and with cell differentiation. In Drosophila embryo cells it is absent, and in yeast, the determining factor is nucleosome stability rather than transcription.Repair of other damage departs further from the paradigm, even in some UV‐mimetic lesions. No selectivity is known for repair of the very frequent minor forms of base damage. And the most interesting consequence of selective repair, selective mutagenesis, normally occurs for UV‐induced, but not for spontaneous mutations. The temptation to extrapolate from mammalian UV repair should be resisted. (shrink)

Abstractβ‐Catenin/CTNNB1 is critical for leukemia initiation or the stem cell capacity of several hematological malignancies. This review focuses on a general evaluation of β‐catenin function in normal T‐cell development and T‐cell acute lymphoblastic leukemia (T‐ALL). The integration of the existing literature offers a state‐of‐the‐art dissection of the complexity of β‐catenin function in leukemia initiation and maintenance in both Notch‐dependent and independent contexts. In addition, β‐catenin mutations are screened for in T‐ALL primary samples, and it is found that they are rare (...) and with little clinical relevance. Transcriptional analysis of Wnt family members (Ctnnb1, Axin2, Tcf7, and Lef1) and Myc in different publicly available T‐ALL cohorts indicates that the expression of these genes may correlate with T‐ALL subtypes and/or therapy outcomes. (shrink)

Activation of resting T lymphocytes through the T cell antigen receptor complex is initiated by critical phosphorylation and dephosphorylation events that regulate the function and interaction of a number of signaling molecules. Key elements in these reactions are members of the Src, Syk and Csk families of protein tyrosine kinases (PTKs) and the phosphotyrosine phosphatases (PTPases) that regulate and/or counteract them, such as CD45. The PTKs can autophosphorylate and phosphorylate each other at multiple sites and, as the result of these (...) interactions, they are induced to phosphorylate other cellular proteins. These phosphorylation events lead to modulation of enzymatic activities and/or serve as binding sites for other signaling molecules having phosphotyrosine‐binding Src homology 2 (SH2) domains. As a result, these proteins translocate to the receptor complexes and are juxtaposed to the kinases that phosphorylate them. Some of the SH2‐domain‐containing polypeptides lack enzymatic activities and, instead, serve as adapter molecules that couple the signal to downstream effectors, such as regulators of the Ras proteins, and further into serine/threonine‐specific protein kinase cascades. Through largely unknown steps these reactions lead to the transcription of previously silent genes, activation of lymphocyte effector functions, progression through the cell cycle and cell proliferation. (shrink)

The last year has unveiled extensive information on the T‐cell antigen receptor genes. For both the α‐ and β‐chains of this molecule, it is clear that an expressed gene is compiled from several coding sequences dispersed along the chromosome. During T‐cell development, recombination events occur which create a single transcription unit from these dispersed elements. Such gene organization shows that the T‐cell receptor has close evolutionary links with immunoglobulins. Both types of molecule use the same genetic mechanisms to create (...) the diversity necessary for antigen recognition. (shrink)

T‐bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells. Recent genome‐wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their (...) roles in the epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion. We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T‐bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking. (shrink)

Many lymphokine genes have now been cloned from activated T cells and their products have been expressed in mammalian cells. Use of these recombinant lymphokines has provided the opportunity to evaluate both the spectrum of their biological activities and the mechanisms of their action in promoting proliferation and differentiation of hemopoietic and lymphoid cells. Characterization of the structure of lymphokine genes will provide information about their regulated expression in T‐cell activation.

This essay offers a theoretical analysis of the changes which are taking place in the musical consciousness of listeners in the present phase of society. The author seeks rather to deduce the conditions of musical reception from the present stage of musical production. The first part of the article deals with changes in production as they affect the general consciousness of listeners. Light music is discussed as well as serious music insofar as it reaches the consumer. Changes in reception are (...) revealed in certain characteristics like the cult of the melody, of the voice, of the master violin, and they are tied up with specific economic concepts. Success plays a particularly important role in this connection.The second part is devoted to the retrogression in listening, analyzed psychologically. Docile passivity, imitation of pre-given patterns, and bitter resentment of the „abnormal“ have become characteristic for the listener. The author shows how this retrogression has become concretized in the formation of a „musical child’s language.“Many listeners seek to overcome passivity by a pseudo-activity. The social function of certain types like the jitter-bug, the radio amateur, or the man with a knack for jazz, are discussed.L’article entreprend d’interpréter sous forme d’une esquisse théorique les transformations qu’a subies la conscience musicale des auditeurs dans la phase actuelle de l’évolution sociale.On n’analyse pas psychologiquement les réactions des auditeurs ; mais on prend pour point de départ Tétât de la production, et de celui-ci on déduit celui de la réception.La première partie traite de la transformation de la production dans la mesure où celle-ci atteint la conscience commune des auditeurs. L’auteur considère aussi bien la musique légère que la soi-disant musique sérieuse et les modifications que connaît celle-ci pour parvenir à la consommation.Ces modifications font de la musique un fétiche. On en prend pour exemple le culte des „idées“ musicales, de la voix et des „violons de maître“. Le caractère fétiche de la musique se mesure au succès accumulé.Ensuite, on développe quelques catégories du fétichisme musical : dépravation, arrangement, „divertissement élevé“, idolâtrie de la perfection.Au fétichisme de la musique correspond du côté de l’auditeur une régression de la faculté d’entendre — phénomène qui fait l’objet de la deuxième partie de l’étude. On l’interprète comme l’attitude auditive caractéristique des „régressifs“. Soumission passive, imitation de l’antérieurement donné, fureur contre ce qui sort de la norme — définissent cette attitude, qui s’objective en un langage musical puéril en formation et dont quelques éléments sont esquissés.A cette passivité, de larges groupes d’auditeurs cherchent vainement à échapper par une pseudo-activité. Quelques types de pseudo-activité sont décrits : l’enthousiaste, le bricoleur et le „chic type“. On montre la fonction sociale de ces types.Enfin, on traite des possibilités dialectiques de l’audition du régressif. Une confrontation de l’expérience fondamentale de la musique radicalement neuve avec le mode régressif d’entendre termine l’article. (shrink)

Constructive Neutral Evolution is an evolutionary mechanism that can explain much molecular inter-dependence and organismal complexity without assuming positive selection favoring such dependency or complexity, either directly or as a byproduct of adaptation. It differs from but complements other non-selective explanations for complexity, such as genetic drift and the Zero Force Evolutionary Law, by being ratchet-like in character. With CNE, purifying selection maintains dependencies or complexities that were neutrally evolved. Preliminary treatments use it to explain specific genetic and molecular structures (...) or processes, such as retained gene duplications, the spliceosome, and RNA editing. Here we aim to expand the scope of such explanation beyond the molecular level, integrating CNE with Multi-Level Selection theory, and arguing that several popular higher-level selection scenarios are in fact instances of CNE. Suitably contextualized, CNE occurs at any level in the biological hierarchy at which natural selection as normally construed occurs. As examples, we focus on modularity in protein–protein interaction networks or “interactomes,” the origin of eukaryotic cells and the evolution of co-dependence in microbial communities—a variant of the “Black Queen Hypothesis” which we call the “Gray Queen Hypothesis”. (shrink)

Any suggestion of altering the genetic makeup of human beings through gene therapy is quite likely to provoke a response involving some reference to a 'slippery slope'. In this article the author examines the topography of two different types of slippery slope argument, the logical slippery slope and the rhetorical slippery slope argument. The logical form of the argument suggests that if we permit somatic cell gene therapy then we are committed to accepting germ line gene therapy in the future (...) because there is no logically sustainable distinction between them. The rhetorical form posits that allowing somatic cell therapy now will be taking the first step on a slippery slope which will ultimately lead to the type of genocide perpetrated by the Nazis. The author tests the validity of these lines of argument against the facts of human gene therapy and concludes that because of their dependence on probabilities that cannot be empirically proven they should be largely disregarded in the much more important debate on moral line-drawing in gene therapy. (shrink)

The model provided by the organismic point of view is quite different. Without having recourse to any transcendent vital force or immanent teleology, it nevertheless rejects the basic ideas of mechanism. More specifically, it replaces the analytical- summative conception by the idea of biological organisms as wholes or systems which have unique system-properties and obey irreducible system-laws. The machine-theoretical conception is replaced by a dynamic interpretation of living things, wherein organic structures are due to a continuous flow of processes combining (...) to produce patterns of immense intricacy. The reaction-theoretical conception is jettisoned in favour of the view that the organism is primarily a center of activity which is autonomous and not a mere response to external stimuli. Finally, the organismic model considers that biological systems are stratified, so that, e.g., viruses, genes, chromosomes, cells, multicellular individuals, supra-individual aggregates, etc., form a hierarchy of "levels" exhibiting an increasing degree of complexity. The whole of nature, indeed, contains "a tremendous architecture, in which subordinate systems are united at successive levels into ever higher and larger systems.". (shrink)

Five partly successive and partly overlapping framings have dominated the public debate about human embryonic stem cells since they first were “derived” a decade ago. Geron Corporation staged the initial framings as 1) basic research and 2) medical hope, but these two were immediately refuted and opposed by 3) bioethical concerns, voiced by influential politicians and leaders of opinion. Thereafter, the research community presented adult stem cells and therapeutic cloning as 4) techno-fix solutions supposed to bypass these ethical (...) concerns. And in recent years, 5) institutional limitations to and hurdles within the university–industrial complex (such as patentability, misconduct and fraud) have attracted more attention. The article purifies the arguments and points out the interests and institutions behind the five framings. It also discusses their interplay and finally addresses the question of what happened to the stem cells? (shrink)

The extent to which society utilises the law to enforce its moral judgments remains a dominant issue in this era of embryonic stem cell research, preimplantation genetic diagnosis, and human reproductive cloning. Balancing the potential health benefits and diverse moral values of society can be a tremendous challenge. In this context, governments often adopt legislative bans and prohibitions and rely on the inflexible and often inappropriate tool of criminal law. Legal prohibitions in the field of reproductive genetics are not likely (...) to reflect adequately the depth and diversity of competing stakeholder positions. Rather, a comprehensive and readily responsive regulatory policy is required. Such a policy must attend to the evolving scientific developments and ethical considerations. We outline a proposal for effective, responsive, and coherent oversight of new reproductive genetic technologies. (shrink)

Alongside a revival of interest in Thomism in philosophy, scholars have realised its relevance when addressing certain contemporary issues in bioethics. This book offers a rigorous interpretation of Aquinas's metaphysics and ethical thought, and highlights its significance to questions in bioethics. Jason T. Eberl applies Aquinas’s views on the seminal topics of human nature and morality to key questions in bioethics at the margins of human life – questions which are currently contested in the academia, politics and the media such (...) as: When does a human person’s life begin? How should we define and clinically determine a person’s death? Is abortion ever morally permissible? How should we resolve the conflict between the potential benefits of embryonic stem cell research and the lives of human embryos? Does cloning involve a misuse of human ingenuity and technology? What forms of treatment are appropriate for irreversibly comatose patients? How should we care for patients who experience unbearable suffering as they approach the end of life? _Thomistic Principles and Bioethics_ presents a significant philosophical viewpoint which will motivate further dialogue amongst religious and secular arenas of inquiry concerning such complex issues of both individual and public concern. (shrink)

Traditionally, plant viruses are viewed as harmful, undesirable pathogens. However, their genomes can provide several useful ‘designer functions’ or ‘sequence modules’ with which to tailor future gene vectors for plant or general biotechnology.The majority (77 %) of known plant viruses have single‐stranded RNA of the messenger (protein coding) sense as their genetic material. Over the past 4 years, improved in vitro transcription systems and the construction of partial of fulllength DNA copies of several plant RNA viruses have enhanced our (...) ability to manipulate and study their genomes, particularly in the context of their pathogenic interactions with host plants.Recently, two forms of genetically engineered protection against plant virus infections have been reported. In both, a virus‐related ‘interfering’ molecule was stably introduced into plants via the DNA‐transfer mechanism of Agro‐bacterium tumefaciens. To date, the choice of ‘interfering’ molecule has been guided by empirical field‐observations and each is effective against only a narrow range of closely‐related viruses. As yet, we do not fully understand the molecular mechanism(s) responsible for the observed protection.The ability to manipulate the plant–pathogen relationship is a powerful tool to increase our knowledge and improve future strategies for uncoventional cropprotection by genetic engineering techniques. (shrink)

‘When did I, a human person, begin to exist?’ In developing an answer to this question, I utilize a Thomistic framework, which holds that the human person is a composite of a biological organism and an intellective soul. Eric Olson and Norman Ford both argue that the beginning of an individual human biological organism occurs at the moment when implantation of the zygote in the uterus occurs and the ‘primitive streak’ begins to form. Prior to this point, there does not (...) exist an individual human organism, but a cluster of biological cells which has the potential to split and develop as one or more separate human organisms (identical twinning). Ensoulment (the instantiation of a human intellective soul in biological matter) does not occur until the point of implantation. This conception of the beginning of human personhood has moral implications concerning the status of pre‐implantation biological cell clusters. A new understanding of the beginning of human personhood entails a new understanding of the morality of certain medical procedures which have a direct affect on these cell clusters which contain human DNA. Such procedures discussed in this article are embryonic stem cell research, in vitro fertilization, procured abortion, and the use of abortifacient contraceptives. (shrink)

The development of T cells and B cells from pluripotent hematopoietic precursors occurs through a stepwise narrowing of developmental potential that ends in lineage commitment. During this process, lineage-specific genes are activated asynchronously, and lineage-inappropriate genes, although initially expressed, are asynchronously turned off. These complex gene expression events are the outcome of the changes in expression of multiple transcription factors with partially overlapping roles in early lymphocyte and myeloid cell development. Key transcription factors promoting B-cell development (...) and candidates for this role in T-cell development are discussed in terms of their possible modes of action in fate determination. We discuss how a robust, stable, cell-type–specific gene expression pattern may be established in part by the interplay between endogenous transcription factors and signals transduced by cytokine receptors, and in part by the network of effects of particular transcription factors on each other. BioEssays 21:726–742, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on this (...) debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

Many of the haemopoietic cell growth factors have now been purified to homogeneity and their structural genes cloned. Methods are also now available for obtaining pure populations of haemopoietic cells. The use of such cells, in combination with pure growth factors, has provided intriguing information about the biological activities and mode of action of the factors in faciliating survival, proliferation and differentiation of the haemopoietic cells.

The endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER stress and (...) UPR activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non‐autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non‐autonomous signals to propagate UPR activation in target cells and tissues. (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)

Classical embryological studies have provided a great deal of information on the autonomy and stability of cell fate determination in early sea urchin embryos. However, these studies were limited by the tools available at the time, and the interpretation of the results of these experiments was limited by the lack of information available at the molecular level. Recent studies which have re‐examined classical experiments at the molecular level have provided important new insights into the mechanism of determination in sea urchins, (...) and require us to re‐evaluate some long standing theories on the process of differentiation. (shrink)

While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in a subset (...) of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

Graphical AbstractA cell translocation mechanism displaces sporadic mutant cells from normal, suppressive epithelial environment during early steps of tumor initiation. This epithelial cell translocation process exerts a selective pressure on early mutant cells to survive and grow in new microenvironment outside of their native niches.

Direct reprogramming of human skin cells makes available a source of pluripotent stem cells without the perceived evil of embryo destruction, but the advent of such a powerful biotechnology entangles stem cell research in other forms of moral complicity. Induced pluripotent stem cell (iPSC) research had its origins in human embryonic stem cell research and the projected biomedical applications of iPS cells almost certainly will require more embryonic stem cell research. Policies that inhibit iPSC research in order (...) to avoid moral complicity are themselves complicit in preventable harms to patients. Moral complicity may be unavoidable, but a Blue Ribbon Panel charged with assessing the need for additional embryonic stem cell lines may ease a transition from embryonic stem cell research to clinical applications of iPS cells. (shrink)

Systemic autoimmune diseases are characterized by the production of antibodies against a broad range of self-antigens. Recent evidence indicates that the majority of these autoantigens are modified in various ways during cell death. This has led to the hypothesis that the primary immune response in the development of autoimmunity is directed to components of the dying cell. In this article, we summarize data on the modification of autoantigens during cell death and the possible consequences of this for autoimmunity. BioEssays 22:627–636, (...) 2000. © 2000 John Wiley & Sons, Inc. (shrink)

The origin of mitosis and the nuclear envelope were the pivotal processes in the evolutionary origin of the nucleus; they probably occurred in a wall‐less mutant bacterium that evolved a cytoskeleton and phagocytosis about 1500 million years ago. Principles of intracellular coevolution clarify their origin, as well as that of nucleosomes, spliceosomes, and the evolution of genome size.

The stereotyped pattern of cell commitments during leech embryogenesis is described. The nature of cell commitments during segmentation differs significantly between leech and fruit fly. Despite the constancy of cell fate assignments in normal development, ablation experiments show that cell interactions are essential in setting some of these commitments. Interacting cells follow a positionally determined hierarchy of fate choices. For other cells, which appear to have fates fixed from birth, the possibility of determinative interactions between mother and daughter (...) cells is discussed. (shrink)

Cellular differentiation is often accompanied by the expression of specialized plasma membrane proteins which accumulate in discrete regions. The biogenesis of these specialized membrane domains involves the assembly and co‐localisation of a spectrin‐based membrane skeleton. While the constituents of the membrane skeleton in non‐erythroid cells are often immunologically related to erythroid spectrin, ankyrin, and protein 4.1, there are structural and functional differences between the isoforms of these membrane skeleton polypeptides, as well as highly variable patterns of expression during cellular (...) differentiation. We consider this heterogeneity of structure and expression during development in the context of the hypothesis that non‐erythroid spectrin, ankyrin, and protein 4.1 are involved in the formation of specialized membrane domains. (shrink)