Bone morphogenetic proteins (BMPs) are typically members of the transforming growth factor β (TGF-β) family with diverse roles in embryonic development. At least five genes with homology to BMPs are expressed during Xenopus development, along with their receptors and intracellular signalling pathways. The evidence suggests that BMPs have roles to play in both mesoderm induction and dorsoventral patterning. Studies in Xenopus have also identified a number of inhibitory binding proteins for the classical BMPs, encoded by genes (...) such as chordin and noggin. These proteins appear to be responsible for establishing a morphogen gradient of BMP4 activity, which specifies different dorsoventral fates in early gastrulae. An emerging theme is that inhibition of BMP signalling is an important mechanism regulating cell fate decisions in early development. BioEssays 21:751–760, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Two recent publications highlight the role of bone‐forming cells, the osteoblasts, in controlling the development of neighboring haematopoietic stem cells (HSCs).1,2 Using two distinct transgenic mouse models, one using the conditional deletion of the Bone Morphogenetic Protein Receptor 1A (BMPR1A) gene, the other using over‐expression of an active PTH/PTHrP receptor (PPR) mutant within osteoblasts, the authors show parallel, concordant increases in the generation of trabecular osteoblasts and the number of HSCs. In situ staining showed that rarely cycling (...) HSCs sporadically attach to endosteal osteoblasts, while in vitro assays indicated that ligation of Jag1 on osteoblasts by Notch1 on HSCs promotes HSC proliferation. These two independent works have revived and revitalized the notion that osteoblasts are a major, defining component of the HSC niche within the bone marrow (BM). This minireview discusses these results in the context of other recent studies of mesenchymal cells within the BM microenvironment, presents one potential unified model of the functional anatomy of the BM HSC niche, and highlights new questions raised by these and other studies of osteoblasts and HSCs. BioEssays 26:595–599, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Secreted signaling molecules act as morphogens to control patterning and growth in many developing tissues. Since locally produced morphogens spread to form a concentration gradient in the surrounding tissue, spreading is generally thought to be the key step in the non‐autonomous actions. Here, we review recent advances in tool development to investigate morphogen function using the role of decapentaplegic (Dpp)/bone morphogenetic protein (BMP)‐type ligand in the Drosophila wing disc as an example. By applying protein binder tools to distinguish (...) between the roles of Dpp spreading and local Dpp signaling, we found that Dpp signaling in the source cells is important for wing patterning and growth but Dpp spreading from this source cells is not as strictly required as previously thought. Given recent studies showing unexpected requirements of long‐range action of different morphogens, manipulating endogenous morphogen gradients by synthetic protein binder tools could shed more light on how morphogens act in developing tissues. (shrink)

A flurry of technological advances in molecular, cellular and developmental biology during the past decade has provided a clearer understanding of mechanisms underlying phenotypic diversification. Building upon such momentum, a recent paper tackles one of the foremost topics in evolution, that is the origin of species‐specific beak morphology in Darwin's finches.1 Previous work involving both domesticated and wild birds implicated a well‐known signaling pathway (i.e. bone morphogenetic proteins) and one population of progenitor cells in particular (i.e. cranial (...) neural crest), as primary factors for establishing beak size and shape. But these results were limited in their ability to explain fully the morphogenetic bases of patterned outgrowth. So in a quest to identify novel genes whose expression correlated with differences in beak anatomy among Darwin's finches, a DNA microarray approach was undertaken using tissues harvested from the Galápagos Islands. The results are striking and point to a protein called calmodulin, which is a mediator of cellular calcium signaling, as a key determinant of beak length. BioEssays 29: 1–6, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

The Transforming growth factor beta (TGF‐β) family of secreted proteins regulates a variety of key events in normal development and physiology. In mammals, this family, represented by 33 ligands, including TGF‐β, activins, nodal, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs), regulate biological processes as diverse as cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine functions. In Drosophila, only 7 members of this family are present, with 4 TGF‐β/BMP and 3 (...) TGF‐β/activin ligands. Studies in the fly have illustrated the role of TGF‐β/BMP ligands during embryogenesis and organ patterning, while the TGF‐β/activin ligands have been implicated in the control of wing growth and neuronal functions. In this review, we focus on the emerging roles of Drosophila TGF‐β/activins in inter‐organ communication via long‐distance regulation, especially in systemic lipid and carbohydrate homeostasis, and discuss findings relevant to metabolic diseases in humans. -/- . (shrink)

Although the genetics of dorsal‐ventral polarity which leads to mesoderm formation in Drosophila are understood in considerable detail, subsequent molecular mechanisms involved in patterning the mesoderm primordium into individual mesodermal subtypes are poorly understood. Two papers published recently (1,2) suggest strongly that an inductive signal from dorsal ectoderm is involved in subdividing the underlying mesoderm, and present evidence that one of the signalling factors is Decapentaplegic (Dpp), a member of the bone morphogenetic protein subgroup of the Transforming Growth (...) Factor‐β (TGF‐β) super family of proteins. (shrink)

Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP‐1) have previously been linked to cell differentiation and pattern formation during development through a proposed role in the activation of latent growth factors of the TGF‐β superfamily. Recent finding(1) indicate that BMP‐1 is identical to pro‐collagen C‐proteinase, which is a metalloproteinase involved in extracellular matrix (ECM) formation. This observation suggests that a functional link may exist between astacin metalloproteinases, growth factors and cell differentiation (...) and pattern formation during development. Taken together, current studies indicate that BMP‐1 and possibly other astacin metalloproteinases are multifunctional enzymes that act directly on growth factors and the ECM. In combination, these dual actions would have profound effects on developmental processes. (shrink)

The dynamic structure and composition of lipid membranes need to be tightly regulated to control the vast array of cellular processes from cell and organelle morphology to protein‐protein interactions and signal transduction pathways. To maintain membrane integrity, sense‐and‐response systems monitor and adjust membrane lipid composition to the ever‐changing cellular environment, but only a relatively small number of control systems have been described. Here, we explore the emerging role of the ubiquitin‐proteasome system in monitoring and maintaining membrane lipid composition. We focus (...) on the ER‐resident RNF145 E3 ubiquitin ligase, its role in regulating adiponectin receptor 2 (ADIPOR2), its lipid hydrolase substrate, and the broader implications for understanding the homeostatic processes that fine‐tune cellular membrane composition. (shrink)

Embryonic development and ontogeny occupy whatis often depicted as the black box betweengenes – the genotype – and the features(structures, functions, behaviors) of organisms– the phenotype; the phenotype is not merelya one-to-one readout of the genotype. Thegenes home, context, and locus of operation isthe cell. Initially, in ontogeny, that cell isthe single-celled zygote. As developmentensues, multicellular assemblages of like cells(modules) progressively organized as germlayers, embryonic fields, anlage,condensations, or blastemata, enable genes toplay their roles in development and evolution.As modules, condensations are (...) fundamentaldevelopmental and selectable units ofmorphology (morphogenetic units) that mediateinteractions between genotype and phenotype viaevolutionary developmental mechanisms. In ahierarchy of emergent processes, gene networksand gene cascades (genetic modules) link thegenotype with morphogenetic units such ascondensations, while epigenetic processes suchas embryonic inductions, tissue interactionsand functional integration, link morphogeneticunits to the phenotype. To support theseconclusions I distinguish units of heredityfrom units of transmission and discussepigenetic inheritance by tracing the historyof relationship between embryology andevolution, especially the role(s) assigned tocells or to cellular components in generatingtheories of morphological change in evolution.The concept of cells as modular morphogeneticunits is modeled and illustrated using themammalian dentary bone. (shrink)

Titin, the largest protein identified to date (over 1 μm long, almost 3 million daltons in mass) is the third most abundant component of the sarcomere. In the mature myofibril, titin molecules span from M line to Z line, forming a third filament system which provides sarcomeric alignment and elastic recoil. In the developing sarcomere, accumulating evidence from studies both in vivo and in vitro implicates titin as part of a morphogenetic scaffolding, upon which critical events in myofibrillogenesis are (...) coordinated in a time‐ and spacedependent manner. (shrink)

Although bone development during embryogenesis and bone repair after injury have a number of features which appear similar, they are distinctly different processes which involve separate controlling elements and cuing parameters. Repair of bone is influenced by bioactive factors which reside in bone itself; some of these factors are not present when embryonic mesenchymal cells first differentiate. For example, a bone protein which induces the conversion of mesenchymal cells into cartilage cells is not present in (...) the embryo at the site where cartilage first differentiates into the anlagen for future bone. Ultimately, the sequence of cellular and molecular events which controls the success of bone repair is dependent on the prior embryologic and developmental packaging of bioactive factors into bone and the release of these factors at a bone break site. The success of the reparative events depends not only upon the release of these bone‐derived factors but also on systemic factors and the identity and numbers of responding cells at the repair site. (shrink)

RAS GTPases play essential roles in normal development and are direct drivers of human cancers. Three decades of study have failed to wholly characterize pathways stimulated by activated RAS, driven by engagement with ‘effector’ proteins that have RAS binding domains (RBDs). Bone fide effectors must bind directly to RAS GTPases in a nucleotide‐dependent manner, and this interaction must impart a clear change in effector activity. Despite this, for most proteins currently deemed effectors there is little mechanistic understanding (...) of how binding to the GTPase alters protein function. There has also been limited effort to comprehensively resolve the specificity of effector binding to the full array of RAS superfamily GTPase proteins. This review will summarize what is known about RAS‐driven activation for an array of potential effector proteins, focusing on structural and mechanistic effects and highlighting how little is still known regarding this key paradigm of cellular signal transduction. (shrink)

Endochondral bone formation can take place in the embryo, during fracture healing, or in postnatal animals after induction by implanted demineralized bone matrix. This matrix‐induced bone formation recapitulates the embryonic sequence of bone formation morphologically and biochemically. The steps in bone formation in both systems include differentiation of cartilage from mesenchyme, cartilage maturation, invasion of the cartilage by blood vessels and marrow precursors, and formation of bone and bone marrow. Recently, bone inductive (...) molecules from demineralized bone matrix have been purified, sequenced and produced as recombinant proteins. While there are similarities between bone development in the embryo and that after induction by these purified molecules, the molecules responsible for bone induction in the embryo have not yet been defined. Because of similarities between the two methods of bone formation, studies of Bone induction by demineralized bone matrix may help to elucidate mechanisms of embryonic bone induction. (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)

Scaling of pattern with size has been described and studied for over a century, yet its molecular basis is understood in only a few cases. In a recent, elegant study, Inomata and colleagues proposed a new model explaining how bone morphogenic protein (BMP) activity gradient scales with embryo size in the early Xenopus laevis embryo. We discuss their results in conjunction with an alternative model we proposed previously. The expansion‐repression mechanism (ExR) provides a conceptual framework unifying both mechanisms. Results (...) of Inomata and colleagues implicate the chordin‐stabilizing protein sizzled as the expander molecule enabling scaling, while we attributed this role to the BMP ligand Admp. The two expanders may work in concert, as suggested by the mathematical model of Inomata et al. We discuss approaches for differentiating the contribution of sizzled and Admp to pattern scaling. (shrink)

A few years ago no one would have suspected that the well‐known disorder of connective tissue, Marfan syndrome, could be caused by mutations in a recently discovered extracellular component, fibrillin. Likewise, nobody would have predicted that fibrillin represents a small family of proteins that are associated with several pheno‐typically overlapping disorders. The fibrillins are integral constituents of the non‐collagenous microfibrils, with an average diameter of 10 nm. These aggregates are distributed in the extracellular matrix of virtually every tissue. Microfibrillar (...) bundles provide the external coating to elastin in elastic fibers, and serve an anchoring function in non‐elastic tissues. At higher resolution, individual microfibrils have a “beads‐on‐a‐string” appearance resulting from the head‐to‐tail polymerization of multiple fibrillin aggregates. Structurally, fibrillin contains a series of repeated sequences homologous to the epidermal growth factor calcium‐binding motif. Characterization of fibrillin mutations in Marfan syndrome patients, together with the elucidation of the structure of the fibrillin proteins, have provided new insights, and raised new questions, about the function of the 10 nm microfibrils. For example, it is possible that the fibrillins, in addition to serving a structural function, might also be involved in regulating cellular activities and morphogenetic programs. It is fitting that the long search for the Marfan syndrome gene has brought a novel group of proteins to the forefront of extracellular matrix biology. (shrink)

The protein tyrosine kinase activity of the v‐abl oncogene has been demonstrated to subvert the normal second messenger systems used by lymphoid cells for growth and differentiation. Transformation of bone marrow with the Abelson murine leukemia virus results in the appearance of B cell lineage cells arrested at the pre‐B cell stage. Recent reports have characterized these cells expressing high v‐abl kinase activity as deficient in detectable NF‐kB DNA binding activity and low level RAG gene expression. These observations suggest (...) that v‐abl may be inhibiting the differentiation of B cells by blocking these two crucial elements in the maturation pathway. (shrink)

The establishment of a functional vascular system requires multiple complex steps throughout embryogenesis, from endothelial cell (EC) specification to vascular patterning into venous and arterial hierarchies. Following the initial assembly of ECs into a network of cord‐like structures, vascular expansion and remodeling occur rapidly through morphogenetic events including vessel sprouting, fusion, and pruning. In addition, vascular morphogenesis encompasses the process of lumen formation, critical for the transformation of cords into perfusable vascular tubes. Studies in mouse, zebrafish, frog, and human (...) endothelial cells have begun to outline the cellular and molecular requirements underlying lumen formation. Although the lumen can be generated through diverse mechanisms, the coordinated participation of multiple conserved molecules including transcription factors, small GTPases, and adhesion and polarity proteins remains a fundamental principle, leading us closer to a more thorough understanding of this complex event. (shrink)

This review discusses the possible role of α‐tubulin detyrosination, a reversible post‐translational modification that occurs at the protein's C‐terminus, in cellular morphogenesis. Higher eukaryotic cells possess a cyclic post‐translational mechanism by which dynamic microtubules are differentiated from their more stable counterparts; a tubulin‐specific carboxypeptidase detyrosinates tubulin protomers within microtubules, while the reverse reaction, tyrosination, is performed on the soluble protomer by a second tubulin‐specific enzyme, tubulin tyrosine ligase. In general, the turnover of microtubules in undifferentiated, proliferating cells is so rapid (...) that the microtubules accumulate very little detyrosinated tubulin; that is, they are enriched in tyrosinated tubulin. However, an early event common to at least three well‐studied morphogenetic events myogenesis, neuritogenesis, and directed cell motility is the elaboration of a polarized array of stable microtubules that become enriched in detyrosinated tubulin. The formation of this specialized array of microtubules in specific locations in cells undergoing morphogenesis suggests that it plays an important role in generating cellular asymmetries. (shrink)

In the rod‐shaped cells of E. coli, chromosome segregation takes place immediately after replication has been completed. A septum then forms between the two sister chromosomes. In the absence of certain membrane proteins, cells grow instead as large, multichromosomal spheres that divide successively in planes that are at right angles to one another. Although multichromosomal, the spherical cells cannot be maintained as heterozygotes. These observations imply that, in these mutants, each individual chromosome gives rise to a separate clone of (...) descendant cells. This suggests a model in which sites for cell division form between pairs of sister chromosomes at the time of segregation, but are not used in spherical cells until further rounds of replication have taken place, thus ensuring clonal (‘hierarchical’) segregation of chromosomes into progeny cells. The role of the morphogenetic membrane proteins is to convert the basically spherical cell into a cylinder that is able to divide as soon as replication and segregation have been completed, and thus to maximise the number of viable cells per genome. (shrink)

The tenascins are a growing family of extracellular matrix proteins of typical multidomain structure. The prototype to be discovered was tenascin‐C. It shows a highly regulated expression pattern during embryonic development and is often transiently associated with morphogenetic tissue interactions during organogenesis. In the adult organism reexpression of tenascin‐C occurs in tumors and many other pathological conditions. Tenascin‐C expression can be regulated by many different growth factors and hormones. Furthermore, mechanical strain exerted by fibroblasts seems to induce the (...) expression of tenascin‐C. This could represent a mechanism of translating mechanical forces into protein patterns, a step of potential relevance in the organization of embryogenesis. Tenascin‐C as well as tenascin‐R are believed to counteract the cell adhesion and spreading activity of fibronectin, thereby facilitating cell movement. (shrink)

Spreds form a new protein family with an N‐terminal Enabled/VASP homology 1 domain (EVH1), a central c‐Kit binding domain (KBD) and a C‐terminal Sprouty‐related domain (SPR). They are able to inhibit the Ras–ERK signalling pathway after various mitogenic stimulations. In mice, Spred proteins are identified as regulators of bone morphogenesis, hematopoietic processes, allergen‐induced airway eosinophilia and hyperresponsiveness. They inhibit cell motility and metastasis and have a high potential as tumor markers and suppressors of carcinogenesis. Moreover, in vertebrates, XtSpreds (...) help together with XtSprouty proteins to coordinate gastrulation and mesoderm specification. Here, we give an overview of this new field and summarize the domain functions, binding partners, expression patterns and the cellular localizations, regulations and functions of Spred proteins and try to give perspectives for future scientific directions. BioEssays 29:897–907, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Tubulin is the ubiquitous protein that makes up the walls of the cytoskeletal elements known as microtubules. These 20 nm diameter cylindrical fibers are the spindle fibers for mitosis, provide the skeletal framework for cellular elongation, constitute the major structural and motile elements of cilia and flagella and probably play a number of other roles in eukaryote cells. In the electron microscope, they are never seen to attach or protrude directly into or on cellular membranes. It was therefore with much (...) skepticism that cell biologists responded to recent claims purporting to show that tubulin is (or can be) a membrane protein. This skepticism comes from a bias based on the generally understood function of cytoskeletal proteins as representing the intracellular ‘bones’ of cells. The traditional thinking was that microtubules may attach to cellular membranes but only via a cross‐linking connecting protein. In recent years, however, an increasing number of workers have come to believe that tubulin can exist as a normal membrane protein possibly independent of its role in microtubule function. (shrink)

Although the segregation of mesenchyme into distinct aggregates is the first step in the development of a range of tissues that includes bones, somites, feathers and nephrons, we still know very little about the mechanisms by which this happens. There are two obvious types of explanation: first, that there are global pre‐patterns within the mesenchyme whose molecular expression leads to tissue fragmentation and, second, that the condensations arise spontaneously through the local morphogenetic abilities of the cells. The only known (...) mechanism for the latter possibility is cell traction and this paper suggests that current studies are compatible with traction playing a primary role in the formation of nephrogenic condensations in the developing kidney and the separation of somites, but not for the generation of feather rudiments where there is evidence of a prepattern of adhesivity. (shrink)

The growing interest and major advances of the last decades in evolutionary developmental biology (EvoDevo) have led to the recognition of the incompleteness of the Modern Synthesis of evolutionary theory. Here we discuss how paleontology makes significant contributions to integrate evolution and development. First, extinct organisms often inform us about developmental processes by showing a combination of features unrecorded in living species. We illustrate this point using the vertebrate fossil record and studies relating bone ossification to life history traits. (...) Second, we discuss exceptionally preserved fossils that document rare ontogenetic sequences and illustrate this case with the patterns of heterochrony observed in Cambrian crustacean larvae preserved three-dimensionally. Third, most fossils potentially document the evolutionary patterns of allometry and modularity, as well as some of the (paleo)ecological factors that had influenced them. The temporal persistence of adaptive patterns in rodent evolution serves to address the importance of ecological constraints in evolution. Fourth, we discuss how the macroevolutionary patterns observed in the tetrapod limb, in the mammal molar proportions, and in the molluscan shell provide independent tests of the validity of morphogenetic models proposed on living species. Reciprocally, these macroevolutionary patterns often act as a source of inspiration to investigate the underlying rules of development, because, at the end, they are the patterns that the neo-Darwinian theory was unable to account for. (shrink)

Fanconi anemia (FA) is generally classified as a DNA repair disorder, conferring a genetic predisposition to cancer and prominent bone marrow failure (BMF) in early childhood. Corroborative human and murine studies point to a fetal origin of hematopoietic stem cell (HSC) attrition under replicative stress. Along with intriguing recent insights into non‐canonical roles and domain‐specific functions of FA proteins, these studies have raised the possibility of a DNA repair‐independent BMF etiology. However, deeper mechanistic insight is critical as current (...) curative options of allogeneic stem cell transplantation and emerging gene therapy have limited eligibility, carry significant side effects, and involve complex procedures restricted to resource‐rich environments. To develop rational and broadly accessible therapies for FA patients, the field will need more faithful disease models that overcome the scarcity of patient samples, leverage technological advances, and adopt investigational clinical trial designs tailored for rare diseases. (shrink)

Fibril‐forming (fibrillar) collagens are extracellular matrix proteins conserved in all multicellular animals. Vertebrate members of the fibrillar collagen family are essential for the formation of bone and teeth, tissues that characterise vertebrates. The potential role played by fibrillar collagens in vertebrate evolution has not been considered previously largely because the family has been around since the sponge and it was unclear precisely how and when those particular members now found in vertebrates first arose. We present evidence that the (...) classical vertebrate fibrillar collagens share a single common ancestor that arose at the very dawn of the vertebrate world and prior to the associated genome duplication events. Furthermore, we present a model, ‘molecular incest’, that not only accounts for the characteristics of the modern day vertebrate fibrillar collagen family but demonstrates the specific effects genome or gene duplications may have on the evolution of multimeric proteins in general. BioEssays 25:142–151, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Collagen is the most abundant vertebrate protein and forms a stable fibrous architecture in connective tissues, such as bone, cartilage, skin and tendon. Much recent research has been directed towards an understanding of the molecular and cellular mechanisms involved in the synthesis and degradation of collagen, because a change in the normal balance, or an increased destruction of collagen, can cause loss of function of specialized tissues. This short review attempts to summarize present knowledge about the proteolytic destruction of (...) collagen and the exciting new work on the factors that are emerging as important controlling agents. An understanding of the regulatory processes is yielding some important clues regarding the levels at which they can fail in pathological conditions and we speculate about evolving strategies for preventing uncontrolled resorption. (shrink)

Tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) is a crucial signaling molecule regulating a diverse array of physiological processes, including adaptive immunity, innate immunity, bone metabolism and the development of several tissues including lymph nodes, mammary glands, skin and the central nervous system. It is a member of a group of six closely related TRAF proteins, which serve as adapter molecules, coupling the TNF receptor (TNFR) superfamily to intracellular signaling events. Among the TRAF proteins, TRAF6 (...) is unique in that, in addition to mediating TNFR family signaling, it is also essential for signaling downstream of an unrelated family of receptors, the interleukin‐1 (IL‐1) receptor/Toll‐like receptor (IL‐1R/TLR) superfamily. Gene targeting experiments have identified several indispensable physiological functions of TRAF6, and structural and biochemical studies have revealed the potential mechanisms of its action. By virtue of its many signaling roles, TRAF6 represents an important target in the regulation of many disease processes, including immunity, inflammation and osteoporosis. BioEssays 25:1096–1105, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

It is hypothesized that human faces judged to be attractive by people possess two features—averageness and symmetry—that promoted adaptive mate selection in human evolutionary history by way of production of offspring with parasite resistance. Facial composites made by combining individual faces are judged to be attractive, and more attractive than the majority of individual faces. The composites possess both symmetry and averageness of features. Facial averageness may reflect high individual protein heterozygosity and thus an array of proteins to which (...) parasites must adapt. Heterozygosity may be an important defense of long-lived hosts against parasites when it occurs in portions of the genome that do not code for the essential features of complex adaptations. In this case heterozygosity can create a hostile microenvironment for parasites without disrupting adaptation. Facial bilateral symmetry is hypothesized to affect positive beauty judgments because symmetry is a certification of overall phenotypic quality and developmental health, which may be importantly influenced by parasites. Certain secondary sexual traits are influenced by testosterone, a hormone that reduces immunocompetence. Symmetry and size of the secondary sexual traits of the face (e.g., cheek bones) are expected to correlate positively and advertise immunocompetence honestly and therefore to affect positive beauty judgments. Facial attractiveness is predicted to correlate with attractive, nonfacial secondary sexual traits; other predictions from the view that parasite-driven selection led to the evolution of psychological adaptations of human beauty perception are discussed. The view that human physical attractiveness and judgments about human physical attractiveness evolved in the context of parasite-driven selection leads to the hypothesis that both adults and children have a species-typical adaptation to the problem of identifying and favoring healthy individuals and avoiding parasite-susceptible individuals. It is proposed that this adaptation guides human decisions about nepotism and reciprocity in relation to physical attractiveness. (shrink)

The c‐Jun N‐terminal kinases (JNKs) are members of the mitogen‐activated protein kinase (MAPK) family. In mammalian genomes, three genes encode the JNK family. To evaluate JNK function, mice have been created with deletions in one or more of three Jnk genes. Initial studies on jnk1−/− or jnk2−/− mice have shown roles for these JNKs in the immune system whereas studies on jnk3−/− mice have highlighted roles for JNK3 in the nervous system. Further studies have highlighted the contributions of JNK1 and/or (...) JNK2 to a range of biological and pathological processes. These include bone remodelling and joint disease, inflammatory and autoimmune diseases, obesity, diabetes, cardiovascular disease, liver disease and tumorigenesis in addition to effects in neurons. These results emphasise the differences in the roles played by JNK isoforms in vivo and suggest that the design of JNK inhibitors for subsequent therapeutic uses may benefit from selective inhibition of individual JNK isoforms. BioEssays 28: 923–934, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Fanconi anaemia (FA) comprises a group of autosomal recessive disorders resulting from mutations in one of eight genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF and FANCG). Although caused by relatively simple mutations, the disease shows a complex phenotype, with a variety of features including developmental abnormalities and ultimately severe anaemia and/or leukemia leading to death in the mid teens. Since 1992 all but two of the genes have been identified, and molecular analysis of their products has revealed a complex (...) mode of action. Many of the proteins form a nuclear multisubunit complex that appears to be involved in the repair of double‐strand DNA breaks. Additionally, at least one of the proteins, FANCC, influences apoptotic pathways in response to oxidative damage. Further analysis of the FANC proteins will provide vital information on normal cell responses to damage and allow therapeutic strategies to be developed that will hopefully supplant bone marrow transplantation. BioEssays 24:439–448, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Rheumatoid arthritis (RA) may not be a multifactorial disease; it can be hypothesized that RA is developed through a series of events following a triggering event, which is the emergence of a chemokine for neutrophils in the synovium. IL‐17A, secreted by infiltrated neutrophils, stimulates synoviocytes to produce CCL20, which attracts various CCR6‐expressing cells, including Th17 cells. Monocytes (macrophages) appear after neutrophil infiltration according to the natural course of inflammation and secrete IL‐1β and TNFα. Then, IL‐17A, IL‐1β, and TNFα stimulate synoviocytes (...) to produce CCL20, amplifying the inflammation. Varieties of chemokines secreted by infiltrating cells accumulate in the synovium and induce synoviocyte proliferation by binding to the corresponding G protein‐coupled receptors, thus expanding the synovial tissue. CCL20 in this tissue attracts circulating monocytes that express both CCR6 and receptor activator of NF‐κB (RANK), which differentiate into osteoclasts in the presence of RANKL. In this way, pannus is formed, and bone destruction begins. (shrink)

A hybrid model of cell dynamics is presented. It is illustrated by model examples and applied to study erythropoiesis (red blood cell production). In this approach, cells are considered as discrete objects while intra-cellular proteins and extra-cellular biochemical substances are described with continuous models. Spatial organization of erythropoiesis occurring in specific structures of the bone marrow, called erythroblastic island, is investigated.

Dyskeratosis congenita is a rare skin and bone marrow failure syndrome caused by defective telomere maintenance in stem cells. The major X‐linked form of the disease is due to mutations in a nucleolar protein, dyskerin, that is part of small nucleolar ribonucleoprotein particles that are involved in processing ribosomal RNA. It is also found in the telomerase complex, pointing to an unexpected link between these two processes. An autosomal dominant form is due to mutations in the RNA component of (...) telomerase (hTR). Patients with this form of the disease are more severely affected in later generations that carry the mutations, possibly due to the inheritance of shortened telomeres, disguising the inherited nature of the disease in some cases classified as aplastic anemia. Because of the importance of telomerase in tumour formation and aging, study of this disease may provide important clues about these fundamental processes. BioEssays 25:126–133, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Osteopotin is a secreted glycosylated phosphoprotein found in bone and other normal and malignant tissues. Osteopontin can be autophosphorylated on tyrosine residues and can also be phosphorylated on serine and threonine residues by several protein kinases. Autophosphorylation of osteopontin may generate sites for specific interactions with other proteins on the cell surface and/or within the extracelluar matrix. These interactions of osteopontin are thought to be essential for bone mineralization and function. The polyaspartic acid motif of osteopontin, in (...) combination with neighboring sequences that include serine residues phosphorylated by protein kinases, could fold and assemble into a molecular structure that participates in the mineralization of the bone matrix. (shrink)

Traditionally, phylogenetic relations among living and extinct species have been estimated from their morphology, particularly that of the bones and teeth. During the past two decades, molecular comparisons of DNA, RNA and proteins have increasingly influenced the taxonomy of living forms. Recently, radio‐immunoassay (RIA) has been applied to the resolution of phylogenetic disputes by testing the relationships of residual fossil proteins with those of living organisms.

This book examines philosophical approaches to linguistic vagueness, a puzzling feature of natural language that gives rise to the ancient Sorites paradox and challenges classical logic and semantics. -/- The Sorites, or Paradox of the Heap, consists in three claims: (1) One grain of sand does not make a heap. (2) One billion grains of sand do make a heap. (3) For any two amounts of sand differing by at most one grain: either both are heaps of sand, or neither (...) one is. The third claim is rendered plausible by an initial conviction that vague predicates like ‘heap’ tolerate small changes. However, the repeated application of a tolerance principle to the second claim yields the further proposition that one grain of sand does make a heap – which contradicts claim number one. Consequently, many philosophers reject or modify tolerance principles for vague predicates. -/- Inga Bones reassesses prominent responses to the Sorites and defends a Wittgensteinian dissolution of the paradox. She argues that vague predicates are, indeed, tolerant and discusses how this finding relates to the paradox itself, to the notion of validity and to the concept of a borderline case . (shrink)

Precarious employment is commonplace within the University-as-business model. Neoliberal and New Public Management agendas have influenced widespread insecurity, and limited career progression pathways within academic work. Qualitative multi-case data inform this investigation of how young academic workers cope with, and justify, their precarious situations in a large Australian university. This article introduces the notion of cruel optimism to analyse the unethical exploitation of desires of precariously employed academics. This analytical engagement extends empathetic engagement with the lived experiences and rationalisations of (...) precariously employed academic workers, paying homage to their desires and negotiations. Findings demonstrate that participants were heavily invested in working towards achieving their good life fantasy which encompassed secure employment and the recognition this provided. Cruel optimism operated as participants developed coping mechanisms to deal with the ongoingness of their troubling situation as precarious workers uncertain how to change their precarious circumstances. Participants experienced cruel optimism as they navigated through issues of identity, control, and desire, related to their present and future lives as academic workers experiencing an impasse of crisis ordinariness. Optimism directed towards the academic scene of desire motivated participants’ daily actions and informed their understandings. Ethical elements of the impasse of precarious employment are presented in relation to the neoliberal and New Public Management-oriented University context. This article provides a novel conceptualisation of how precarious employment contributes to a relation of cruel optimism among workers by highlighting how organisations exploit the desires of insecure employees for extended periods of time, contributing to an impasse of crisis ordinariness. (shrink)

In this article, drawing upon a feminist epistemology, we examine the critical roles that philosophical standpoint, historical usage, gender, and language play in a knowledge arena which is increasingly opaque to the general public. Focussing on the language dimension in particular, in its historical and social dimensions, we explicate how some keywords in use across artificial intelligence (AI) discourses inform and misinform non-expert understandings of this area. The insights gained could help to imagine how AI technologies could be better conceptualised, (...) explained, and governed, so that they are leveraged for social good. (shrink)

Veterinary oaths are public declarations sworn by veterinarians, usually when they enter the profession. As such, they may reflect professional and social concerns. Analysis of contemporary veterinary oaths may therefore reveal their ethical foundations. The objective of this article is to contextualize the ethical content of contemporary oaths, in terms of the origin and development of veterinary medicine and wider societal changes such as the intensification of farming and the rise of animal welfare. This informs a comparison of oaths from (...) the United States, Canada, the United Kingdom, and Brazil. This analysis suggests some ways in which the oaths might be developed to better reflect contemporary societal values. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Katharine Jane Tait, 1923–2021Andrew Bone and Sheila Turcon Click for larger view View full resolutionIt was with great sadness that the Bertrand Russell Research Centre learned of the death on 26 July 2021 of Katharine Tait, Bertrand Russell’s daughter. Dr. Tait was a founder of the Bertrand Russell Society, attended several of its annual meetings, and was always strongly supportive of, and involved in, research and inquiry into (...) the life, times and writings of her father. She attended McMaster’s Russell Centenary Celebrations in 1972. Her scholarly interests and commitments extended to the McMaster edition of Russell’s Collected Papers, of whose Advisory Editorial Board she was a longstanding member. Kate herself wrote an important and poignant memoir, My Father Bertrand Russell; she was an always charming and friendly visitor to McMaster on those occasions she undertook work in the Russell Archives, which included an annotated, as yet unpublished edition of her correspondence with her father. She contributed articles and reviews to this journal. Several members of the McMaster community cherish her personal letters, notes and greeting cards to them.— Andrew Bone; photo by Sheila Turcon [End Page 98]Copyright © 2021 McMaster University... (shrink)

At the 2021 conference of the Society for the Study of Christian Ethics, Linda Woodhead presented a paper entitled ‘Truth and Deceit in Institutions’. Amra Bone was then invited to deliver a response to this paper drawing on her knowledge of Islamic traditions and culture. This article is her response. The article highlights the importance the Qur’anic scripture gives to justice and neither distorting nor refusing to give testimony. It then briefly explores the Arabic term Kufr found in the (...) Qur’an. Whilst more commonly interpreted to mean disbelief, this term literally means hiding or covering up truth. Dishonesty can therefore be equated to disbelief which makes it a very serious matter for Muslims. Therefore ethics determine that the road to greater institutional honesty must be adopted. In Islamic Law the end does not justify the means; rather the outcome rests with God alone and the responsibility given to men and women is to act honestly and ethically. For any institution or society to develop positively, every individual must play their part and take this responsibility seriously and not to rely on a few courageous individuals. (shrink)

In recent times developments in the natural sciences and in the sphere of environmental politics have compelled social scientists, and also some natural scientists, to rethink the relations that hitherto have been held, in Western thought generally and within particular disciplines, to characterize ‘nature’ on the one side and ‘culture’ on the other. This article considers the history of this conceptual boundary and looks at new conceptualizations of nature/culture, stimulated by developments both in biotechnology and in the ongoing controversies about (...) environmental degradation. It argues that while some of the contributions to reconfiguring, or abolishing, the nature/ culture division have been productive and stimulating of new ways of conceiving the world, there has nonetheless been an unfortunate tendency for social scientists to bring to bear inherited analytic dispositions on biotechnological and environmental matters. Instead of using these issues as means of challenging social scientific disciplinary dogmas and of engaging in constructive rapprochement with natural scientists, social scientists have in their analyses of such matters often merely asserted the hegemony of ‘culture’ over ‘nature’, and thus in effect the superiority of social scientific over natural scientific conceptualizations of the world. Far from overcoming the nature/culture boundary, social scientists have too often merely asserted the primacy of the sorts of subject matters and analytic techniques they feel comfortable with, rather than subjecting their practices to fully reflexive self-scrutiny. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Social and Moral Aspects of the WarBertrand Russell and Introduced by Andrew G. BoneAmong nine loose-leaf folders of typed transcriptions of Russell's History of Western Philosophy lectures at the Barnes Foundation1 are two copies of a fourteen-page stenographic record of a political talk he gave there on 2 March 1941.2 The bulk of this significant new accrual to the Russell Archives, bearing as it does on Russell's most successful (...) philosophical work, could stimulate much further research and textual study. But his isolated Barnes lecture, about the politics of American neutrality, Nazi Germany's brutal and expansionist dictatorship, and the causes and possible consequences of the war against it, is also of considerable interest.The transcription reads more like detailed notes than a verbatim account, and there is no evidence that Russell approved this text.3 The stenographer initially recorded Russell in the third person, dispensed with this device before the second [End Page 52] paragraph, but then occasionally returned to it.4 There is also more enumeration of Russell's points than he would have supplied in a prepared script. Even the title may not be his: there is nothing in the text on any social changes wrought by the war. But this title has been retained in the absence of a more plausible alternative in a short report of the speech (quoting sixteen sentences) in the next day's Philadelphia Evening Bulletin.5 Russell's hour-long address on the "Social and Moral Aspects of the War" appears to have been the only occasion when he "laid philosophy aside"6 at the Barnes Foundation. It was delivered on a Sunday to an audience of 160 students (and possibly some invitees, although none are mentioned in the newspaper article), sandwiched between two of his weekly philosophical lectures (on Socrates and Sparta7) in the series scheduled for each Thursday.In opening his case for the United States joining the Allied war effort, Russell challenged the arguments for the "policy of conciliation" which, by his own recent admission in the New York Times,8 he had earlier endorsed. Published two weeks before Russell spoke on a similar topic at the Barnes Foundation, this 2,000-word letter to the editor served as a very detailed and public renunciation of the pacifist viewpoint—neutrality for national governments combined with non-resistance for individuals—which Russell had promoted in Which Way to Peace? (1936) and continued to condone after the Munich Agreement (September 1938) and even the dismemberment of Czechoslovakia (March 1939).Yet Russell the "relative political pacifist"9 also admitted in this most programmatic statement of his prewar position that "In other times and other circumstances, I should be prepared to consider gains and losses, and to concede that war might be worth while" (WWP, pp. 151–2).That moment had obviously arrived and may have done so already when on 15 October 1939 Russell confided to Constance Malleson that his passionate desire for a British victory made a "thorough-going pacifism difficult" (ra Rec. Acq. 596). But six months later he still did "not feel sufficiently sure of the opposite to say anything publicly by way of recantation"—before adding in this letter to Gilbert Murray that "it may come to that" (21 April 1940, ra Rec. Acq. 71g). It clearly did shortly afterwards—when the "phoney war" in Western Europe was dramatically ended by the invasion of France and the [End Page 53] Low Countries. On 13 May Russell asked the editor of the New Statesman and Nation to notify its readers that he had abandoned his once strongly held pacifist convictions.10In his lecture to the Barnes Foundation, Russell turned next to the defence of American non-intervention by Robert M. Hutchins (see n. 16 below)—which he had already critiqued in the New York Times. Although rather precariously situated as a resident alien in the United States, Russell was hardly circumspect about pushing a policy that so sharply divided American opinion.11 He also listed the faults of the League of Nations and the most grievous diplomatic mistakes made since the end of the last war and the fatally... (shrink)