The cell theory--history, present state and prospects (on the 150th anniversary of the development of the cell theory)

The main stages of history of this most important biological conception are presented and the state of the modern cell theory and its future prospects are considered. Since 1839, when T. Schwann expounded his conception of the cell, a long pathway in cognition of the cell function and organization has been covered. From the original picture of the complex organism as a "cellular state", made up of relatively independent "elementary organisms", i.e. cells the modern biology has come to the idea of the cell as an integral system either being a part of a complex organism, or living free in the nature (protists). The cell represents certain qualitatively peculiar level in a complex evolutionary established hierarchy of biological systems. Some particular tight relations, existing between cytology, as a fundamental biological science and molecular biology, genetics, ecology and other biological disciplines are considered. The importance of the cell conception is ascertained for practical aims, especially in medicine.     

Health as Normal Function: a Weak Link in Daniels's Theory of Just Health Distribution

Drawing on Christopher Boorse's Biostatistical Theory (BST), Norman Daniels contends that a genuine health need is one which is necessary to restore normal functioning – a supposedly objective notion which he believes can be read from the natural world without reference to potentially controversial normative categories. But despite his claims to the contrary, this conception of health harbors arbitrary evaluative judgments which make room for intractable disagreement as to which conditions should count as genuine health needs and therefore which needs should be met. I begin by offering a brief summary of Boorse's BST, the theory to which Daniels appeals for providing the conception of health as normal functioning upon which his overall distributive scheme rests. Next, I consider what I call practical objections to Daniels's use of Boorse's theory. Finally I recount Elseljin Kingma's theoretical objection to Boorse's BST and discuss its impact on Daniels's overall theory. Though I conclude that Boorse's view, so weakened, will no longer be able to sustain the judgments which Daniels's theory uses it to reach, in the end, I offer Daniels an olive branch by briefly sketching an alternative strategy for reaching suitably objective conclusions regarding the health and/or disease status of various conditions.     

A network theory of mental disorders

In recent years, the network approach to psychopathology has been advanced as an alternative way of conceptualizing mental disorders. In this approach, mental disorders arise from direct interactions between symptoms. Although the network approach has led to many novel methodologies and substantive applications, it has not yet been fully articulated as a scientific theory of mental disorders. The present paper aims to develop such a theory, by postulating a limited set of theoretical principles regarding the structure and dynamics of symptom networks. At the heart of the theory lies the notion that symptoms of psychopathology are causally connected through myriads of biological, psychological and societal mechanisms. If these causal relations are sufficiently strong, symptoms can generate a level of feedback that renders them self‐sustaining. In this case, the network can get stuck in a disorder state. The network theory holds that this is a general feature of mental disorders, which can therefore be understood as alternative stable states of strongly connected symptom networks. This idea naturally leads to a comprehensive model of psychopathology, encompassing a common explanatory model for mental disorders, as well as novel definitions of associated concepts such as mental health, resilience, vulnerability and liability. In addition, the network theory has direct implications for how to understand diagnosis and treatment, and suggests a clear agenda for future research in psychiatry and associated disciplines.     

The Ideological Bases of Lévi-Strauss's Structuralism

It is clear that Lévi-Strauss combines in his writings, and often inextricably, the roles of anthropologist (read scientist) and philosopher (read ideologist). This rather unusual combination of anthropological and philosophical dimensions of Lévi-Strauss's thought is the result of two tendencies that often seem to be pulling in different directions: his scientific conception of socio-cultural phenomena (or the delineation of a scientific method for harnessing human behavior under the rubric of sociological laws), on the one hand, and his conception of what society should be (or the ideological statement of what constitutes a "good sociological life"), on the other. In order to understand the nature of structuralism and Lévi-Strauss's contributions to anthropological theory and practice, these two aspects of his thought must be clearly distinguished. This is what I hope to accomplish in this article.     

The galenic and hippocratic challenges to Aristotle's conception theory

Conclusion As a result of this case study, additional questions arise. These can be cast into at least three groups. The first concerns the development of critical empiricism in the ancient world: a topic of much interest in our own century, expecially with regard to the work of the logical empiricists. Many of the same arguments are present in the ancient world and were hotly debated from the Hippocratic writers through and beyond Galen. Some of the ways in which Galen reacts to Hippocratic and Aristotelian influences may, in part, be explained by Galen's own posture as a so-called Dogmatist. Both the Empirics and the Methodists offered alternative viewpoints on the place, role, and limits of observation in biomedical research. Though I have written on this relationship in the Hippocratic writers and Aristotle,⁴⁴ it remains to be discussed in detailed fashion just how critical empiricism acted in Galen's evaluation of biomedical problems (aporiai). Contrasts between Galen and his predecessors might further clarify this issue both as a historical question and as it affects the construction of biological theory.The second area explores the question of how one develops comprehensive theories. In this respect Galen follows Aristotle's methodology rather closely. Both look at what theories are available to them and then systematically review the problems raised, at the same time refuting what they find inadequate. This is an effective strategy, for it permits utilizing the best features of earlier work to fashion a new whole. Indeed, Galen himself seems to attribute his use of such a methodology to his ecletic medical and philosophical training. Both Aristotle and Galen endeavor to employ techniques of theory integration. That is, they use aspects of theories they have already espoused to deal with new problems. This suggests the emergence of formal, logical coherence as an element in theory evaluation. The obvious drawback is that it can cause mistakes in one area to be repeated and ingrained in other areas. Such errors, because they are at the very core of an explanatory framework, may take centuries to correct. Future studies may shed light on how theory integration acts both in a positive and in a negative way.Finally, this case study offers a glimpse of how science progresses. Even though the advances in medical technology were comparatively minor, there is a great deal more sophistication in the conception theoreis of Aristotle and Galen than was present in the Hippocratic writers. Some of this (in Galen's case) had to do with increased anatomic and physiological knowledge, but most, I believe, is due to the evolution of scientific knowledge. If further work were done specifically on this question, it might document more completely how scientific knowledge on a specific topic evolves. The mode of advancement is primarily through gradual refinement of the types of questions being asked by these ancient authors, and the ramifications of their answers.Ancient theories of conception offer a fine case study in the history and philosophy of how a theory begins the develops. I have tried to suggest some interrelationships among the more important theories, as they focused upon Aristotle's own conception theory. There has been renewed interest in such cases in recent years. It is my hope that future specialized studies will increase our knowledge of method and practice in these important case studies and thereby augment our understanding of the genesis and application of biological theories.     

Characteristics of the autonomic regulation in humans with different susceptibility to cold

To determine the strained adaptation to cold, the cardiovascular reactivity under local cold exposure and the characteristics of regulation of the circulatory system in persons with high individual susceptibility to cold was studied. It was shown that the subjective characteristics of high susceptibility to cold in the form of initial symptoms of Raynaud’s phenomenon correlated with the symptoms of aggravated and generalized cold-induced vasoconstriction (CIV) during the local cold test. The analysis of the heart rate variability (HRV) in persons with aggravated CIV revealed a decrease in the parameters of the time-domain characteristics of HRV (RRNN, SDNN, RMSSD, pNN₅₀, and coefficient of variation) as well as a decrease in the total power (TP) of the frequency-domain characteristics and the absolute values of the frequency bands (VLF, LF, and HF) with a relative increase of the LF component. This reflects possible changes in the autonomic regulation of the cardiovascular system, which manifest themselves in a reduced contribution of reflectory mechanisms to the heart rate regulation followed by relative predominance of baroreflex regulation. The diagnostic value of aggravated cold-induced vasoconstriction in identifying disorders of adaptation to cold or premorbid state of the cardiovascular system is discussed.     

Control of tissue homeostasis,tumorigenesis, and degeneration by coupled bidirectional bistable switches

The Hippo-YAP/TAZ signaling pathway plays a critical role in tissue homeostasis, tumorigenesis, and degeneration disorders. The regulation of YAP/TAZ levels is controlled by a complex regulatory network, where several feedback loops have been identified. However, it remains elusive how these feedback loops contain the YAP/TAZ levels and maintain the system in a healthy physiological state or trap the system in pathological conditions. Here, a mathematical model was developed to represent the YAP/TAZ regulatory network. Through theoretical analyses, three distinct states that designate the one physiological and two pathological outcomes were found. The transition from the physiological state to the two pathological states is mechanistically controlled by coupled bidirectional bistable switches, which are robust to parametric variation and stochastic fluctuations at the molecular level. This work provides a mechanistic understanding of the regulation and dysregulation of YAP/TAZ levels in tissue state transitions.     

Expanding role for the apelin/APJ system in physiopathology

Apelin is a bioactive peptide known as the ligand of the G protein-coupled receptor APJ. Diverse active apelin peptides exist under the form of 13, 17 or 36 amino acids, originated from a common 77-amino-acid precursor. Both apelin and APJ mRNA are widely expressed in several rodent and human tissues and have functional effects in both the central nervous system and peripheral tissues. Apelin has been shown to be involved in the regulation of cardiovascular functions, fluid homeostasis, vessel formation and cell proliferation. More recently, apelin has been described as an adipocyte-secreted factor (adipokine), up-regulated in obesity. By acting as circulating hormone or paracrine factor, adipokines are involved in physiological regulations (fat depot development, energy storage, metabolism or eating behavior) or in the promotion of obesity-associated disorders (type 2 diabetes and cardiovascular dysfunctions). In this regard, expression of apelin gene in adipose tissue is increased by insulin and TNFalpha. This review will consider the main roles of apelin in physiopathology with particular attention on its role in energy balance regulation and in obesity-associated disorders.     

Internet access

A 65-year-old man undergoes a routine checkup before retiring. His wife has urged him to have his prostate examined, because she has read about testing for prostate cancer and a friend has just died of this disease. During the rectal examination, the man''s physician discovers some firmness in the right lobe of the prostate gland. The patient has had no urinary symptoms and is in excellent general health. Sexual function is normal. There is no history of prostate cancer; his father died of a stroke at age 86 years. Testing shows that the patient''s prostate-specific antigen level is 9.3 ng/mL, and he is referred to a urologist. Transrectal ultrasound-guided needle biopsy reveals adenocarcinoma with a Gleason score of 7 (intermediate grade). At a follow-up meeting with his physician, the patient says, "I have been doing some research, and it appears that I should have treatment. However, what is less clear to me is what form of therapy is best--surgery or radiation treatment. Please tell me what you can about the state of the art with respect to surgery."     

Targeting ubiquitin specific proteases for drug discovery

Deregulation of the ubiquitin-proteasome system has been implicated in the pathogenesis of many human diseases, including cancer, neurodegenerative disorders and viral diseases. The recent approval of the proteasome inhibitor bortezomib (Velcade) for the treatment of multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to interact at the level of the upstream, ubiquitin conjugation/deconjugation system to generate more specific, less toxic anticancer agents. Ubiquitin specific proteases (USP) are de-ubiquitinating enzymes which remove ubiquitin from specific protein substrates and allow protein salvage from proteasome degradation, regulation of protein localization or activation. Due to their protease activity and their involvement in several pathologies, USPs are emerging as potential target sites for pharmacological interference in the ubiquitin regulatory machinery. We will review here this class of enzymes from target validation to small molecule drug discovery.     

The Tragedy of a priori Selectionism: Dennett and Gould on Adaptationism

In his recent book on Darwinism, Daniel Dennett has offered up a species of a priori selectionism that he calls algorithmic. He used this view to challenge a number of positions advocated by Stephen J. Gould. I examine his algorithmic conception, review his unqualified enthusiasm for the a priori selectionist position, challenge Dennett's main metaphors (cranes vs. skyhooks and a design space), examine ways in which his position has lead him to misunderstand or misrepresent Gould (spandrels, exaptation, punctuated equilibrium, contingency and disparity), and discuss recent results in developmental biology that suggest that an a priori position does not fill the demands of an evolutionary biology. I conclude by insisting that evolutionary biology is many leveled, complicated, and is carried on an ever shifting and expanding empirical base that when disregarded results in caricature.     

The Unabomber’s ethics

In this paper, I present and criticize Ted Kaczynski’s (“The Unabomber”) theory that industrialization has been terrible for humanity, and that we should use any means necessary, including violent means, to induce a return to pre‐industrial ways of living. Although Kaczynski’s manifesto, Industrial society and its future, has become widely known, his ideas have never before been subject to careful philosophical criticism. In this paper I show how Kaczynski’s arguments rely on a number of highly implausible philosophical premises. I further make the case that, although his theory as a whole should be rejected, Kaczynski raises a number of worries about technological development that ought to receive serious attention. Some of these worries have recently come to be shared by prominent defenders of human enhancement, including Nick Bostrom and Julian Savulescu. In the last section I indicate why I believe it is important that academic philosophers scrutinize ideas that motivate acts of violence.     

Menstrual cycle phase alters women's sexual preferences for composers of more complex music

Over 140 years ago Charles Darwin first argued that birdsong and human music, having no clear survival benefit, were obvious candidates for sexual selection. Whereas the first contention is now universally accepted, his theory that music is a product of sexual selection through mate choice has largely been neglected. Here, I provide the first, to my knowledge, empirical support for the sexual selection hypothesis of music evolution by showing that women have sexual preferences during peak conception times for men that are able to create more complex music. Two-alternative forced-choice experiments revealed that woman only preferred composers of more complex music as short-term sexual partners when conception risk was highest. No preferences were displayed when women chose which composer they would prefer as a long-term partner in a committed relationship, and control experiments failed to reveal an effect of conception risk on women''s preferences for visual artists. These results suggest that women may acquire genetic benefits for offspring by selecting musicians able to create more complex music as sexual partners, and provide compelling support for Darwin''s assertion ‘that musical notes and rhythm were first acquired by the male or female progenitors of mankind for the sake of charming the opposite sex’.     

The neutral theory of molecular evolution and the world view of the neutralists

The main tenet of the neutral theory is that the great majority of evolutionary changes at the molecular level are caused not by Darwinian selection but by random fixation of selectively neutral (or very nearly neutral) alleles through random sampling drift under continued mutation pressure. The theory also asserts that the majority of protein and DNA polymorphisms are selectively neutral, and that they are maintained in the species by mutational input balanced by random extinction rather than by "balancing selection." The neutral theory is based on simple assumptions. This enabled us to develop mathematical theories (using the diffusion equation method) that can treat these phenomena in quantitative terms and that permit theory to be tested against actual observations. Although the neutral theory has been severely criticized by the neo-Darwinian establishment, supporting evidence has accumulated over the last 20 years. In particular, the recent burst of DNA sequence data helped to strengthen the theory a great deal. I believe that the neutral theory triggered reexamination of the traditional "synthetic theory of evolution." In this paper, I review the present status of the neutral theory, including discussions of such topics as "molecular evolutionary clock," very high evolutionary rates observed in RNA viruses, a deviant coding system found in Mycoplasm together with the concept of mutation-driven neutral evolution, and the origin of life. I also present a worldview based on the conception of what I call "survival of the luckiest."     

Effect of oxygen on activation state of complex I and lack of oxaloacetate inhibition of complex II in Langendorff perfused rat heart

Two main entry points for electrons into the mitochondrial respiratory chain are NADH:ubiquinone oxidoreductase (complex I) and succinate:ubiquinone oxidoreductase (complex II). Metabolic regulation of these two respiratory complexes is not understood in detail. It has been suggested that the Krebs cycle metabolic intermediate oxaloacetate (OAA) inhibits complex II in vivo, whereas complex I undergoes a reversible active/de-active transition. In normoxic and anoxic hearts it has been shown that the proportion of complex I in the active and de-active states is different suggesting a possible mode of regulation of the enzyme by oxygen concentration. In the current studies rapid isolation of mitochondrial membranes in a state that preserves the activity of both complex I and complex II has been achieved using Langendorff perfused rat hearts. The findings indicate that the state of activation of complex I is controlled by the oxygen saturation in the perfusate. In addition, these studies show that complex II is fully active in the mitochondrion and not inhibited by OAA regardless of the oxygen concentration.     

DNA supercoiling in Escherichia coli is under tight and subtle homeostatic control, involving gene-expression and metabolic regulation of both topoisomerase I and DNA gyrase.

DNA of prokaryotes is in a nonequilibrium structural state, characterized as 'active' DNA supercoiling. Alterations in this state affect many life processes and a homeostatic control of DNA supercoiling has been suggested [Menzel, R. & Gellert, M. (1983) Cell 34, 105-113]. We here report on a new method for quantifying homeostatic control of the high-energy state of in vivo DNA. The method involves making small perturbation in the expression of topoisomerase I, and measuring the effect on DNA supercoiling of a reporter plasmid and on the expression of DNA gyrase. In a separate set of experiments the expression of DNA gyrase was manipulated and the control on DNA supercoiling and topoisomerase I expression was measured [part of these latter experiments has been published in Jensen, P.R., van der Weijden, C.C., Jensen, L.B., Westerhoff, H.V. & Snoep, J.L. (1999) Eur. J. Biochem. 266, 865-877]. Of the two regulatory mechanisms via which homeostasis is conferred, regulation of enzyme activity or regulation of enzyme expression, we quantified the first to be responsible for 72% and the latter for 28%. The gene expression regulation could be dissected to DNA gyrase (21%) and to topoisomerase I (7%). On a scale from 0 (no homeostatic control) to 1 (full homeostatic control) we quantified the homeostatic control of DNA supercoiling at 0.87. A 10% manipulation of either topoisomerase I or DNA gyrase activity results in a 1.3% change of DNA supercoiling only. We conclude that the homeostatic regulation of the nonequilibrium DNA structure in wild-type Escherichia coli is almost complete and subtle (i.e. involving at least three regulatory mechanisms).     

Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex

Background

Primary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na⁺ channel Na_V1.7 have been linked with primary erythromelalgia. Recently, a new substitution Na_V1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9–22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8–10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all Na_V1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III.

Results

In this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents.

Conclusion

The I136V substitution in Na_V1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in erythromelalgia. The smaller shift in voltage-dependence of activation of Na_V1.7, compared to the other reported cases of inherited erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation.     

The energy-transducing NADH: quinone oxidoreductase,complex I

The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. The need to elucidate the molecular mechanisms of complex I has greatly increased. Many devastating neurodegenerative disorders have been associated with complex I deficiency. The structural and functional complexities of complex I have already been established. However, intricate biogenesis and activity regulation functions of complex I have just been identified. Based upon these recent developments, it is apparent that complex I research is entering a new era. The advancement of our knowledge of the molecular mechanism of complex I will not only surface from bioenergetics, but also from many other fields as well, including medicine. This review summarizes the current status of our understanding of complex I and sheds light on new theories and the future direction of complex I studies.     

Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.

Carnitine palmitoyltransferase I (CPT I) catalyzes the formation of acylcarnitine, the first step in the oxidation of long-chain fatty acids in mitochondria. The enzyme exists as liver (L-CPT I) and muscle (M-CPT I) isoforms that are encoded by separate genes. Genetic deficiency of L-CPT I, which has been reported in 16 patients from 13 families, is characterized by episodes of hypoketotic hypoglycemia beginning in early childhood and is usually associated with fasting or illness. To date, only two mutations associated with L-CPT I deficiency have been reported. In the present study we have identified and characterized the mutations underlying L-CPT I deficiency in six patients: five with classic symptoms of L-CPT I deficiency and one with symptoms that have not previously been associated with this disorder (muscle cramps and pain). Transfection of the mutant L-CPT I cDNAs in COS cells resulted in L-CPT I mRNA levels that were comparable to those expressed from the wild-type construct. Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability. The patient with atypical symptoms had approximately 20% of normal L-CPT I activity and was homozygous for a mutation (c.1436C-->T) that substituted leucine for proline at codon 479. Assays performed with his cultured skin fibroblasts indicated that this mutation confers partial resistance to the inhibitory effects of malonyl-CoA. The demonstration of L-CPT I deficiency in this patient suggests that the spectrum of clinical sequelae associated with loss or alteration of L-CPT I function may be broader than was previously recognized.