D‐amino acids are being recognized as functionally important molecules in mammals. We recently identified endogenous D‐cysteine in mammalian brain. D‐cysteine is present in neonatal brain in substantial amounts (mM) and decreases with postnatal development. D‐cysteine binds to MARCKS and a host of proteins implicated in cell division and neurodevelopmental disorders. D‐cysteine decreases phosphorylation of MARCKS in neural progenitor cells (NPCs) affecting its translocation. D‐cysteine controls NPC proliferation by inhibiting AKT signaling. Exogenous D‐cysteine inhibits AKT phosphorylation at Thr 308 and Ser (...) 473 in NPCs. D‐cysteine treatment of NPCs led to 50% reduction in phosphorylation of Foxo1 at Ser 256 and Foxo3a at Ser 253. We hypothesize that in the developing brain endogenous D‐cysteine is as a physiologic regulator of NPC proliferation by inhibiting AKT signaling mediated by Foxo1 and Foxo3a. Endogenous D‐cysteine may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer's disease (AD). (shrink)

At first glance, what scientific progress means seems to be a quickly answered question. It is not easy to think of the sciences without progress; sciences and the notion of progress seem identical in general. Describing the nature of scientific progress is an important task that will have practical and theoretical consequences. The approach, which argues that the background on which sciences are based does not have a historical or cultural character following the positivist interpretation, accepts sciences as testing the (...) validity of observation and experiment data to a large extent. On the other hand, the tendency that emphasizes that the complex functioning of the history of science has an indelible mark on scientific theories prefers to build sciences on a historical and social basis. How both major approaches ground the idea of scientific progress profoundly affects both our understanding of the nature of scientific knowledge and the way we do science. This paper aims to evaluate scientific progress based on the views of prominent philosophers of science in the twentieth century. (shrink)

Bu çalışmada, bir yandan bilgiye yol açması bağlamında deneyimin inanca kaynak oluşturması, öte yandan insan edimlerine yol açması bağlamında inancın deneyimlenmesine olanak oluşturması nedeniyle inanç-deneyim ilişkisi irdelenecektir. İnanç-deneyim ilişkisinin olanaklılığı ve bu ilişkinin kuşkulu doğası, Davidson ve Wittgenstein gibi iki önde gelen çözümleyici filozofun konuyla ilgili açıklamaları dikkate alınarak araştırılmaktadır.Yazının ana savını şu temel fikir oluşturmaktadır: Sanılanın aksine, ne deneyimler inanç için sağlam ve kesin bir temel oluştururlar ne de deneyimler bilinmek için inançlara gereksinim duyarlar. In this paper, the relationship (...) between belief and experience will be investigated because on the one hand, experience creates a source for beliefs which leads knowledge and on the other hand it makes the experience possible, which leads human actions. Considering the analysis of two prominent analytic philosophers Davidson and Wittgenstein, the relationship of belief and experience, and the questionable nature of this relationship will be studied. The basic claim of this paper consists of the following primary idea: Contrary to what is believed, neither experiences form a firm and certain basis for beliefs, nor experiences are in need of beliefs to be known. (shrink)

This article describes the development of a computerized version of a measure of ethical sensitivity to racial and gender intolerance, the Racial Ethical Sensitivity Test. The REST was based on James Rest's 4-component model of moral development and the professional codes of ethics from school-based professions. The new version, Racial and Ethical Sensitivity Test-Compact Disk, consists of 5 videotaped scenarios followed by an interactive "interview" presented on compact discs. Data from a study with 58 students provides initial validation of the (...) REST-CD. Ethical sensitivity to racial and gender intolerance in schools, as measured by the REST-CD, was moderately related to attitudes toward racial and gender equity issues in society as measured by the Quick Discrimination Index. The results provide evidence for both interrater and internal reliability of the REST-CD scores. This study also tests the hypothesized relationship between REST-CD scores and previous multicultural and ethics course work. Students with multicultural and ethics course experience have scored significantly higher on the REST-CD than students without course work. The paper-and-pencil tests are not significantly related to previous ethics/multicultural course work. In this article, we discuss the implications of the results and directions for future research. (shrink)

Modern insan eleştiriyi, neredeyse hava kadar, su kadar yaşamsal saymaktadır. Daha iyi bir dünyada yaşama isteği, verili olanlarla yetinmemeyi, gelenekleri, yerleşik değerleri sorgulamayı beraberinde getirmektedir. Felsefi eleştiri, sadece belli bir görüşe itiraz etmekle sınırlı bir tutum değildir; o aynı zamanda kendi dayanaklarının sağlamlığı ile de ilgilidir. Bilimlerde sıklıkla karşılaşılan yapıcı ya da olumlu eleştiri, başta felsefe olmak üzere sosyal bilimlerde yıkıcı bir niteliğe bürünmektedir. Felsefi eleştirinin yıkıcılığının nihilizmle sonuçlanmaması için bu eleştiri türünün de yapıcı bir nitelikle donatılması gerekir. Bu çalışmada (...) felsefi eleştirinin normları olabileceği öne sürülmektedir. Bu normlardan en bilinen ve kabul gören üç ilke tespit edilerek bu ilkelerin felsefi eleştirinin temellendirilmesinde oynadıkları rolün gösterilmesi amaçlanmaktadır. Böylelikle felsefenin de tıpkı bilimler gibi siyasal iktidarların hizmetinde olmak yerine, gerçeğin peşinden gidebileceğinin olası olduğu gösterilecektir. (shrink)

This qualitative study analysed the agency of eight non-abusing mothers in the Turkish Cypriot Community after disclosure that their child had been sexually abused by someone outside the family. The aim was to discover how, after disclosure, such mothers act to protect their children in the contexts of their family and community. The data were gathered via semi-structured in-depth interviews and analysed using Interpretative Phenomenological Analysis. In the nuclear family context, maternal agency emerged in the form of motherhood skills, including (...) emotionally supporting the abused child, double-checking the child’s safety or limiting the child’s mobility, and controlling the actions of adult sons. In the community context, maternal agency was manifested in efforts to prevent men in the extended family or the abuser’s family from concealing the abuse and to obtain informal support from others such as birth or extended family members. The women were usually successful in hiding their reactions or making decisions in their children’s best interest despite frequently having to cope with the reality of living in a restrictive and patriarchal culture. The results emphasise the need for working with the general public and professionals to change the culture of silence and to improve the social support network for sexually abused children and non-abusing family members, especially mothers. (shrink)

Various approaches have been made for understanding the nature of science and scientific knowledge. The social factors that played some role during the choice of scientific theories in the nineteenth century popularised the opinion that the scientific knowledge is the subject of a sociological research. During the ongoing discussions, one of the explanation or the justification models that was proposed is known as “the Strong Programme.” The main claim of “the Strong Programme” is that the social factors have a determining (...) role for the choice of scientific theories, rather than the rational and universal criteria one may expect. Hence, those who were behind this view rejected all of the rational analyses made for the sciences and the scientific methods. In this paper, we try to investigate the validity of the claims of “the Strong Programme,” and to clarify whether it is possible to understand the real nature of science without any rational approach. It is argued that it would be insufficient to determine the content of the science merely by the social factors, the natural facts might be meaningful by themselves as well. -/- Bilimin ve bilimsel bilginin doğasını açıklamak için farklı pek çok yaklaşım geliştirilmiştir. Özellikle ondokuzuncu yüzyıldaki bazı bilimsel kuramların tercihinde toplumsal etmenlerin rolünün gözlemlenmesi, bilimsel bilginin toplumbilimsel bir araştırma konusu olduğu kanısını yaygınlaştırmıştır. Bu süreçte ortaya konan açıklama ve gerekçelendirme modellerinden biri de “Strong Programme” olarak anılandır. “Strong Programme” ın temel savı, bilimsel kuramların tercihinde sanıldığı gibi ussal ve evrensel ölçütlerin değil, toplumsal etmenlerin belirleyici olduğu yönündeydi. Dolayısıyla bu görüşü savunanlar, bilim ve bilimsel yöntem için ortaya konan tüm ussalcı çözümlemeleri reddettiler. Bu çalışmada, “Strong Programme”ın ileri sürdüğü savların haklılığı ve sanıldığı gibi usçu bir yaklaşım olmaksızın bilimin gerçek doğasını anlamanın olanaklı olup olmadığı soruşturulmaktadır. Bilimin içeriğinin bütünüyle ve sadece toplumsal etmenlerce belirlenemeyeceği, doğa olaylarının da kendi başlarına anlamlı olabileceği ileri sürülmektedir. (shrink)

Crisis management is a complex problem raised by the scientific community currently. Decision support systems are a suitable solution for such issues, they are indeed able to help emergency managers to prevent and to manage crisis in emergency situations. However, they should be enough flexible and adaptive in order to be efficient to solve complex problems that are plunged in dynamic and unpredictable environments. The approach we propose in this paper addresses this challenge. First, we expose a modelling of information (...) for an emergency environment. Then, we describe an architecture of a multiagent DSS that deals with these information in order to prevent and to manage crisis situations. We focus here on the first level of the system mechanism which intends to perceive and to reflect the evolution of the current situation. Finally, we provide an implementation and an experimentation of the approach using the RoboCupRescue Simulation System. (shrink)

This study examined possible ways to ensure that participants provide fully informed consent for online surveys. Participants were randomly assigned to read either a traditional informed consent or one of three modified versions: enhanced, consent for each key element, or a combination of these two. Those who read the combination version scored higher on a comprehension quiz, guessed at fewer questions, and were more likely to read all of the informed consent than those who received the traditional version. These findings (...) suggest that comprehension can be improved by adopting alternatives to the traditional informed consent. (shrink)

Viyana Çevresi, sunduğu program ve felsefe-bilim ilişkisine dair görüşleriyle 20. yüzyıl felsefesinin kurucu unsurlarından biridir. Viyana Çevresi felsefesini tarihsel bağlamından bağımsız olarak, mantıkçı olguculuk ve benzeri birtakım kavramlarla sınırlı anlama girişimleri, çevrenin gerçekte nasıl bir program önerdiğinin kavranmasını güçleştirmiştir. Hatta bu tür girişimler, Viyana Çevresinin metafiziğe ilişkin savlarından da yola çıkarak, çevrenin programının, toplumsal ve insani olanı dışlayıcı bir öze sahip olduğu biçiminde yorumlanmasına neden olmuştur. Bu yazıda, Viyana Çevresinin bilim ve felsefeye dair sunduğu programın, günümüz felsefesinin biçimlenmesinde etkin bir (...) rol oynadığı, bu rolün de sanılanın aksine Viyana Çevresinin toplumsal konulara ilişkin ortaya koyduğu tezlerden de kaynaklandığı, tarihsel ve düşünsel bir arkaplan soruşturmasıyla gösterilmeye çalışılacaktır.With its considerations on the relations between science and philosophy and its declared program, Vienna Circle is one of the constitutive elements of the twentieth century philosophy. Attempts to understand the Circle limited with some expressions like logical positivism, regardless of its historical context, have led to some difficulties about the real nature of its program. Such attempts, moreover, have adduced from the thoughts of the Vienna Circle on metaphysics that the program of the Circle, in essence, was hostile to anything that is social and human. In this paper, through a historical and intellectual background inquiry it is tried to put that the declared program of Vienna Circle about science and philosophy has played a crucial role for the formation of the philosophy today, and unlike as one may think, this role can only be conceived fully if one respects the theses of the Circle about the social problems properly. (shrink)

Highly committed teachers spend more effort helping their schools achieve the academic goals. The Covid-19 pandemic had a dire effect on education worldwide. However, just after a few semesters, teachers were asked to return back to schools to teach in person. This study aims to analyze the organizational commitment levels of school teachers before and after the implementation of the Covid-19 pandemic measures that resulted in a two semester break in face-to-face teaching. In this study, a quantitative research method was (...) utilized. A total of 300 teachers’ commitment levels were assessed in a longitudinal test by using a popular tool in order to see the relative change as result of Covid-19 pandemic in Cyprus. The study mainly focuses on gender, marital status, education levels, job experience, and duration of work in the organizations in which the information from responses were statistically analyzed. According to the results of the quantitative analysis, the organizational commitment sampling average were determined to be at medium-high levels. The commitment levels of teachers were observed to decrease after the Covid-19 pandemic measures came to be implemented in schools. A detailed investigation of the school teachers’ commitment levels corresponding to the different demographic characteristics before Covid-19 and after the implementation of normalization measures is presented herein. (shrink)

We present computational modeling results based on a self‐paced reading study investigating number attraction effects in Eastern Armenian. We implement three novel computational models of agreement attraction in a Bayesian framework and compare their predictive fit to the data using k‐fold cross‐validation. We find that our data are better accounted for by an encoding‐based model of agreement attraction, compared to a retrieval‐based model. A novel methodological contribution of our study is the use of comprehension questions with open‐ended responses, so that (...) both misinterpretation of the number feature of the subject phrase and misassignment of the thematic subject role of the verb can be investigated at the same time. We find evidence for both types of misinterpretation in our study, sometimes in the same trial. However, the specific error patterns in our data are not fully consistent with any previously proposed model. (shrink)

This article explores the combined construction of the concepts of race, sex and reproduction, both in natural history and in the rearing of birds and animals in eighteenth-century France. The analysis is based on the article “Canary” (Serin des Canaries) in Buffon’s Histoire naturelle. It firstly examines the social and cultural significance of keeping canaries in eighteen-century Paris, a particularly popular pastime among women of the leisured class. The analysis then focuses on Buffon’s article, to show how scientific descriptions of (...) the sex differences in animals lead to the naturalization of differences in humans, through what we shall describe as an “anthropocentric circle of naturalization”. Finally, the article will demonstrate how the two categories of sex and race are constructed in relation to each other in both Buffon’s natural history and in the practices of rearing birds in that period. (shrink)

Members of the serine/arginine (SR)‐rich protein family of splicing factors play versatile roles in RNA processing steps and are often essential for normal development. Dynamic changes in RNA processing and turnover allow fast cellular adaptions to a changing microenvironment and thereby closely cooperate with transcription factor networks that establish cell identity within tissues. SR proteins play fundamental roles in the processing of pre‐mRNAs by regulating constitutive and alternative splicing. More recently, SR proteins have also been implicated in other aspects (...) of RNA metabolism such as mRNA stability, transport and translation. The‐ emerging noncanonical functions highlight the multifaceted functions of these SR proteins and identify them as important coordinators of gene expression programmes. Accordingly, most SR proteins are essential for normal cell function and their misregulation contributes to human diseases such as cancer. (shrink)

Mild and massive DNA damage are differentially integrated into the cellular signaling networks and, in consequence, provoke different cell fate decisions. After mild damage, the tumor suppressor p53 directs the cellular response to cell cycle arrest, DNA repair, and cell survival, whereas upon severe damage, p53 drives the cell death response. One posttranslational modification of p53, phosphorylation at Serine 46, selectively occurs after severe DNA damage and is envisioned as a marker of the cell death response. However, the molecular (...) mechanism of action of the p53 Ser46 phospho‐isomer, the molecular timing of this phosphorylation event, and its activating effects on apoptosis and ferroptosis still await exploration. In this essay, the current body of evidence on the molecular function of this deadly p53 mark, its evolutionary conservation, and the regulation of the key players of this response, the p53 Serine 46 kinases, are reviewed and dissected. (shrink)

Serine proteinase cleavage of proteins is essential to a wide variety of biological processes and is primarily regulated by protein inhibitors. Many inhibitors are conformationally rigid simulations of optimal serine proteinase substrates, which makes them highly efficient competitive inhibitors of target proteinases. In contrast, members of the serpin family of serine proteinase inhibitors display extensive flexibility and polymorphism, particularly in their reactive site segments and in β‐sheet secondary structure, which can take up and expel strands. Reactive site (...) and β‐sheet polymorphism appear to be coupled in the serpins and may account for the extreme stability of serpinproteinase complexes through the insertion of the reactive site strand into a β‐sheet. These unusual properties may have opened an adaptive pathway of proteinase regulation that was unavailable to the conformationally rigid proteinase inhibitors. (shrink)

Transcription factors provide nodes of information integration by serving as nuclear effectors of multiple signaling cascades, and thus elaborate layers of regulation, often involving post-translational modifications, modulating and coordinate activities. Such modifications can rapidly and reversibly regulate virtually all transcription factor functions, including subcellular localization, stability, interactions with cofactors, other post-translational modifications and transcriptional activities. Aside from analyses of the effects of serine/threonine phosphorylation, studies on post-translational modifications of transcription factors are only in the initial stages. In particular, the (...) regulatory possibilities afforded by combinatorial usage of and competition between distinct modifications on an individual protein are immense, and with respect to large families of closely related transcription factors, offer the potential of conferring critical specificity. Here we will review the post-translational modifications known to regulate ETS transcriptional effectors and will discuss specific examples of how such modifications influence their activities to highlight emerging paradigms in transcriptional regulation. BioEssays 27:285–298, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

One distinguishing feature of vertebrate oocyte meiosis is its discontinuity; oocytes are released from their prophase I arrest, usually by hormonal stimulation, only to again halt at metaphase II, where they await fertilization. The product of the c‐mos proto‐oncogene, Mos, is a key regulator of this maturation process. Mos is a serine‐threonine kinase that activates and/or stabilizes maturation‐promoting factor (MPF), the master cell cycle switch, through a pathway that involves the mitogen‐activated protein kinase (MAPK) cascade. Oocytes arrested at prophase (...) I lack detectable levels of Mos, which must be synthesized from a pool of maternal mRNAs for proper maturation. While Mos is necessary throughout maturation in Xenopus, it seems to be required only for meiosis II in the mouse. The translational activation of c‐mos mRNA at specific times during meiosis requires cytoplasmic polyadenylation. Cis‐ and trans‐acting factors for polyadenylation are, therefore, essential elements of maturation. (shrink)

Plasminogen activator inhibitor‐1 (PAI‐1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI‐1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI‐1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the “PAI‐1 paradox”. Many factors are responsible for the upregulation of PAI‐1 in the tumor microenvironment. We hypothesize that there is a breast (...) cancer predisposition to a more aggressive stage when PAI‐1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyperinsulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the “PAI‐1 cycle”. Sustained by MetS, adipocytokines alter PAI‐1 expression to promote angiogenesis, tumor‐cell migration and procoagulant microparticle formation from endothelial cells, which generates thrombin and further propagates PAI‐1 synthesis. All of these factors culminate in a chemotherapy‐resistant breast tumor microenvironment. The PAI‐1 cycle may partly explain the PAI‐1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI‐1 and how an increased level of PAI‐1 can be linked to a poor prognosis. BioEssays 29:1029–1038, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

O‐glycosylation is the post‐translational process whereby carbohydrate is added to hydroxylated amino acids of proteins. The major O‐glycosylation pathway in animal cells is involved in the synthesis of oligosaccharides linked by N‐acetylgalactosamine to serine or threonine residues in ‘mucin‐type’ proteins or their analogs. In this review, we discuss the evidence for the cellular localization of the biosynthetic steps in this pathway and propose a simplified, consensus version. We also propose variations of the simple pathway to account for its heterogeneity (...) and variability in different cell types and differentiation states. (shrink)

In eukaryotes, folate metabolism is compartmentalized between the cytoplasm and organelles. The folate pathways of mitochondria are adapted to serve the metabolism of the organism. In yeast, mitochondria support cytoplasmic purine synthesis through the generation of formate. This pathway is important but not essential for survival, consistent with the flexibility of yeast metabolism. In plants, the mitochondrial pathways support photorespiration by generating serine from glycine. This pathway is essential under photosynthetic conditions and the enzyme expression varies with photosynthetic activity. (...) In mammals, the expression of the mitochondrial enzymes varies in tissues and during development. In embryos, mitochondria supply formate and glycine for purine synthesis, a process essential for survival; in adult tissues, flux through mitochondria can favor serine production. The differences in the folate pathways of mitochondria depending on species, tissues and developmental stages, profoundly alter the nature of their metabolic contribution. BioEssays 28: 595–605, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Toxoplasma gondii is a highly successful parasite capable of infecting virtually all warm-blooded animals by actively invading nucleated host cells and forming a modified compartment where it replicates within the cytosol. The parasite-containing vacuole provides a safe haven, even in professional phagocytes such as macrophages, which normally destroy foreign microbes. In an effort to eliminate the parasite, the host up-regulates a family of immunity-related p47 GTPases (IRGs), which are recruited to the parasite-containing vacuole, resulting in membrane rupture and digestion of (...) the parasite. To avoid this fate, highly virulent strains of Toxoplasma coat the external surface of their vacuole with a secretory serine/threonine kinase, known as ROP18. At this host-pathogen interface, ROP18 phosphorylates and inactivates IRGs, thereby protecting the parasite from killing. These findings reveal a novel molecular mechanism by which the parasite disarms host innate immunity. (shrink)

Steroid hormones are signaling molecules important for normal growth, development and differentiation of multicellular organisms. Brassinosteroids (BRs) are a class of polyhydroxylated steroids that are necessary for plant development. Molecular genetic studies in Arabidopsis thaliana have led to the cloning and characterization of the BR receptor, BRI1, which is a transmembrane receptor serine/threonine kinase. The extracellular domain of BRI1, which is composed mainly of leucine‐rich repeats, can confer BR responsivity to heterologous cells and is required for BR binding. Although (...) downstream components of BR action are mostly unknown, multiple genes whose expression are regulated by BRs have been identified and suggest mechanisms by which BRs affect cell elongation and division. BioEssays 23:1028–1036, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Serpins are members of a family of structurally related protein inhibitors of serine proteinases, with molecular masses between 40 and 100kDa. In contrast to other, simpler, proteinase inhibitors, they may interact with proteinases as inhibitors, as substrates, or as both. They undergo conformational interconversions upon complex formation with proteinase, upon binding of some members to heparin, upon proteolytic cleavage at the reactive center, and under mild denaturing conditions. These conformational changes appear to be critical in determining the properties of (...) the serpin. The structures and stabilities of these various forms may differ significantly. Although the detailed structural changes required for inhibition of proteinase have yet to be worked out, it is clear that the serpin does undergo a major conformational change. This is in contrast to other, simpler, families of protein inhibitors of serine proteinases, which bind in a substrate‐like or product‐like manner. Proteolytic cleavage of the serpin can result in a much more stable protein with new biological properties such as chemo‐attractant behaviour. These structural transformations in serpins provide opportunities for regulation of the activity and properties of the inhibitor and are likely be important in vivo, where serpins are involved in blood coagulation, fibrinolysis, complement activation and inflammation. (shrink)

One of the most dynamic areas of plant molecular biology is the investigation of the actions of three classes of herbicides: s‐triazines (atrazine, simazine), glyphosate, and sulfonylureas (chlorsulfuron, sulfometuron methyl) (Figure 1). The results of this work are expected to provide the first significant applications of plant biotechnology: directly, in the genetic engineering of crop plants resistant to specific herbicides and, indirectly, in providing a molecular basis for the rational design of new herbicides for specific biological targets.s‐Triazines affect photosynthesis by (...) inhibiting the binding of quinones to the chloroplast membrane QB protein. An s‐triazine resistant QB protein isolated from weeds in fields consistently treated with the herbicide has a serine in place of a glycine in this highly conserved protein. Glyphosate inhibits 5‐enolpyruvyl‐shikimate‐3‐phosphate synthase (EPSP synthase), an enzyme in the aromatic amino acid biosynthetic pathway. Mutagenized bacteria produce a resistant EPSP synthase with a substitution of serine for proline. Sulfonylureas inhibit the acetolactate synthase (ALS) of bacteria, yeast, and higher plants; this enzyme catalyzes the first step in the synthesis of branched chain amino acids. Resistant ALS has been found in bacteria, yeast and tobacco with a proline substituted by serine in yeast ALS. These findings provide a strong basis for developing projected plant biotechnology applications. (shrink)

The DAP (Death Associated Protein) kinase family is a novel subfamily of pro-apoptotic serine/threonine kinases. All five DAP kinase family members identified to date are ubiquitously expressed in various tissues and are capable of inducing apoptosis. The sequence homology of the five kinases is largely restricted to the N-terminal kinase domain. In contrast, the adjacent C-terminal regions are very diverse and link individual family members to specific signal transduction pathways. There is increasing evidence that DAP kinase family members are (...) involved in both extrinsic and intrinsic pathways of apoptosis and may play a role in tumor progression. This review will focus on structural composition and subcellular localization of DAP kinase family members and on signal transduction pathways leading to their activation. Potential mechanisms of DAP kinase family-mediated apoptosis will be discussed. BioEssays 23:352–358, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Phagocytosis is an uptake of large particles governed by the actin-based cytoskeleton. Binding of particles to specific cell surface receptors is the first step of phagocytosis. In higher Eucaryota, the receptors able to mediate phagocytosis are expressed almost exclusively in macrophages, neutrophils, and monocytes, conferring immunodefence properties to these cells. Receptor clustering is thought to occur upon particle binding, that in turn generates a phagocytic signal. Several pathways of phagocytic signal transduction have been identified, including the activation of tyrosine kinases (...) and (or) serine/threonine kinase C in pivotal roles. Kinase activation leads to phosphorylation of the receptors and other proteins, recruited at the sites of phagocytosis. Monomeric GTPases of the Rho and ARF families are likely to be engaged downstream of activated receptors. The GTPases, in cooperation with phosphatidylinositol 4-phosphate 5-kinase and phosphatidylinositol 3-kinase lipid modifying enzymes, can modulate locally the assembly of the submembranous actin filament system leading to particle internalization. BioEssays 21:422–431, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The reversible phosphorylation of proteins on serine/threonine residues preceding proline (Ser/Thr‐Pro) is a major regulatory mechanism for the control of a series of cell cycle events. Although phosphorylation is thought to regulate protein function by inducing conformational changes, little is known about most of these conformational changes and their significance. Recent studies indicate that the conformation and function of a subset of these phosphorylated proteins are controlled by the prolyl isomerase Pin1 through isomerization of specific phosphorylated Ser/Thr‐Pro bonds. Furthermore, (...) compelling evidence supports the idea that proline‐directed phosphorylation and subsequent isomerization play a critical role not only in cell cycle control, but also in the development of Alzheimer's disease, where postmitotic neurons display various cell cycle markers, especially mitotic events, prior to degeneration. BioEssays 25:174–181, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The DNase I hypersensitive sites (DHSs) of chromatin constitute one of the best landmarks of eukaryotic genes that are poised and/or activated for transcription. For over 35 years, the high‐mobility group nucleosome‐binding chromosomal proteins HMGN1 and HMGN2 have been shown to play a role in the establishment of these chromatin‐accessible domains at transcriptional regulatory elements, namely promoters and enhancers. The critical presence of HMGNs at enhancers, as highlighted by a recent publication, suggests a role for them in the structural and (...) functional fine‐tuning of the DHSs in vertebrates. As we review here, while preferentially out‐competing histone H1 binding and invading neighbor nucleosomes, HMGNs may also modulate histone H3 at serine 10 (H3S10ph), which plays an important role in enhancer function and transcriptional initiation. (shrink)

Methionine aminopeptidases with a universal specificity have been revealed from the sequences of the amino‐terminal region of mutant forms of yeast iso‐1‐cytochrome c and from a systematic examination of the literature for amino‐terminal sequences formed at initiation sites. The aminopeptidase removes amino‐terminal residues of methionine when they precede certain amino acids, with a specificity that appears to be determined mainly by the residue adjacent to the methionine residue at the amino terminus. The result with the mutationally altered iso‐1‐cytochromes c and (...) the results from published sequences of other proteins from a wide range of prokaryotes and eukaryotes suggest that the aminopeptidase usually cleaves amino‐terminal methionine when it precedes residues of alanine, cysteine, glycine, proline, serine, threonine and valine but not when it precedes residues of arginine, asparagine, aspartic acid, glutamine, glutamic acid, isoleucine, leucine, lysine or methionine. We suggest that the specificity is almost always determined simply by the size of the side chain of the penultimate residue; methionine is usually cleaved from residues with a side chain having a radius of gyration of 1·29 Å or less, but is not cleaved from residues with larger side chains. (shrink)

Significant advances have recently been made in our understanding of the mechanisms of activation of proteins that require processing. Often this involves endoproteolytic cleavage of precursor forms at basic residues, and is carried out by a group of serine endoproteinases, termed the proprotein convertases. In mammals, seven different convertases have been identified to date. These act in both the regulated secretory pathway for the processing of prohormones and proneuropeptides and in the constitutive secretory pathway, in which a variety of (...) proproteins are activated endoproteolytically. The recently completed sequence of the nematode Caenorhabditis elegans genome affords a unique opportunity to examine the entire proprotein convertase family in a multicellular organism. Here we review the nature of the family, emphasising the structural features, characteristic of the four nematode genes, that supply all of the necessary functions unique to this group of serine endoproteinases. Studies of the C. elegans genes not only provide important information about the evaluation of this gene family but should help to illuminate the roles of these proteins in mammalian systems. BioEssays 22:545–553, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Epithelial development dictates the shape of an organism. The metamorphic development of a Drosophila leg precursor into an adult leg is a well‐defined example of epithelial morphogenesis that can be analyzed from the perspectives of genetics and molecular and cell biology. The steroid hormone 20‐hydroxyecdysone induces and regulates the entire process. Mutants affecting Drosophila leg morphogenesis characteristically have short thick legs (the malformed phenotype) resulting from a failure to execute normal cell shape changes at a specific stage of development. Mutations (...) that cause the malformed phenotype have already led to the identification and cloning of genes encoding transcription factors, a transmembrane serine protease presumably required for modification of the apical extracellular matrix, and components of the contractile cytoskeleton and adherens junctions. All of these products are required for the execution of normal changes in leg cell shape. (shrink)

Three recent reports (1–3) identify two genes, thick veins (tkv) and saxophone (sax), which encode serine/threonine transmembrane proteins that act as receptors for mediating different aspects of the Drosophila TGF‐β‐related signal, dpp. tkv is required for patterning the entire embryonic dorsal region, while sax is required for patterning only amnioserosa, the dorsalmost cell fates. dpp signaling in other developmental processes again requires both tkv and sax, but to differing degrees. tkv and sax, encode type I receptors, which appear to (...) directly bind ligand, unlike what has been observed for other type I receptors. (shrink)

The integrins are receptors for proteins of the extracellular matrix, both providing a physical link to the cytoskeleton and transducing signals from the extracellular matrix. Activation of integrins leads to tyrosine and serine phosphorylation of a number of proteins, elevation of cytosolic calcium levels, cytoplasmic alkalinization, changes in phospholipid metabolism and, ultimately, changes in gene expression. The recently discovered focal adhesion kinase localizes to focal contacts, which are sites of integrin clustering, and focal adhesion kinase can physically associate with (...) integrins in vitro. As integrins lack intrinsic catalytic activity, focal adhesion kinase is a candidate for a signaling molecule that is recruited by integrins in order to trigger the generation of intracellular second messengers. Thus, focal adhesion kinase may play a central role in signal transduction through integrins. (shrink)

Site‐specific phosphorylation of intermediate filament (IF) proteins on serine and threonine residues leads to alteration of the filament structure, in vitro and in vivo. Protein kinases involved in cell signaling and those activated in mitosis dynamically control spatial and temporal organization of intracellular IF phosphorylation. Thus, IF phosphorylation appears to be one of the most predominant strategies in coordinating intracellular organization of the IF network.

Metabolic Syndrome is a cluster of risk factors (including obesity, hypertension and insulin resistance), which is associated with late‐onset diabetes and coronary heart disease. Elevated levels of the protease inhibitor PAI‐1 are well‐known molecular markers of the Metabolic Syndrome. Here, however, we present a hypothesis that PAI‐1 acts as a causative factor in the development of Metabolic Syndrome and its clinical sequelae. We propose that PAI‐1 inhibits the activity of members of the proprotein convertase (PC) class of serine proteases (...) and that this underlies, at a molecular level, many of the other features of the Metabolic Syndrome cluster. BioEssays 28: 629–641, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Courtesans and Tantric Consorts: Sexualities in Buddhist Narrative, Iconograhy, and RitualRita M. GrossCourtesans and Tantric Consorts: Sexualities in Buddhist Narrative, Iconograhy, and Ritual. By Serinity Young. New York and London: Routledge, 2004. 256 pp.This book is a welcome addition to the growing literature on Buddhism and gender. It presents information and explores issues on this topic in new and innovative ways. It is also well researched and well (...) written. Part of Young's innovation is her use of Buddhist art and iconography, which she takes as seriously as textual sources are usually taken in Buddhist studies. Many of her most interesting suggestions and conclusions result from the seriousness with which she takes Buddhist art as resource for understanding Buddhism more accurately and completely. The other foci are clear from her subtitle: narrative and ritual. There is much less attention to the canonical and philosophical texts of Buddhism that are so often invoked in studies of Buddhism and gender.Studies of sexuality or gender often end up primarily discussing new information about women and new ways of understanding women's participation in or exclusion from religion. This study is no exception, which is not in any way to fault the book. Young's analyses center on ways that women have been both included in the Buddhist world and excluded from that world. Among the many varieties of Buddhism, Young primarily focuses on early Indian Buddhism and Tantric Buddhism, which have the most provocative teachings about gender and sexuality. In Young's analyses, we see how women participated in early Buddhism in ways that have not been recognized in most earlier scholarship and ways in which they are excluded from Tantric Buddhism and most later forms of Buddhism that have not always been acknowledged.Young's interpretations of the traditional life stories of the Buddha are extremely innovative and interesting. She argues that the future Buddha's rejection of women when he left his home and family must be balanced with his reintegration into the world of women before and during his enlightenment experience. She argues that this reintegration is evidenced especially in his acceptance of food from Sujata and in the help he received from the Earth Goddess during his trials with Mara. Young argues that many Buddhists throughout the ages have focused on episodes in his life that deal with rejection of women but have not fully taken in the implications of the stories in which women become important allies in the mission of the Buddha.The sources for early Indian Buddhism most invoked by Western scholars of Buddhism are textual. These textual sources present a very mixed picture of women's lot in early Indian Buddhism. On the one hand, the Therigatha and some stories from the life of the Buddha present a relatively optimistic picture of women's possibilities and their acceptance in the early Buddhist community. On the other hand, texts present a constant message of the importance of renunciation, and much of the recommended renunciation involves women. Texts written by and for monks frequently conflate women with sexuality and hold women responsible for wayward monks' sexual temptations. Against this widely known material, Young calls upon the evidence of early Indian Buddhist art to argue that the monks' anti-women texts [End Page 174] do not tell the whole story about women in early Indian Buddhism. The art work, which was much more important for tutoring largely illiterate Buddhist laypeople, consistently portrays women voluptuously and positively. This contrast between text and art is so great that recently, during a slide show in a class I taught on ancient Indian Buddhism, a student asked point blank how monks could possibly sanction the voluptuous portrayals of women common in early Indian Buddhist sanctuaries. I didn't remember Young's cogent analysis at first, but eventually did reply, using her analysis. The monastic establishment controlled the discourse that eventually became the texts of early Buddhism, but the lay donors controlled the visual representations that decorated the sites where Buddhism was preserved. The lay donors were more than happy to represent the fecundity and beauty of women, without whom there would be no future donors or... (shrink)

Rho, a member of the Ras superfamily of small GTPases, has multiple biological roles: it regulates signal trasduction pathways linking extracellular growth factors to the assembly of actin stress fibres and focal adhesion complexes; it is required for G1 progression and activates the SRF transcription factor when quiescent fibroblasts are stimulated to grow; and it plays a role later in the cell cycle during cytokinesis. Two groups have recently succeeded in identifying downstream effectors of Rho that may mediate some of (...) these biological effects. One protein identified by both groups is protein kinase N (PKN), a serine/threonine kinase whose catalytic domain is closely related to that of protein kinase C(1,2). (shrink)

Recent evidence indicates that the presence of serine proteinase inhibitors in plant leaves can reduce predation by insects. Plants can now be transformed with proteinase inhibitor genes with strong promoters to express the inhibitor proteins in relatively high levels at specific times. Inhibitors having variable specificities against digestive proteinases of insects and pathogens can now be assessed for their possible role(s) in natural plant defense and for their potential usefulness in protecting crop plants against herbivores.

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)

Many functional glycoproteins are expressed on the lymphocyte cell surface. Some of them carry O-linked oligosaccharides (O-glycans), which are conjugated through serine or threonine residues. During various biological processes, including T-cell activation, a tetrasaccharide on the T-cell surface is dramatically converted to a branched hexasaccharide, called core2 O-glycan. The same structural change in O-glycans is also found on the lymphocytes from patients with immunodeficiency conditions such as Wiskott-Aldrich syndrome and AIDS. Several studies revealing the roles of core2 O-glycans in (...) immune responses show that this is a biologically significant change. In particular, core2 O-glycans expressed on the cell surface reduce cell–cell interactions, thereby regulating immune responses. Furthermore, core2 O-glycan is a key backbone structure in forming selectin ligands. Thus, O-linked oligosaccharides, in particular those containing core2 branches, play vital roles in immune responses and may play dual roles in certain situations. This review will summarize the results obtained from various studies investigating the roles of O-glycans in immunological processes. BioEssays 23:46–53, 2001. © 2001 John Wiley & Sons, Inc. (shrink)