Proteins turn "Proteans" - The over 40-year delayed paradigm shift in structural biology: From "native proteins in uniquely defined configurations" to "intrinsically disordered proteins".

The current millennium brought up a revolutionary paradigm shift in molecular biology: many operative proteins, rather than being quasi-rigid polypeptide chains folded into unique configurations - as believed throughout most of the past century - are now known to be intrinsically disordered, dynamic, pleomorphic, and multifunctional structures with stochastic behaviors. Yet, part of this knowledge, including suggestions about possible mechanisms and plenty of evidence for the same, became available by the 1950s and 1960s to remain then nearly forgotten for over 40 years. Here, we review the main steps toward the classic notions about protein structures, as well as the neglected precedents of present views, discuss possible explanations for such long oblivion, and offer a sketch of the current panorama in this field.

Genetic/genomic testing: defining the parameters for ethical, legal and social implications (ELSI).

BACKGROUND: Genetic/genomic testing (GGT) are useful tools for improving health and preventing diseases. Still, since GGT deals with sensitive personal information that could significantly impact a patient's life or that of their family, it becomes imperative to consider Ethical, Legal and Social Implications (ELSI). Thus, ELSI studies aim to identify and address concerns raised by genomic research that could affect individuals, their family, and society. However, there are quantitative and qualitative discrepancies in the literature to describe the elements that provide content to the ELSI studies and such problems may result in patient misinformation and harmful choices. METHODS: We analyzed the major international documents published by international organizations to specify the parameters that define ELSI and the recognized criteria for GGT, which may prove useful for researchers, health professionals and policymakers. First, we defined the parameters of the ethical, legal and social fields in GGT to avoid ambiguities when using the acronym ELSI. Then, we selected nine documents from 44 relevant publications by international organizations related to genomic medicine. RESULTS: We identified 29 ELSI sub-criteria concerning to GGT, which were organized and grouped within 10 minimum criteria: two from the ethical field, four from the legal field and four from the social field. An additional analysis of the number of appearances of these 29 sub-criteria in the analyzed documents allowed us to order them and to determine 7 priority criteria for starting to evaluate and propose national regulations for GGT. CONCLUSIONS: We propose that the ELSI criteria identified herein could serve as a starting point to formulate national regulation on personalized genomic medicine, ensuring consistency with international bioethical requirements.

What is in a word? Neuron: Early usage and evolution in antiquity to its long-lasting current significance.

Neuron, a Greek term with a rustic background, made much of its way to its current significance since antiquity, when full recognition was achieved that sensory and motor signals travel through the animal body along nerves (neura, plural). Drawing from classic and recent historical scholarship, this study identifies the successive steps toward such a major breakthrough, starting from the usage of the expression in archaic times and continuing up to the much later transference of a mature theory into the modern world. It is shown that four main consecutive stages may be distinguished in the process: (a) incorporation of the word into early anatomical terminology; (b) theorizing on material composition, origin, properties, and role of the neura in animal bodies; (c) functional association of the neura with a transmitting vehicle; (d) identification of true anatomical and physiological correspondences. Upon this over 2000-year-old foundation is still being built one of the most relevant and fascinating scientific adventures of all time.

Assessing Individual Intellectual Output in Scientific Research: Mexico's National System for Evaluating Scholars Performance in the Humanities and the Behavioral Sciences.

Assessing the research of individual scholars is currently a matter of serious concern and worldwide debate. In order to gauge the long-term efficacy and efficiency of this practice, we carried out a limited survey of the operation and outcome of Mexico's 30-year old National System of Investigators or SNI, the country's main instrument for stimulating competitive research in science and technology. A statistical random sample of researchers listed in the area of Humanities and Behavioral Sciences-one of SNI's first and better consolidated academic divisions comprising a wide range of research disciplines, from philosophy to pedagogy to archaeology to experimental brain research-was screened comparing individual ranks or "Levels of distinction" to actual compliance with the SNI's own evaluation criteria, as reflected in major public databases of scholarly production. The same analysis was applied to members of a recent Review Committee, integrated by top-level researchers belonging to that general area of knowledge, who have been in charge of assessing and ranking their colleagues. Our results for both sets of scholars show wide disparity of individual productivity within the same SNI Level, according to all key indicators officially required (books issued by prestigious publishers, research articles appeared in indexed journals, and formation of new scientists), as well as in impact estimated by numbers of citations. Statistical calculation from the data indicates that 36% of members in the Review Committee and 53% of researchers in the random sample do not satisfy the official criteria requested for their appointed SNI Levels. The findings are discussed in terms of possible methodological errors in our study, of relevance for the SNI at large in relation to independent appraisals, of the cost-benefit balance of the organization as a research policy tool, and of possible alternatives for its thorough restructuring. As it currently stands SNI is not a model for efficient and effectual national systems of research assessment.

Neura, nerves, nerve fibers, neurofibrils, microtubules: multidimensional routes of pain, pleasure, and voluntary action in images across the ages.

Available records indicate that the human body has always been conceived, in different periods and cultures, as spanned by multiple channels for internal communication and coherent functioning as a unit-"meridians" in treatises of Chinese medicine, metu in Egyptian papyri, srotas in Ayurvedic Indian texts, and neura in the Western scientific heritage from ancient Greece. Unfortunately, the earliest extant figurative depictions of such pathways of general control, complementary to the blood vessels, are late medieval copies of old crude sketches that attempted to show the main anatomico-physiological systems. The scarcity of adequate illustrations was more than compensated in the Renaissance, when the efforts of both artists and anatomists for the first time produced basically correct renditions of the human nervous system and many other bodily structures. As attention was next focused on microscopic structure as a requisite to understand physiological mechanisms, during the Enlightenment the nerves were revealed to consist of numerous thin tubes or fibers aligned in parallel. Improved microscopy techniques in the nineteenth century led to discovering and delineating still finer fibrils coursing along the cores of the nerve fibers themselves. Electron microscopy, developed throughout the twentieth century, recognized some of these fibrils within nerve fibers as being also tubular. All the progressive stages in understanding nerve construction, at increasingly more detailed scales, have been accompanied by technological advances and by debate about the structure and function relationship. And every step has been a source of amazing imagery.

Pneuma-fire interactions in Hippocratic physiology.

Hippocratic treatises written in the late fifth and early fourth centuries BCE contain some of the earliest conjectures known concerning the physiological roles of the pneuma, or "breath," that was supposed to be involved in various functions within human and animal bodies. A cross-referenced survey of these texts suggests that the contemporary theories on the subject may have gone far beyond the well-known attribution of epilepsy and other diseases to disorders in the flow of pneuma within the vessels. A pattern of co-dependent interplay between air-pneuma and fire-heat is evident among the different sources, despite disagreements of the authors on general outlook and other matters. The mutual engagement of those two elements, in turn, is found woven into elaborate mechanisms to explain, with a cause-to-effect approach, vital processes such as the regulation of body temperature through respiration, embryonic growth through morphogenetic differentiation, and even plant germination. Viewed in a historical context, these features suggest that Hippocratic speculation about pneuma may be representative of a conceptual bridging step, i.e., a stage intermediate between some seminal precedents of Presocratic thought and the more mature Aristotelian and Hellenistic theories.

Cajal's second great battle for the neuron doctrine: the nature and function of neurofibrils.

One hundred years ago, a novel kind of reticularism threatened to displace the neuron doctrine as the established model of functional organization of the nervous system. The challenging paradigm, championed by Stephan von Apáthy and Albrecht Bethe, held that nerve impulses propagate along neurofibrils connected in a continuous network throughout all nerve cells. Santiago Ramón y Cajal, a leading figure in the conception of the neuron doctrine, headed again the battle against this return of reticularism. Dissatisfied with the available staining techniques, he devised the "reduced silver nitrate method" that even Camillo Golgi recognized as the best at the time for revealing the neurofibrils. In 1904 Cajal already published over a dozen papers in three languages describing neurofibril distributions in the nervous systems of diverse vertebrates and invertebrates, under both normal and experimental conditions. Next he investigated the involvement of neurofibrils in the process of nerve regeneration. This unprecedented survey led him to the conclusion that the neurofibrils are linear "colonies" of particles constituting a semi-solid, dynamic internal skeleton of the nerve cell. Apáthy reacted with a long invective paper that Cajal had no choice but acknowledging. His comprehensive reply, published in 1908, meant the effective end of the renewed reticularist campaign against the neuron doctrine. Along the way, a visionary and today almost forgotten chapter in the history of the cytoskeleton had also been written.

Muscle microanatomy and its changes during contraction: the legacy of William Bowman (1816-1892).

Striated muscle fine structure began to be really understood following a comprehensive survey of the matter carried out by William Bowman in the late 1830s. The publications resulting from such a study, the first of which earned for the author a precocious election as Fellow of the Royal Society, are herewith examined in the context of contemporary views on the subject as well as of their subsequent repercussion and current knowledge today. It is shown that not only Bowman succeeded in establishing the true architecture of striated muscle fibres to the extent possible with the most advanced technology available in his day--explaining and eradicating alternative erroneous concepts in the process--but also in correctly describing the basic microstructural changes associated with contraction. In addition, although unrecognized by him or others at the time, his experiments with muscle provided direct evidence for the existence of a selectively permeable cell membrane--in the present meaning of the word--over half a century before its officially accepted discovery. Yet, in spite of these remarkable advances, Bowman arrived at the conclusion that the structure of striated muscle fibres is essentially irrelevant for the mechanism of contraction. Possible reasons behind Bowman's breakthrough accomplishments as a pioneer of modern muscle research, and his failure to understand their significance for muscle physiology, are discussed.

Mechanical responses of single non-confluent epithelial cells to low extracellular calcium.

Single non-confluent MDCK cells respond immediately to a sharp decrease in extracellular Ca2+ (< or = 5 microM) with an intense reversible retraction, along with an increase in cell height, correlating in overall rate and extent with initial cell size. Optical sectioning of individual cells by confocal microscopy showed that this structural response, observed in about 50% of the population, involves narrowing and even furrowing near the base of the cell by a thickened peripheral belt of actin filaments, which remains associated with the cortex instead of being internalized in the cytoplasm. Single cells retracted significantly in response to low Ca2+ under conditions that have been found largely inhibitory for retraction of confluent cells, such as Ca2+ replacement with Ba2+ and the substitution of Na+ with choline, a non-permeant cation. Conversely, the Na(+)-ionophore monensin applied in the normal-Ca2+ medium elicited by itself an earlier and much greater retraction in single cells than in confluent cultures. These observations indicate that single cells can retract more readily than those forming confluent cultures, suggesting that retraction in typical monolayers is resisted in part by the cell junctions. According to this view, inward actin-myosin mediated tension around the periphery of individual cells precedes and probably helps dissociation of E-cadherins in confluent cultures exposed to low Ca2+.

Sigmund Freud's contribution to the history of the neuronal cytoskeleton.

In the summers of 1879 and 1881, while Freud was a research student in Ernst von Brücke's laboratory at the Institute of Physiology at the University of Vienna, he carried out an important though seldom remembered investigation on the internal structure of nerve fibers and cells. His contribution to this field is here examined in the context of the 19th-century debate regarding the existence of neurofibrils and of present views on the cytoskeleton. Freud was able to discern separate fine fibrils following straight courses within the nerve fibers, as well as concentric loops of striae surrounding the nuclei and converging towards the processes of the cell bodies in crayfish nervous tissue. He thus confirmed and extended observations made by Robert Remak almost 40 years earlier, which had remained controversial. Electron microscopy of the crustacean nervous system confirmed Freud's main points, which in turn vindicated those of Remak. Both researchers were looking at small bundles of microtubules, and thus they were among the first to picture the lacy intracellular framework that future cell biologists would call the cytoskeleton.

Impacto de nuevas metodologías en el estudio de parásitos: V. Dinámica del disparo del filamento polar en el microsporidio Nosema algerae, analizado por videomicroscopía de contraste acentuado electrónicamente / Impact of new methodologies in the study of parasites: V. Dynamics of the polar filament shot in the microsporidium Nosema algerea, analyzed by electronically enhanced contrast videomicroscopy

Por medio de video-microscopía de contraste acentuado electrónicamente, se consiguió el primer análisis cinemático de la descarga del filamento polar y el esporoplasma por esporas de un microsporidio. La estimulación in vitro de esporas de Nosema algerea, un parásito de los mosquitos, provoca la salida explosiva del filamento polar con una velocidad instantánea máxima de 105 µm/s en promedio, seguida por la expulsión del esporoplasma en el extremo del filamento luego de un lapso variable con un máximo de 500 ms. La descarga total se completa en menores de 2 s. La morfología de la parte del filamento ya descargada en cada instante no cambia durante la salida, lo que sugiere que el alargamiento ocurre tan solo en el extremo distal, conforma a la opinión de que el filamento es extruido por eversión. Por lo común, la longitud del filamento disminuye entre 5 y un 10 por ciento después de la expulsión del esporoplasma, lo que indica elasticidad del material constitutivo y presurización interna durante el proceso. Una vez liberado el esporoplasma aumenta de volumen, como es de esperar de una alta presión osmótica residual que, de acuerdo con la hipótesis prevaleciente, es ocasionada por la estimulación. Los resultados apoyan el modelo de que las esporas de los microsporidios germinan cuando el estímulo causa un aumento de presión osmótica interna, que a su vez determina un influjo de agua de manera que la presión hidrostática se eleva y finalmente rompe la tapa polar de la espora, por donde son entonces expulsados el filamento y enseguida el esporoplasma.