基因工程改造噬菌体应用于细菌感染的研究进展

噬菌体作为细菌病毒,在细菌性感染尤其是多重耐药菌感染的治疗方面具有抗生素无法比拟的优势。目前人工改造噬菌体的理论和技术已趋成熟,研究者通过基因工程技术解决了噬菌体特异性高、半衰期短、释放内毒素等问题,使基因工程改造噬菌体具有了较强的临床应用潜力。本文主要就基因工程改造噬菌体在扩大宿主范围、增强抗生素疗效、延缓免疫清除、避免内毒素释放等方面所具有的优势,及其在剂量确定、细菌耐受、宿主安全性等方面可能会出现的问题进行了阐述。     

Fred Neufeld and pneumococcal serotypes: foundations for the discovery of the transforming principle

During the first decade of the twentieth century, the German bacteriologist Fred Neufeld, later Director of the Robert Koch-Institute in Berlin, first described the differentiation of pneumococci into serotypes on the basis of type-specific antisera. This finding was essential for subsequent research at the Rockefeller Institute of Medical Research (RIMR) in New York, and elsewhere, aiming for the conquest of human pneumococcal pneumonia, including antiserum therapy, the discovery that the type-specific antigens were carbohydrates, and the development of effective multivalent pneumococcal polysaccharide vaccines. Moreover, on the basis of pneumococcal serotypes Fred Griffith, in 1928 in London, discovered pneumococcal transformation, and Oswald T. Avery and coworkers, in 1944 at RIMR, identified DNA as the transforming substance. This sequence of events, leading to today’s knowledge that genes consist of DNA, was initiated by a farsighted move of Simon Flexner, first Director of the RIMR, who asked Neufeld to send his pneumococcal typing strains, thus setting the stage for pneumococcal research at RIMR. Here, we describe Fred Neufeld’s contributions in this development, which have remained largely unknown.     

Determination of trace elements in peripheral lymphocytes from tumor-bearing rats.

Neutron activation analysis of peripheral lymphocytes from healthy and Walker 256 carcinosarcoma-bearing rats resulted in the quantitative determination of Co, Cu, K, Mn, Rb, Se and Zn, and a qualitative determination of Au and Sb. From corresponding plasma samples, Co, Zn, Rb, Se and Cs were analyzed. Differences in trace element concentrations could only be detected in plasma of tumor-bearing animals which showed a decreased Zn and Co content of 50% and 30%, respectively, and a rise of Rb when compared to plasma of control animals.     

La diffraction des électrons et ses applications

Summary The diffraction of electrons, based on the theories of undulatory mechanics (Louis de Broglie), has grown now to a method of investigation into the structure of matter, complementing the analysis by X-rays and electronic microscopy.Its use is developing every day in the most heterogeneous fields: study of crystalline structures, of metallic layers, of oxidation, corrosion, adsorption, catalysis, of polishing and of the conditions of superficies, as also of lubrication and of isolated molecules, etc.The article gives some instances of the diverse applications.     

Chemistry and Chemists at the London Institution 1807-1912

The London Institution, established in the City of London in 1807, was devoted, as its full title proclaimed, to the 'advancement of Literature and the Diffusion of Useful Knowledge'. With its extensive lecture programme, splendid reference library, reading rooms, laboratory and other amenities, it provided for its members a scientific and cultural centre, modelled on the highly successful and fashionable Royal Institution in London's West End. Among its scientific activities, chemistry long maintained a leading role, in terms of both the sheer volume and variety of its presentations, and the high standing of its lecturers; they included Faraday, Playfair, Hofmann, Roscoe, Odling, Norman Lockyer, Meldola, and Sir William Ramsay, as well as other visiting lecturers, specially selected for their ability to present their subject in an interesting and attractive fashion to a wider lay public. The laboratory of the Institution, although limited in size and facilities, was the scene of instruction in practical chemistry, and between 1863 and 1884 attained the reputation of a significant centre of chemical research during the successive tenure of the professorship in chemistry by J. A. Wanklyn and H. E. Armstrong. Their publications, appearing under the device 'From the Laboratory of the London Institution', were a frequent feature of the leading chemical periodicals. Thus, within its many-sided activities, the Institution promoted significantly the public appreciation of the function of chemistry, as a contributor both to pure knowledge, and to technical and economic progress. It achieved this in an environment of influential City merchants, manufacturers and financiers and doubtless led to beneficient, if unrecorded, consequences. It was only towards the close of the nineteenth century, when the universities had become increasingly concerned with the systematic study of the discipline, that chemistry lost its direct impact in the London Institution, but continued to maintain a presence within its cultural framework.     

Helminthosporoside,a host-specific toxin fromHelminthosporium sacchari: A structure revision and a new partial structure

Summary Reevaluation of the previously proposed structure of helminthosporoside, a host-specific toxin fromHelminthosporium sacchari, reveals a sesquiterpenoid bis-digalactoside. The carbohydrate portion of the toxin was characterized by¹³C-NMR spectroscopy, methylation analyses, FD and FAB mass spectroscopy. The ring size and anomeric configuration of the galactose moieties were determined by utilizing a¹³C-NMR structural analysis method. A new partial structure is proposed.Acknowledgment. We extend special thanks to C.E. Costello, Department of Chemistry, M.I.T., Cambridge, MA, for FD mass spectral analyses, and to C.E. Ballou, Department of Biochemistry, University of California, Berkeley, CA, for FAB mass spectral analyses. We submit sincere appreciation to both V.N. Reihold, Harvard Medical School, Boston, MA, and P. Albersheim, Department of Chemistry, University of Colorado, Boulder, CO, for methylation analyses. We thank J.S. Frye at the Colorado State University Regional NMR-Center, funded by National Science Foundation grant No. DHE 78-18581, Department of Chemistry, Colorado State University, Fort Collins, Co, for high resolution CMR and NMR, and we are grateful to P.W. Jennings, Department of Chemistry, Montana State University, Bozeman, Mt, for total carbon analyses. This work was supported in part by a Herman Frasch Foundation grant to G.A. Strobel, by NSF grant PCM-78-22517, and funds from the Montana Agricultural Experiment Station. B.P. Mundy acknowledges the partial support of NSF (ISP-801149).     

Examination of the potential mutagenicity of hair dye constituents using the micronucleus test

Summary 12 compounds which are constitutents of hair dyes or chemically related aromatic amines, aminophenols, their nitroderivatives and aromatic hydroxyderivatives were examined for evidence of mutagenic potential by means of the micronucleus test. None of the compounds tested caused an increase in the incidence of micronucleated erythrocytes after oral dosing.Acknowledgment. These investigations were conducted on behalf and with the assistance of Elida-Gibbs GmbH, Hamburg, Goldwell GmbH, Darmstadt, Thera-Chemie GmbH, Dusseldorf, L'Oreal-Haarkosm, und Parf. GmbH, Karlsruhe, Kadus-Werk K.G., Lenzkirch, Hans Schwarzkopf GmbH, Hamburg, Wella AG, Darmstadt.     

Francesco Patrizi’s two books on space: geometry, mathematics, and dialectic beyond Aristotelian science

Francesco Patrizi was a competent Greek scholar, a mathematician, and a Neoplatonic thinker, well known for his sharp critique of Aristotle and the Aristotelian tradition. In this article I shall present, in the first part, the importance of the concept of a three-dimensional space which is regarded as a body, as opposed to the Aristotelian two-dimensional space or interval, in Patrizi’s discussion of physical space. This point, I shall argue, is an essential part of Patrizi’s overall critique of Aristotelian science, in which Epicurean, Stoic, and mainly Neoplatonic elements were brought together, in what seems like an original theory of space and a radical revision of Aristotelian physics. Moreover, I shall try to show Patrizi’s dialectical method of definition, his geometrical argumentation, and trace some of the ideas and terms used by him back to Proclus’ Commentary on Euclid. This text of Proclus, as will be shown in the second part of the article, was also important for Patrizi’s discussion of mathematical space, where Patrizi deals with the status of mathematics and redefines some mathematical concepts such as the point and the line according to his new theory of space.     

Lipid-lowering drugs

Although a change in life-style is often the method of first choice for lipid lowering, lipid-lowering drugs, in general, help to control elevated levels of different forms of lipids in patients with hyperlipidemia. While one group of drugs, statins, lowers cholesterol, the other group, fibrates, is known to take care of fatty acids and triglycerides. In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia. As lipids are very critical for cardiovascular diseases, these drugs reduce fatal and nonfatal cardiovascular abnormalities in the general population. However, a number of recent studies indicate that apart from their lipidlowering activities, statins and fibrates exhibit multiple functions to modulate intracellular signaling pathways, inhibit inflammation, suppress the production of reactive oxygen species, and modulate T cell activity. Therefore, nowadays, these drugs are being considered as possible therapeutics for several forms of human disorders including cancer, autoimmunity, inflammation, and neurodegeneration. Here I discuss these applications in the light of newly discovered modes of action of these drugs. Received 5 September 2005; received after revision 29 December 2005; accepted 26 January 2006     

Nucleic acid sensing pattern recognition receptors in the development of colorectal cancer and colitis

Colorectal cancer (CRC) is a leading cause of cancer-related deaths that is often associated with inflammation initiated by activation of pattern recognition receptors (PRRs). Nucleic acid sensing PRRs are one of the major subsets of PRRs that sense nucleic acid (DNA and RNA), mainly including some members of Toll-like receptors (TLR3, 7, 8, 9), AIM2-like receptors (AIM2, IFI16), STING, cGAS, RNA polymerase III, and DExD/H box nucleic acid helicases (such as RIG-I like receptors (RIG-I, MDA5, LPG2), DDX1, 3, 5, 7, 17, 21, 41, 60, and DHX9, 36). Activation of these receptors eventually leads to the release of cytokines and activation of immune cells, which are well known to play crucial roles in host defense against intracellular bacterial and virus infection. However, the functions of these nucleic acid sensing PRRs in the other diseases such as CRC and colitis remain largely unknown. Recent studies indicated that nucleic acid sensing PRRs contribute to CRC and/or colitis development, and therapeutic modulation of nucleic acid sensing PRRs may reduce the risk of CRC development. However, until now, a comprehensive review on the role of nucleic acid sensing PRRs in CRC and colitis is still lacking. This review provided an overview of the roles as well as the mechanisms of these nucleic acid sensing PRRs (AIM2, STING, cGAS, RIG-I and its downstream molecules, DDX3, 5, 6,17, and DHX9, 36) in CRC and colitis, which may aid the diagnosis, therapy, and prognostic prediction of CRC and colitis.     

Melatonin,clock genes and mitochondria in sepsis

After the characterization of the central pacemaker in the suprachiasmatic nucleus, the expression of clock genes was identified in several peripheral tissues including the immune system. The hierarchical control from the central clock to peripheral clocks extends to other functions including endocrine, metabolic, immune, and mitochondrial responses. Increasing evidence links the disruption of the clock genes expression with multiple diseases and aging. Chronodisruption is associated with alterations of the immune system, immunosenescence, impairment of energy metabolism, and reduction of pineal and extrapineal melatonin production. Regarding sepsis, a condition coursing with an exaggerated response of innate immunity, experimental and clinical data showed an alteration of circadian rhythms that reflects the loss of the normal oscillation of the clock. Moreover, recent data point to that some mediators of the immune system affects the normal function of the clock. Under specific conditions, this control disappears reactivating the immune response. So, it seems that clock gene disruption favors the innate immune response, which in turn induces the expression of proinflammatory mediators, causing a further alteration of the clock. Here, the clock control of the mitochondrial function turns off, leading to a bioenergetic decay and formation of reactive oxygen species that, in turn, activate the inflammasome. This arm of the innate immunity is responsible for the huge increase of interleukin-1β and entrance into a vicious cycle that could lead to the death of the patient. The broken clock is recovered by melatonin administration, that is accompanied by the normalization of the innate immunity and mitochondrial homeostasis. Thus, this review emphasizes the connection between clock genes, innate immunity and mitochondria in health and sepsis, and the role of melatonin to maintain clock homeostasis.     

Fritz London and the scale of quantum mechanisms

Fritz London's seminal idea of “quantum mechanisms of macroscopic scale”, first articulated in 1946, was the unanticipated result of two decades of research, during which London pursued quantum-mechanical explanations of various kinds of systems of particles at different scales. He started at the microphysical scale with the hydrogen molecule, generalized his approach to chemical bonds and intermolecular forces, then turned to macrophysical systems like superconductors and superfluid helium. Along this path, he formulated a set of concepts—the quantum mechanism of exchange, the rigidity of the wave function, the role of quantum statistics in multi-particle systems, the possibility of order in momentum space—that eventually coalesced into a new conception of systems of equal particles. In particular, it was London's clarification of Bose-Einstein condensation that enabled him to formulate the notion of superfluids, and led him to the recognition that quantum mechanics was not, as it was commonly assumed, relevant exclusively as a micromechanics.     

The ‘Darwin-Marx correspondence’: a correction and revision

The logical links between the Judaeo-Christian doctrine of creation and the practice of natural philosophy on the one hand, and the rejection of belief in demonic agency on the other, were made explicit in the seventeenth century by, among others, Balthasar Bekker (1634–98), whose ideas I argue to have been not without influence. In section 1, I present the accounts of three historians of the opposition to belief in witchcraft and of the decline of the witch-persecution, Hugh Trevor-Roper, Keith Thomas, and Brian Easlea. In section 2, I maintain that Bekker has been underestimated both by Trevor-Roper and by Easlea. In section 3, I investigate more generally some of the connections between the new natural philosophy and belief in supernatural interventions, cast doubt on the view that rejection of belief in witchcraft and the devil requires rejection of belief in creation, and thus supplement or qualify the accounts of Trevor-Roper, Thomas, and Easlea of why belief in witchcraft faded away.     

The Chemistry of the Universe: Historical Roots of Modern Cosmochemistry

During the second half of the twentieth century, the domain of geochemistry has greatly expanded and the field is today often seen as a branch of an extended chemistry of the Earth, called cosmochemistry. This paper is a historical introduction to cosmochemistry in which the wider cosmic aspects are surveyed up to about 1915, when nuclear physics changed the scene. These wider aspects or themes include, firstly, the attempts to determine the relative abundances of the elements, secondly, the extension of geochemistry to include physical geochemistry, thirdly, the study of meteorites and, fourthly, the spectroscopic study of the stars within the astrochemical tradition. Because of the lack of reliable data, a great deal of the protocosmochemistry described in the present paper was speculative. Nonetheless, by 1915 the contours of the cosmochemistry of the future were just visible and the developments here singled out can thus be seen as belonging to the prehistory of modern cosmochemistry.     

Quantum dissidents: Research on the foundations of quantum theory circa 1970

This paper makes a collective biographical profile of a sample of physicists who were protagonists in the research on the foundations of quantum physics circa 1970. We study the cases of Zeh, Bell, Clauser, Shimony, Wigner, Rosenfeld, d’Espagnat, Selleri, and DeWitt, analyzing their training and early career, achievements, qualms with quantum mechanics, motivations for such research, professional obstacles, attitude towards the Copenhagen interpretation, and success and failures. Except for Rosenfeld, they were all dissidents, fighting against the dominant attitude among physicists at the time according to which foundational issues had already been solved by the founding fathers of the discipline. Theirs is a story of success as the foundations of quantum mechanics finally entered the physics mainstream despite the fact that their expectations of breaking down quantum mechanics were not fulfilled.     

Repertoires: A post-Kuhnian perspective on scientific change and collaborative research

We propose a framework to describe, analyze, and explain the conditions under which scientific communities organize themselves to do research, particularly within large-scale, multidisciplinary projects. The framework centers on the notion of a research repertoire, which encompasses well-aligned assemblages of the skills, behaviors, and material, social, and epistemic components that a group may use to practice certain kinds of science, and whose enactment affects the methods and results of research. This account provides an alternative to the idea of Kuhnian paradigms for understanding scientific change in the following ways: (1) it does not frame change as primarily generated and shaped by theoretical developments, but rather takes account of administrative, material, technological, and institutional innovations that contribute to change and explicitly questions whether and how such innovations accompany, underpin, and/or undercut theoretical shifts; (2) it thus allows for tracking of the organization, continuity, and coherence in research practices which Kuhn characterized as ‘normal science’ without relying on the occurrence of paradigmatic shifts and revolutions to be able to identify relevant components; and (3) it requires particular attention be paid to the performative aspects of science, whose study Kuhn pioneered but which he did not extensively conceptualize. We provide a detailed characterization of repertoires and discuss their relationship with communities, disciplines, and other forms of collaborative activities within science, building on an analysis of historical episodes and contemporary developments in the life sciences, as well as cases drawn from social and historical studies of physics, psychology, and medicine.