Biomedicine and Diseases: Review¶Assembling the human immunodeficiency virus type 1

Retroviral assembly proceeds through a series of concerted events that lead to the formation and release of infectious virion particles from the infected cell. Upon translation, structural proteins are targeted to the plasma membrane where they accumulate. There, the nascent particle forces the plasma membrane to form a bud, which pinches off releasing the virion particle from the cell. In this review we describe the molecular mechanisms now known to be behind the process of virion assembly. In particular, we focus on the human immunodeficiency virus type 1, the prototype member of the lentivirus subfamily of the Retroviridae.     

Contributions in the domain of cancer research: Review¶Negative regulators of cyclin-dependent kinases and their roles in cancers

In the past decade, the discovery and characterization of cyclin-dependent kinases (CDKs), the engine cores of the cell cycle machinery, have advanced our understanding of the cell cycle. Both positive and negative regulators of CDKs have been characterized, accelerating the important research to unravel the mechanisms of the cell cycle disease--cancer. Cancer can originate from overexpression of positive regulators, such as cyclins, or from underexpression of negative regulators, such as CDK inhibitors (CKIs). CKIs are the focus of much cancer research because they are capable of controlling cell cycle proliferation--the Holy Grail for cancer treatment. CDKs can be inactivated by several mechanisms:, (i) by association with CKIs including p16 (INK4a), p15 (INK4b), p21 (Cip1), p27 (Kip1), and p57 (Kip2), (ii) by disassociation from their cyclin regulatory unit, (iii) by dephosphorylation of a conserved threonine residue in the T-loop, and (iv) by adding inhibitory phosphate. Here we discuss what is known about each mechanism with a hope that these insights will become useful in developing strategies to eliminate cancer in the future.     

Contributions in the domain of cancer research: Review¶Human papillomaviruses and their role in cervical cancer

Human papillomaviruses (HPVs) have been linked to a variety of human diseases, most notably cancer of the cervix, a disease responsible for at least 200,000 deaths per year worldwide. Over 100 different types of HPV have been identified and these can be divided into two groups. Low-risk HPV types are the causative agent of benign warts. High-risk HPV types are associated with cancer. This review focuses on the role of high-risk HPV types in cervical tumorigenesis. Recent work has uncovered new cellular partners for many of the HPV early proteins and thrown light on many of the pathways and processes in which these viral proteins intervene. At the same time, structural and biochemical studies are revealing the molecular details of viral protein function. Several of these new avenues of research have the potential to lead to new approaches to the treatment and prevention of cervical cancer.     

Human Genome and Diseases:¶The molecular pathogenesis of the Marfan syndrome

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a range of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS and other related disorders of connective tissue collectively termed type-1 fibrillinopathies. Fibrillin-1 is a main component of the 10- to 12-nm extracellular microfibrils that are important for elastogenesis, elasticity, and homeostasis of elastic fibers. Mutations in fibrillin-1 are hypothesized to exert their effects by dominant negative mechanisms, but recent work has also emphasized the potential role of proteases and disturbances in tissue homeostasis in the pathogenesis of the MFS. This article provides an overview of the clinical aspects of the MFS and current thinking on the pathogenesis of this disorder.     

Epigenetic dysregulation of brainstem nuclei in the pathogenesis of Alzheimer’s disease: looking in the correct place at the right time?

Even though the etiology of Alzheimer’s disease (AD) remains unknown, it is suggested that an interplay among genetic, epigenetic and environmental factors is involved. An increasing body of evidence pinpoints that dysregulation in the epigenetic machinery plays a role in AD. Recent developments in genomic technologies have allowed for high throughput interrogation of the epigenome, and epigenome-wide association studies have already identified unique epigenetic signatures for AD in the cortex. Considerable evidence suggests that early dysregulation in the brainstem, more specifically in the raphe nuclei and the locus coeruleus, accounts for the most incipient, non-cognitive symptomatology, indicating a potential causal relationship with the pathogenesis of AD. Here we review the advancements in epigenomic technologies and their application to the AD research field, particularly with relevance to the brainstem. In this respect, we propose the assessment of epigenetic signatures in the brainstem as the cornerstone of interrogating causality in AD. Understanding how epigenetic dysregulation in the brainstem contributes to AD susceptibility could be of pivotal importance for understanding the etiology of the disease and for the development of novel diagnostic and therapeutic strategies.     

Introduction: p53 – the first twenty years

The p53 protein was discovered 20 years ago, as a cellular protein tightly bound to the large T oncoprotein of the SV40 DNA tumour virus. Since then, research on p53 has developed in many exciting and sometimes unexpected directions. p53 is now known to be the product of a major tumour suppressor gene that is the most common target for genetic alterations in human cancer. The nonmutated wild-type p53 protein (wtp53) is often found within cells in a latent state and is activated in response to various intracellular and extracellular signals. Activation involves an increase in overall p53 protein levels, as well as qualitative changes in the protein. Upon activation, wtp53 can induce a variety of cellular responses, most notable among which are cell cycle arrest and apoptosis. To a great extent, these effects are mediated by the ability of p53 to activate specific target genes. In addition, the p53 protein itself possesses biochemical functions which may facilitate DNA repair as well as apoptosis. The role of p53 in normal development and particularly in carcinogenesis has been elucidated in depth through the use of mouse model systems. The insights provided by p53 research over the years are now beginning to be utilized towards better diagnosis, prognosis and treatment of cancer.     

Introduction to the special issue Hermann Weyl and the philosophy of the ‘New Physics’

This Special Issue Hermann Weyl and the Philosophy of the ‘New Physics’ has two main objectives: first, to shed fresh light on the relevance of Weyl's work for modern physics and, second, to evaluate the importance of Weyl's work and ideas for contemporary philosophy of physics. Regarding the first objective, this Special Issue emphasizes aspects of Weyl's work (e.g. his work on spinors in n dimensions) whose importance has recently been emerging in research fields across both mathematical and experimental physics, as well as in the history and philosophy of physics. Regarding the second objective, this Special Issue addresses the relevance of Weyl's ideas regarding important open problems in the philosophy of physics, such as the problem of characterizing scientific objectivity and the problem of providing a satisfactory interpretation of fundamental symmetries in gauge theories and quantum mechanics. In this Introduction, we sketch the state of the art in Weyl studies and we summarize the content of the contributions to the present volume.     

Reflecting ‘Popular Culture’: The Introduction,Diffusion, and Construction of the Reflecting Telescope in the Netherlands

The eighteenth century was an era in which science came to play a major role in the cultural ideal of the city elite. The phenomenon of the ‘gentleman-scientist’ arose: a layman without a scientific education who for a variety of often socially desirable reasons devoted himself to scientific endeavours. Scientific instruments were the tools for this interest. This article describes the introduction, diffusion, and construction in the Netherlands of one of the most prominent eighteenth-century instruments: the reflecting telescope. The reception of this instrument casts new light on the usually almost invisible network of gentleman-scientists and instrument-makers in this region. The specific economic and political factors of the Netherlands led to a totally different development of this instrument compared with the ‘motherland’ England. Whereas in Great Britain the reflecting telescope was a great success well into the nineteenth century, in the Netherlands it became a symbol of technical inability and stagnation.     

Epigenetic tinkering and evolution: is there any continuity in the role of cytosine methylation from invertebrates to vertebrates?

The function of DNA methylation has been investigated in depth in vertebrate and plant genomes, establishing that it is involved in gene silencing and transposon control. Data regarding insect methylation, even if still scanty, apparently argue against evolutionary conservation of DNA methylation functions. Cytosine methylation, therefore, proves to be an epigenetic tool repeatedly used to accomplish different functions in different taxa according to a sort of epigenetic tinkering occurring during evolution.     

Purification of α-ketoaldehyde dehydrogenase from the human liver and its possible significance in the control of glycation

Summary Alfa-ketoaldehyde dehydrogenase, which was extracted and purified from human livers, may act on carbonyl compounds, such as 3-deoxyglucosone, and be involved in the control of glycation (Maillard reaction) in the body.     

α-Endosulfine, a new entity in the control of insulin secretion

ATP-dependent potassium (K_ATP) channels occupy a key position in the control of insulin release from the pancreatic β cell since they couple cell polarity to metabolism. These channels close when more ATP is produced via glucose metabolism. They are also controlled by sulfonylureas, a class of drugs used in type 2 diabetic patients for triggering insulin secretion from β cells that have lost part of their sensitivity to glucose. We have demonstrated the existence of endogenous counterparts to sulfonylureas which we have called ‘endosulfines.’ In this review, we describe the discovery, isolation, cloning, and biological features of the high-molecular-mass form, α-endosulfine, and discuss its possible role in the physiology of the β cell as well as in pathology. Received 1 February 1999; received after revision 26 March 1999; accepted 26 March 1999     

Dissection of the molecular mechanisms that control the nuclear accumulation of transport factors importin-α and CAS in stressed cells

The physiological state of eukaryotic cells controls nuclear trafficking of numerous cargos. For example, stress results in the inhibition of classical protein import, which is characterized by the redistribution of several transport factors. As such, importin-alpha and cellular apoptosis susceptibility protein (CAS) accumulate in nuclei of heat-shocked cells; however, the mechanisms underlying this relocation are not fully understood. We now show that heat upregulates the initial docking of importin-alpha at the nuclear envelope and stimulates the translocation of CAS into the nuclear interior. Moreover, heat exposure compromises the exit of importin-alpha from nuclei and drastically increases its retention in the nucleoplasm, whereas CAS nuclear exit and retention are less affected. Taken together, our results support the idea that heat shock regulates importin-alpha and CAS nuclear accumulation at several levels. The combination of different stress-induced changes leads to the nuclear concentration of both transport factors in heat-stressed cells.     

A specialized mitochondrial molecular chaperone system:¶A role in formation of Fe/S centers

Mitochondria contain a specialized system of molecular chaperones that plays a critical role in the biogenesis of Fe/S centers. This Hsp70:J-protein system shows many similarities to the system found in bacteria, but the precise role of neither chaperone system has been defined. However, evidence to date suggests an interaction with the scaffold protein on which a transient Fe/S center is assembled, and thus implies a role in either assembly of the center or its transfer to recipient proteins.     

State of the field: Are the results of science contingent or inevitable?

This paper presents a survey of the literature on the problem of contingency in science. The survey is structured around three challenges faced by current attempts at understanding the conflict between “contingentist” and “inevitabilist” interpretations of scientific knowledge and practice. First, the challenge of definition: it proves hard to define the positions that are at stake in a way that is both conceptually rigorous and does justice to the plethora of views on the issue. Second, the challenge of distinction: some features of the debate suggest that the contingency issue may not be sufficiently distinct from other philosophical debates to constitute a genuine, independent philosophical problem. And third, the challenge of decidability: it remains unclear whether and how the conflict could be settled on the basis of empirical evidence from the actual history of science. The paper argues that in order to make progress in the present debate, we need to distinguish more systematically between different expressions that claims about contingency and inevitability in science can take. To this end, it introduces a taxonomy of different contingency and inevitability claims. The taxonomy has the structure of an ordered quadruple. Each contingency and each inevitability claim contains an answer to the following four questions: (how) are alternatives to current science possible, what types of alternatives are we talking about, how should the alternatives be assessed, and how different are they from actual science?     

Good, bad or offal? The evaluation of raw pancreas therapy and the rhetoric of control in the therapeutic trial, 1925

In 1925 a debate erupted in the correspondence columns of the British Medical Journal concerning the effectiveness of eating raw pancreas as a treatment for diabetes. Enthusiasts were predominantly general practitioners (GPs), who claimed success for the therapy on the basis of their clinical impressions. Their detractors were laboratory-oriented 'biochemist-physicians,' who considered that their own experiments demonstrated that raw pancreas therapy was ineffective. The biochemist-physicians consistently dismissed the GPs' observations as inadequately 'controlled'. They did not define the meaning of 'control' in this context, although it clearly did not have the term's present-day meaning of a trial employing an untreated comparison group of patients. Rather, the physician-biochemists' 'properly controlled' experiments involved careful regulation of their patients' diet and other environmental factors, and evaluation of the therapy's success through biochemical, rather than just clinical, criteria. However, my analysis suggests that these factors alone are inadequate to account for the biochemist-physicians' dismissal of the GPs' work as 'uncontrolled'. I suggest that the biochemist-physicians were deliberately exploiting the powerful rhetorical connotations of the term 'control'. Ultimately, they implied that only a trial which they themselves had conducted could be deemed 'adequately controlled'.