Recent findings necessitate revision of the traditional view of G protein‐coupled receptor (GPCR) signaling and expand the diversity of mechanisms by which receptor signaling influences cell behavior in general. GPCRs elicit signals at the plasma membrane and are then rapidly removed from the cell surface by endocytosis. Internalization of GPCRs has long been thought to serve as a mechanism to terminate the production of second messengers such as cAMP. However, recent studies show that internalized GPCRs can continue to either (...) stimulate or inhibit cAMP production in a sustained manner. They do so by remaining associated with their cognate G protein subunit and adenylyl cyclase at endosomal compartments. Once internalized, the GPCRs produce cellular responses distinct from those elicited at the cell surface. (shrink)

The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell‐cell contact or determine epithelial cell polarity which, in a tissue‐specific manner, use intracellular complexes containing FERM domain and actin‐binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha12/13 (...) such as the protease activated receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F‐)actin. Morever, cell architectures that promote F‐actin assembly per se also activate YAP by kinase‐dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells. (shrink)

This paper tells the story of G-protein coupled receptors, one of the most important scientific objects in contemporary biochemistry and molecular biology. By looking at how cell membrane receptors turned from a speculative concept into a central element in modern biochemistry over the past 40 years, we revisit the role of manipulability as a criterion for entity realism in wet-lab research. The central argument is that manipulability as a condition for reality becomes meaningful only once scientists have decided how (...) to conceptually coordinate measurable effects distinctly to a specific object. We show that a scientific entity, such as GPCRs, is assigned varying degrees of reality throughout different stages of its discovery. The criteria of its reality, we further claim, cannot be made independently of the question about how this object becomes a standard by which the reality of neighbouring elements of enquiry is evaluated. (shrink)

Here we review concepts related to an ensemble description of G-protein-coupled receptors. The ensemble is characterized by both inactive and active states, whose equilibrium populations and exchange rates depend sensitively on ligand, environment, and allosteric factors. This review focuses on the adenosine A2 receptor, a prototypical class A GPCR. 19F Nuclear Magnetic Resonance studies show that apo A2AR is characterized by a broad ensemble of conformers, spanning inactive to active states, and resembling states defined earlier for rhodopsin. In keeping (...) with ideas associated with a conformational selection mechanism, addition of agonist serves to allosterically restrict the overall degrees of freedom at the G protein binding interface and bias both states and functional dynamics to facilitate G protein binding and subsequent activation. While the ligand does not necessarily “induce” activation, it does bias sampling of states, increase the cooperativity of the activation process and thus, the lifetimes of functional activation intermediates, while restricting conformational dynamics to that needed for activation. GPCRs represent a ubiquitous class of transmembrane receptors, responsible for cell signaling and cell homeostasis. Their activation gives rise to conformational changes that allow the receptor to engage downstream partners. Activation can be thought of in terms of a free energy landscape associated with distinct conformers, responsible for the process. Here, the action of ligands is seen to alter this landscape by enabling transitions between key intermediates. (shrink)

Since most of the functions in cells are mediated by multimeric protein complexes, the determination of protein–protein interactions is an important step in the study of cellular mechanisms. Traditionally, after screening for possible target interactors by means of a yeast two‐hybrid screen, several methods are used to validate the initial result before carrying out functional experiments. Nowadays, non‐invasive fluorescence‐based methods like Bioluminescence Resonance Energy Transfer (BRET) and Fluorescence Resonance Energy Transfer (FRET) are widely used in the study (...) of protein–protein interactions in living cells. In the present review, we address the individual strengths and weaknesses of both RET approaches, providing information on their possible future use in the study of G protein‐coupled receptor oligomerization. BioEssays 30:82–89, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Mechanical stimulation has a critical role in the development and maintenance of the skeleton. This function requires the perception of extracellular stimuli as well as their conversion into intracellular biochemical responses. This process is called mechanotransduction and is mediated by a plethora of molecular events that regulate bone metabolism. Indeed, mechanoreceptors, such as integrins, G protein‐coupled receptors, receptor protein tyrosine kinases, and stretch‐activated Ca2+ channels, together with their downstream effectors coordinate the transmission of load‐induced signals to the nucleus (...) and the expression of bone‐related genes. During the past decade, scientists have gained increasing insight into the molecular networks implicated in bone mechanotransduction. In the present paper, we consider the major signaling cascades and transcription factors that control bone and cartilage mechanobiology and discuss the influence of the mechanical microenvironment on the determination of skeletal morphology. (shrink)

Lysophosphatidic acid (LPA) is a lipid mediator with a wide variety of biological actions, particularly as an inducer of cell proliferation, migration and survival. LPA binds to specific G‐protein‐coupled receptors and thereby activates multiple signal transduction pathways, including those initiated by the small GTPases Ras, Rho, and Rac. LPA signaling has been implicated in such diverse processes as wound healing, brain development, vascular remodeling and tumor progression. Knowledge of precisely how and where LPA is produced has long proved elusive. (...) Excitingly, it has recently been discovered that LPA is generated from precursors by ‘autotaxin’, a once enigmatic exo‐phosphodiesterase implicated in tumor cell motility. Exogenous phospholipases D can also produce LPA, which may contribute to their toxicity. Here we review recent progress in our understanding of LPA bioactivity, signaling and synthesis. BioEssays 26:870–881, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl glycerol; R59022, DAG kinase inhibitor; AA, (...) arachidonic acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the (...) activity and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the (...) activity and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

The severe hereditary progeroid disorder Cockayne syndrome is a consequence of a defective transcription‐coupled repair (TCR) pathway. This special mode of DNA repair aids a RNA polymerase that is stalled by a DNA lesion in the template and ensures efficient DNA repair to permit resumption of transcription and prevent cell death. Although some key players in TCR, such as the Cockayne syndrome A (CSA) and B (CSB) proteins have been identified, the exact molecular mechanism still remains illusive. A recent report (...) provides new unexpected insights into TCR in yeast.1 The identification and characterisation of a novel protein co‐purifying with the yeast homologue of CSB (Rad26) imposes reassessment of our current understanding of TCR in yeast. What about humans? BioEssays 24:780–784, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Heterotrimeric G proteins, consisting of α, β, and γ subunits, couple ligand-bound seven transmembrane domain receptors to the regulation of effector proteins and production of intracellular second messengers. G protein signaling mediates the perception of environmental cues in all higher eukaryotic organisms, including yeast, Dictyostelium, plants, and animals. The nematode Caenorhabditis elegans is the first animal to have complete descriptions of its cellular anatomy, cell lineage, neuronal wiring diagram, and genomic sequence. In a recent paper, Jansen et al.(1) used (...) sequence searches of the C. elegans genome database to identify all heterotrimeric G protein genes (20 Gα, 2 Gβ, 2 Gγ). C. elegans encodes one ortholog of each of the four Gα classes found in metazoans and 16 new Gα genes. The orthologous genes are widely expressed, whereas 14 of the divergent Gα genes are almost exclusively expressed in sensory neurons where they may regulate perception and chemotaxis.BioEssays 21:713–717, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Heterotrimeric G proteins, consisting of α, β, and γ subunits, couple ligand-bound seven transmembrane domain receptors to the regulation of effector proteins and production of intracellular second messengers. G protein signaling mediates the perception of environmental cues in all higher eukaryotic organisms, including yeast, Dictyostelium, plants, and animals. The nematode Caenorhabditis elegans is the first animal to have complete descriptions of its cellular anatomy, cell lineage, neuronal wiring diagram, and genomic sequence. In a recent paper, Jansen et al.(1) used (...) sequence searches of the C. elegans genome database to identify all heterotrimeric G protein genes (20 Gα, 2 Gβ, 2 Gγ). C. elegans encodes one ortholog of each of the four Gα classes found in metazoans and 16 new Gα genes. The orthologous genes are widely expressed, whereas 14 of the divergent Gα genes are almost exclusively expressed in sensory neurons where they may regulate perception and chemotaxis.BioEssays 21:713–717, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Wnt proteins form a family of secreted signaling proteins that play a key role in various developmental events such as cell differentiation, cell migration, cell polarity and cell proliferation. It is currently thought that Wnt proteins activate at least three different signaling pathways by binding to seven transmembrane receptors of the Frizzled family and the co-receptor LRP6. Despite our growing knowledge of intracellular components that mediate a Wnt signal, the molecular events at the membrane have remained rather unclear. Now several (...) publications1-4 indicate that Frizzled receptors are G-protein coupled and kinases were identified that phosphorylate the co-receptor LRP6. These data deepen our understanding of Wnt-mediated signal transduction and provide more insight into how specificity may be achieved. BioEssays 28: 339–343, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Rhodopsin, upon activation by light, transduces the photon signal by activation of the G‐protein, transducin. The well‐studied rhodopsin/transducin system serves as a model for the understanding of signal transduction by the large class of G‐protein‐coupled receptors. The interactive form of rhodopsin, R*, is conformationally similar or identical to rhodopsin's photolysis intermediate Metarhodopsin II (MII). Formation of MII requires deprotonation of rhodopsin's protonated Schiff base which appears to facilitate some opening of the rhodopsin structure. This allows a change in (...) conformation at rhodopsin's cytoplasmic surface that provides binding sites for transducin. Rhodopsin's 2nd, 3rd and putative 4th cytoplasmic loops bind transducin at sites including transducin's 5 kDa carboxyl‐terminal region. Site‐specific mutagenesis of rhodopsin is being used to distinguish sites on rhodopsin's surface that are important in binding transducin from those that function in activating transducin. These observations are consistent with and extend studies on the action of other G‐protein‐coupled receptors and their interactions with their respective G proteins. (shrink)

Resistance to inhibitors of cholinesterase 8A (Ric‐8A) is a prominent non‐receptor GEF and a chaperone of G protein α‐subunits (Gα). Recent studies shed light on the structure of Ric‐8A, providing insights into the mechanisms underlying its interaction with Gα. Ric‐8A is composed of a core armadillo‐like domain and a flexible C‐terminal tail. Interaction of a conserved concave surface of its core domain with the Gα C‐terminus appears to mediate formation of the initial Ric‐8A/GαGDP intermediate, followed by the formation of (...) a stable nucleotide‐free complex. The latter event involves a large‐scale dislocation of the Gα α5‐helix that produces an extensive primary interface and disrupts the nucleotide‐binding site of Gα. The distal portion of the C‐terminal tail of Ric‐8A forms a smaller secondary interface, which ostensibly binds the switch II region of Gα, facilitating binding of GTP. The two‐site Gα interface of Ric‐8A is distinct from that of GPCRs, and might have evolved to support the chaperone function of Ric‐8A. (shrink)

This paper reviews the technical and social problems concerned in donor insemination in the light of recent developments. The most important of these is the declining number of babies available for adoption by subfertile couples because modern methods and attitudes have reduced the number of unplanned births. At the same time the technique of donor insemination is being developed as public attitudes to it are changing.

Regulators of G protein signaling (RGS) proteins provide timely termination of G protein‐coupled receptor (GPCR) responses. Serving as a central control point in GPCR signaling cascades, RGS proteins are promising targets for drug development. In this review, we discuss the involvement of RGS proteins in the pathophysiology of the gastrointestinal inflammation and their potential to become a target for anti‐inflammatory drugs. Specifically, we evaluate the emerging evidence for modulation of selected receptor families: opioid, cannabinoid and serotonin by RGS (...) proteins. We discuss how the regulation of RGS protein level and activity may modulate immunological pathways involved in the development of intestinal inflammation. Finally, we propose that RGS proteins may serve as a prognostic factor for survival rate in colorectal cancer. The ideas introduced in this review set a novel conceptual framework for the utilization of RGS proteins in the treatment of gastrointestinal inflammation, a growing major concern worldwide. (shrink)

G protein‐coupled receptors (GPCRs) constitute the largest family of transmembrane proteins and play a crucial role in regulating diverse cellular functions. They transmit their signaling via binding to intracellular signal transducers and effectors, such as G proteins, GPCR kinases, and β‐arrestins. To influence specific GPCR signaling behaviors, β‐arrestins recruit effectors to form larger signaling complexes. Intriguingly, they facilitate divergent functions for the binding to different receptors. Recent studies relying on advanced structural approaches, novel biosensors and interactome analyses bring us (...) closer to understanding how this specificity is achieved. In this article, we share our hypothesis of how active GPCRs induce specific conformational rearrangements within β‐arrestins to reveal distinct binding interfaces, enabling the recruitment of a subset of effectors to foster specialized signaling complexes. Furthermore, we discuss methods of how to comprehensively assess β‐arrestin conformational states and present the current state of research regarding the functionality of these multifaceted scaffolding proteins. (shrink)

G protein‐coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and β‐arrestins. Many agonists of GPCRs promote “biased” responses, in which different cellular signaling pathways are activated with varying efficacies. The mechanisms underlying biased signaling have not been fully elucidated, with many potential “hidden variables” that regulate this behavior. One contributor is “location bias,” which refers to the generation of unique signaling cascades from a given GPCR depending upon (...) the cellular location at which the receptor is signaling. Here, we review evidence that GPCRs are expressed at and traffic to various subcellular locations and discuss how location bias can impact the pharmacologic properties and characterization of GPCR agonists. We also evaluate how differences in subcellular environments can modulate GPCR signaling, highlight the physiological significance of subcellular GPCR signaling, and discuss the therapeutic potential of exploiting GPCR location bias. (shrink)

CtBP family proteins predominantly function as transcriptional corepressors. Studies with mutant mouse suggest that the two mouse genes, Ctbp1 and Ctbp2, play unique and redundant gene regulatory roles during development.1 Ctbp1-deficient mice are viable, but are small and die early, while Ctbp2 deficiency leads to embryonic lethality. Ctbp2-null mutation causes defects in axial patterning, heart morphogenesis and neural development. The Ctbp2 mutant phenotype is more severe in the absence of Ctbp1. The studies with Ctbp2 mutant embryos suggest that CtBP can (...) also activate transcription. A plant CtBP homolog, Angustifolia (AN), has recently been identified.2, 3 AN controls polar elongation of leaf cells via the microtubule cytoskeleton. Microarray analysis suggests that AN also functions as a transcriptional repressor. Thus, the CtBP family proteins control cellular processes by serving as transcriptional activators and regulators of the cytoskeleton as well as transcriptional corepressors. BioEssays 25:9–12, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

Antipathy towards the possibility that God exists is a common attitude, which has recently been clearly expressed by Thomas Nagel. This attitude is presumably irrelevant to the question whether God does exist. But it raises two other interesting philosophical issues. First, to what extent does this attitude motivate irrational belief? And secondly, how should the attitude be evaluated? This paper investigates that latter issue. Is the hope that God does not exist a morally proper hope? I simplify this question by (...) interpreting the relevant attitude as an aversion towards the Christian picture of the world coupled with a preference for the naturalist atheistic picture. And comparing the content of those two world pictures, I argue that the attitude, though partly explicable, is morally unjustifiable, for clearly recognisable reasons. Regardless, then, of further concerns about the doxastic influence of this attitude, we ought to be ashamed of our antipathy to God, which reflects badly upon us. (shrink)

Members of the CAR group of Ig‐like type I transmembrane proteins mediate homotypic cell adhesion, share a common overall extracellular domain structure and are closely related at the amino acid sequence level. CAR proteins are often found at tight junctions and interact with intracellular scaffolding proteins, suggesting that they might modulate tight junction assembly or function. However, impairment of tight junction integrity has not been reported in mouse knockout models or zebrafish mutants of CAR members. In contrast, in the same (...) knockout models deficits in gap junction communication were detected in several organ systems, including the atrioventricular node of the heart, smooth muscle cells of the intestine and the ureter and in Sertoli cells of the testes. Possible interactions between BT‐IgSF and connexin41.8 on the disturbed pattern of pigment stripes found in zebrafish mutants and between ESAM and connexin43 during hematopoiesis in the mouse are also discussed. On the basis of the combined data and phenotypic similarities between CAR member mutants and connexin mutants I hypothesize that they primarily play a role in the organization of gap junction communication. Also see the video abstract here: https://youtu.be/i0yq2KhuDAE. (shrink)

In June 2005, Italy held a referendum on repealing the law on medically assisted fertilization , which limits access to artificial reproduction to infertile couples, and prohibits the donation of gametes, the cryopreservation of embryos, preimplantation genetic diagnosis , and research on human embryos. The referendum was invalidated, and the law remained unchanged. The Italian political e bioethical debate on assisted reproduction was manipulated by the Catholic Church, which distorted scientific data and issues at stake with the help of Catholic (...) politicians and bioethicists. What happened in Italy shows that some perverse socio-cultural e political mechanisms are spreading the absurd and anti-historical view that scientific and technological advancements are threatening democracy and personal freedom. Scientists should not only contrast the political attempts at limiting freedom of scientific research, but also tell politicians, humanists and citizens that the invention of Western science with its view of scientific community as an “open society”, contributed and still contributes, through scientific education, to the construction and maintaining of the moral and political values underlying Western democracies. (shrink)

The world is not on track to achieve Agenda 2030—the approach chosen in 2015 by all UN member states to engage multiple stakeholders for the common goal of sustainable development. The creation of the 17 Sustainable Development Goals (SDGs) arguably offered a new take on sustainable development by adopting hybrid and principle-based governance approaches, where public, private, not for profit and knowledge-institutions were invited to engage around achieving common medium-term targets. Cross-sector partnerships and multi-stakeholder engagement for sustainability have consequently taken (...) shape. But the call for collaboration has also come with fundamental challenges to meaningful engagement strategies—when private enterprises try to establish elaborate multi-stakeholder configurations. How can the purpose of businesses be mitigated through multi-stakeholder principle-based partnerships to effectively serve the purpose of a common sustainability agenda? In selecting nine scholarly contributions, this special issue aims at advancing this discourse. To stimulate further progress in business studies, this introductory essay, furthermore, identifies three pathways for research on multi-stakeholder engagement processes in support of the Decade of Action along three coupling lines: multi-sector alignment (relational coupling), operational perception alignment (cognitive coupling) and goal and strategic alignment (material coupling). (shrink)

In lieu of an abstract, here is a brief excerpt of the content:The Power of PersuasionG. Bennett HumphreyA long white coat, the title of doctor, a practiced professional persona and an appointment to the staff of a prestigious university medical center allows the physician to be a persuader of clinical decisions affecting patient management. When this power of persuasion is used to encourage patient compliance with a therapeutic regimen that might be curative for a fatal disease, there is justification for (...) trying to influence the patient to make choices resulting in a positive outcome. But when a physician is asking permission to enter the patient into a research protocol where the primary goal of the study is the hope of advancing knowledge, then much thought needs to be given to the potential abuse of this power of persuasion.In the 1960s, I found myself having to think about recruiting children into research protocols. I had just finished two years of residency in internal medicine and wanted to pursue a career in academic medicine. My primary interest was in laboratory research. To strengthen my training in research, I had competed for a position as clinical fellow in a western university. The fellowship program was designed to expose young physicians to both clinical and laboratory research. The first year was spent on one of the clinical research wards and the second year in a research laboratory. The program was open to residents from surgery, medicine and pediatrics but because there was a shortage of pediatricians in the program, I was required to work on the children’s leukemia ward for one year.The learning curve was steep during the first few months. Naturally, the faculty in pediatrics and the medical literature gave me a technical education in the use of protocols for therapeutic treatment of leukemia. For example, the first protocol used was designated as Phase III, and the goal was to try to cure the patient. A remission could be achieved in over 90 percent of children but the disease recurred. The median duration of these remissions in the mid–1960s was one year. A relapse was followed by progressive disease and death in a matter of weeks, but a new drug of unknown efficacy could be administered. This was a Phase II protocol, and while there was a chance of prolonging life for a month or so, the primary goal was the identification of drugs anti–leukemic activity.The pediatric leukemia ward experience for me as a fellow was unusual. There was more to learn than the treatment of leukemia. To my surprise, the children and their mothers gave me insight into the care of pediatric patients. Each month, the patients were admitted for five days of intravenous chemotherapy. The first day was traumatic with venipunctures, bone marrow aspirations and the establishment of an IV for the daily infusion of drugs. The remaining four days were for social rounds: listening to the children who liked to talk; talking with the ones who liked to listen; putting puzzles together with some toddlers; responding to a request to listen to the heart of a much loved teddy bear; exchanging jokes and riddles; stories about school, the family dog, or a favorite friend; enjoying the banter of the adolescents; and not invading the privacy of a few who didn’t like me, the ward or the therapy. These children were sharing their childhood with me and it took couple of months for me to recognize I was bonding with these little patients. I observed and listened to the mothers caring for their children and stood in awe of the resources that they brought to bear on having children with a fatal disease. A feeling of mutual respect and trust developed between these mothers and me. For an internist, these experiences were profound and very different from my experience treating adults.A professor, an internationally known researcher in the field of leukemia, was in charge of the ward. Formal rounds were conducted on Tuesday mornings when the result of the bone marrow aspirates and the toxicity of the chemotherapy were reviewed. The day–to–day responsibility for [End Page 101] treatment and informing the mothers on the remission status on Mondays was my responsibility... (shrink)

Open peer commentary on the article “A Computational Constructivist Model as an Anticipatory Learning Mechanism for Coupled Agent–Environment Systems” by Filipo Studzinski Perotto. Upshot: The CALM cognitive agent with its learning mechanism, as presented by the author, can be described as “trivially constructivist.” Probably, at best, it can be seen as a model of the empirical abstraction but not of the reflective abstraction. The “intrinsic motivations” in the simulated agent presented as “evaluative signals” sent from the agent’s “body” to its (...) “mind” can be seen as low-level physiological drives. They cannot account for far more sophisticated intrinsic motivations such as curiosity. (shrink)

The human genome project's lasting legacies are the emerging insights into human physiology and disease, and the ascendance of biology as the dominant science of the 21st century. Sequencing revealed that >90% of the human genome is not coding for proteins, as originally thought, but rather is overwhelmingly transcribed into non‐protein coding, or non‐coding, RNAs (ncRNAs). This discovery initially led to the hypothesis that most genomic DNA is “junk”, a term still championed by some geneticists and evolutionary biologists. In (...) contrast, molecular biologists and biochemists studying the vast number of transcripts produced from most of this genome “junk” often surmise that these ncRNAs have biological significance. What gives? This essay contrasts the two opposing, extant viewpoints, aiming to explain their bases, which arise from distinct reference frames of the underlying scientific disciplines. Finally, it aims to reconcile these divergent mindsets in hopes of stimulating synergy between scientific fields. (shrink)

Oocytes, eggs and blastomeres of the embryo are special cells that undergo rapid changes in structure and function at developmental transitions. These changes are frequently regulated by cytoplasmic signaling events, particularly at the developmental transition of fertilization, because the genome is largely inactivated at this time. Protein kinase C (PKC) is a signaling agent that acts after the sperm‐induced rise in calcium and has a central role in the remodeling of the structure of the egg into the zygote in (...) many species. PKC also acts during other developmental transitions. This kinase serves as a chronometer, which can choreograph the cell's remodeling events in both space and time. Several technical advancements discussed in this review have permitted a better understanding of the actions of PKC. (shrink)

Fluorescence imaging has become an indispensable tool in cell and molecular biology. GFP‐like fluorescent proteins have revolutionized fluorescence microscopy, giving experimenters exquisite control over the localization and specificity of tagged constructs. However, these systems present certain drawbacks and as such, alternative systems based on a fluorogenic interaction between a chromophore and a protein have been developed. While these systems are initially designed as fluorescent labels, they also present new opportunities for the development of novel labeling and detection strategies. This (...) review focuses on new labeling protocols, actuation methods, and biosensors based on fluorogenic protein systems. (shrink)

The advent of IVF and advances in reproductive technologies largely reflect the importance in our society of biological parenthood and genetic kinship. As illustrated in the controversy piece by Merle Spriggs,1 however, the same technology has confused our understanding of what makes a parent.An embryo mixup in Britain has resulted in a white couple giving birth to two black twins. Genetic tests have established that the wrong sperm was used to inseminate the ova of the white woman who gave birth (...) to the twins. The two couples involved are apparently both seeking custody. Who should have parental rights and responsibilities for the twins?While once it may have been obvious who a child’s parents were and who had obligations and claims with regard to children, the separation of genetic, gestational, and nurturing roles now makes it impossible to “discover” who is the real parent. As Ruth Macklin points out, the question: “Which role should entitle a woman to a greater claim on the baby in the case of a dispute?” is a moral question which cannot be answered by discovery, say through a blood test, but is a matter for decision.2 Which are the morally …. (shrink)

SummaryHeterozygous 4.1 hereditary elliptocytosis results from the absence of one haploid set of protein 4.1, a major component of the red cell skeleton. Two successive epidemiological investigations revealed fifteen probands in the French Northern Alps. The frequency of this disease seems to be very high in four small villages isolated in the Aravis mountains. The genealogical study shows that eleven probands share common ancestors who lived eight or ten generations ago in these villages. Thus there was probably a founder (...) effect from one pair of ancestors, strengthened by endogamy. In contrast, four probands originate from another area and are not genealogically related. Recent results in molecular genetics support the present data. (shrink)

I suggest that classical General Relativity in four spacetime dimensions incorporates a Principal of Maximal Tension and give arguments to show that the value of the maximal tension is $\frac{{c^4 }}{{4G}}$ . The relation of this principle to other, possibly deeper, maximal principles is discussed, in particular the relation to the tension in string theory. In that case it leads to a purely classical relation between G and the classical string coupling constant α′ and the velocity of light c (...) which does not involve Planck's constant. (shrink)

This concluding section applies the results of the previous part to some important thermodynamical systems. Even if time reversibility is allowed, it is shown that the flow vectors used to derive Onsager reciprocity from time translational invariance is of questionable validity. The fundamental fluctuation dissipation theorem of Callen, Welton, Green and Kubo which underpin descriptions of irreversibility, insofar as they are derived from time translational invariance, is also questioned; from Part I, they cannot be derived properly from time reversal symmetry. (...) The common view of entropy as some type of caloric fluid flow is critiqued as not conforming to the Kelvin Clausius Planck definition. An example of developing reciprocal relations to any order in the coupling indices based on the peculiar physical and defining characteristics of conductive heat is given for the steady state whenever a temperature gradient is present, free from time reversible and translation assumptions. A major challenge in the theory is to extend it to isothermal states. It is concluded that other more deterministic views mediated by authentic work anamnesis may be needed for long term coherence. (shrink)

The question of the moral acceptability of infertility treatment to HIV positive persons raises a number of interesting ethical points regarding the responsibility of the infertility specialist for the outcome of his or her actions. The analysis of the physician’s responsibility is conducted within the framework of accomplice liability. The physician is a collaborator in the parental project of the principals—that is, the intentional parents. Both causal contribution and intention are considered as elements of complicity. It is concluded that a (...) two per cent risk of vertical transmission when the woman is HIV positive is insufficient to blame the infertility specialist who helps her to conceive. Helping an infertile HIV positive infertile couple to have a child does not constitute reckless behaviour. When the couple is fertile, infertility treatment is directed at risk reduction and falls under the physician’s obligation to act in the best interests of his patients. (shrink)

The widespread abandonment of frozen embryos by the gamete providers or intentional parents urgently demands a solution. Most centres react by requiring patients to enter a prior agreement governing the future disposition of their embryos in all foreseeable circumstances. These dispositional directives are inappropriate and self defeating in the event of contingencies in which the patients remain competent to execute an updated directive. Internal and external changes may invalidate the prior directive by altering the situation as represented by the couple (...) at the initiation of treatment to such an extent that it no longer corresponds with the actual situation at the time of the execution of the disposition. The prior agreement should only be considered binding if the agreement among the partners on a specific option was a material condition for one of the partners to start treatment. (shrink)

The immunology of falciparum malaria, the lethal type of human malaria, has been transformed by two developments. First, a culture system for the asexual blood stages of Plasmodium falciparum.1 Secondly, the cloning and expression of genes coding for a large number of the protein antigens of this malaria parasite over the past two years. Data on proteins, protein antigens and epitopes of P. falciparum supplied by gene cloning techniques have been supplemented by monoclonal antibody approaches, peptide synthesis, and (...) high‐resolution immunochemistry. (shrink)

Alpha‐fetoprotein (AFP)AFP, alpha‐fetoprotein; T3R, thyroid hormone (triiodothyronine) receptor; RAR, retionic acid receptor; erbA, putative thyroid hormone receptor proto‐oncogene products; VDR, vitamin D receptor; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; HRE, hormone response element on DNA; RXR, retionic‐X‐receptor; RAP, receptor auxiliary (accessory) proteins; E, estrogen. is a tumor‐associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise function is unknown, has been classified as belonging to a protein superfamily together (...) with albumin and vitamin D‐binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA‐hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine‐zipper dimerization (heptad) motif in the carboxy‐terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, e‐erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40–60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth‐regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade. (shrink)

Les thérapies psychanalytiques auprès des couples apportent un bénéfice thérapeutique personnel à chacun des patients et, souvent, à leur lien douloureux ambivalent, comme en témoigne une méta-analyse comparative des approches thérapeutiques anciennes ou contemporaines. Une compréhension psychanalytique plus groupale s’impose aujourd’hui pour mieux saisir les problématiques identitaires mises en jeu par les processus inconscients qui structurent tout groupe humain, mais aussi la spécificité groupale transgénérationnelle des familles et des couples, laquelle donne à leur vie émotionnelle et affective une si grande (...) intensité. (shrink)

The major portion of this important work is the "Summary of the Republic." Coordinated with Grube’s translation, it proceeds book by book, first summarizing a chunk of text anywhere from a couple of Stephanus sections to several pages, then commenting in lettered notes of from two lines to four and a half pages. More technical material, aimed at advanced students and scholars, appears occasionally in smaller type. There is a fine bibliography. The format is successful: the book is easy to (...) use and attractive in appearance. (shrink)