Associationism without associative links: Thomas Brown and the associationist project

There are two roles that association played in 18th–19th century associationism. The first dominates modern understanding of the history of the concept: association is a causal link posited to explain why ideas come in the sequence they do. The second has been ignored: association is merely regularity in the trains of thought, and the target of explanation. The view of association as regularity arose in several forms throughout the tradition, but Thomas Brown (1778–1820) makes the distinction explicit. He argues that there is no associative link, and association is mere sequence. I trace this view of association through the tradition, and consider its implications: Brown's views, in particular, motivate a rethinking of the associationist tradition in psychology. Associationism was a project united by a shared explanandum phenomenon, rather than a theory united by a shared theoretical posit.     

Neurovascular development and links to disease

The developing central nervous system (CNS) is vascularized via ingression of blood vessels from the outside as the neural tissue expands. This angiogenic process occurs without perturbing CNS architecture due to exquisite cross-talk between the neural compartment and invading blood vessels. Subsequently, this intimate relationship also promotes the formation of the neurovascular unit that underlies the blood–brain barrier and regulates blood flow to match brain activity. This review provides a historical perspective on research into CNS blood vessel growth and patterning, discusses current models used to study CNS angiogenesis, and provides an overview of the cellular and molecular mechanisms that promote blood vessel growth and maturation. Finally, we highlight the significance of these mechanisms for two different types of neurovascular CNS disease.     

Intrinsic links among sex,emotion, and reproduction

Species survival is dependent on successful reproduction. This begins with a desire to mate, followed by selection of a partner, copulation and in monogamous mammals including humans, requires emotions and behaviours necessary to maintain partner bonds for the benefit of rearing young. Hormones are integral to all of these stages and not only mediate physiological and endocrine processes involved in reproduction, but also act as neuromodulators within limbic brain centres to facilitate the expression of innate emotions and behaviours required for reproduction. A significant body of work is unravelling the roles of several key hormones in the modulation of mood states and sexual behaviours; however, a full understanding of the integration of these intrinsic links among sexual and emotional brain circuits still eludes us. This review summarises the evidence to date and postulates future directions to identify potential psycho-neuroendocrine frameworks linking sexual and emotional brain processes with reproduction.     

带前置光放大的星间微波光子链路建模及性能优化

摘要考虑到星间微波光子链路中信号经远距离传输损耗大,利用前置光放大来提高链路的信噪比．建立了带前置光放大的星间微波光子链路模型,利用Bessel函数展开和Graf加法定理推导出了信噪比（SNR）的解析表达式．确定了对链路影响最大的主要噪声成分,在不同前置放大器增益的条件下,对调制器直流偏置相移进行了优化,使得在给定SNR要求下所需激光器输出光功率最小,并进一步分析了前置放大器增益对最小激光器输出功率和最优直流偏置相移的影响．数值仿真结果表明：随着前置放大器增益的增加,达到指定SNR所需的激光器输出功率变小,相应的最优直流偏置相移先减小后增大．对于QPSK调制信号,未加前置放大器时,SNR要达到15．56dB（BER=10-9）,激光器输出光功率至少为45dBm,而前置放大器增益为15dB时,只需要22．57dBm．     

Bridging epigenomics and complex disease: the basics

The DNA sequence largely defines gene expression and phenotype. However, it is becoming increasingly clear that an additional chromatin-based regulatory network imparts both stability and plasticity to genome output, modifying phenotype independently of the genetic blueprint. Indeed, alterations in this “epigenetic” control layer underlie, at least in part, the reason for monozygotic twins being discordant for disease. Functionally, this regulatory layer comprises post-translational modifications of DNA and histones, as well as small and large noncoding RNAs. Together these regulate gene expression by changing chromatin organization and DNA accessibility. Successive technological advances over the past decade have enabled researchers to map the chromatin state with increasing accuracy and comprehensiveness, catapulting genetic research into a genome-wide era. Here, aiming particularly at the genomics/epigenomics newcomer, we review the epigenetic basis that has helped drive the technological shift and how this progress is shaping our understanding of complex disease.     

HBsAg uptake by macrophages in vitro: An immunofluorescence study

Summary The uptake of HBsAg by in vitro cultured macrophages was studied by immunofluorescence method. Intracytoplasmic fluorescent particles appeared 3 h after the contact with HBsAg-positive serum, while after 24–48 h only a few cells contained these particles, which are probably destroyed within the cytoplasm.This work was supported by a grant of the Italian National Research Council (CNR), Progetto Finalizzato Virus.     

Chemotaxis of rabbit macrophages in vitro: Inhibition by drugs

Summary Chemotaxis of rabbit macrophages was inhibited in vitro by phenylbutazone and sodium salicylate, but not by other antiinflammatory agents. Other inhibitory compounds were colchicine, vincristine, PHA, Con A, iodoacetic acid, cytochalasin B, and EDTA. Some of these in vitro results contrast apparently with in vivo effects.     

The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease

Although originally identified as putative negative regulators of the cell cycle, recent studies have demonstrated that the PHB proteins act as a chaperone in the assembly of subunits of mitochondrial respiratory chain complexes. The two PHB proteins, Phb1p and Phb2p, are located in the mitochondrial inner membrane where they form a large complex that represents a novel type of membrane-bound chaperone. On the basis of its native molecular weight, the PHB-complex should contain 12-14 copies of both Phb1p and Phb2p. The PHB complex binds directly to newly synthesised mitochondrial translation products and stabilises them against degradation by membrane-bound metalloproteases belonging to the family of mitochondrial triple-A proteins. Sequence homology assigns Phb1p and Phb2p to a family of proteins which also contains stomatins, HflKC, flotillins and plant defence proteins. However, to date only the bacterial HflKC proteins have been shown to possess a direct functional homology with the PHB complex. Previously assigned actions of the PHB proteins, including roles in tumour suppression, cell cycle regulation, immunoglobulin M receptor binding and apoptosis seem unlikely in view of any hard evidence in their support. Nevertheless, because the proteins are probably indirectly involved in ageing and cancer, we assess their possible role in these processes. Finally, we suggest that the original name for these proteins, the prohibitins, should be amended to reflect their roles as proteins that hold badly formed subunits, thereby keeping the nomenclature already in use but altering its meaning to reflect their true function more accurately. Received 21 May 2001; received after revision 2 July 2001; accepted 24 July 2001     

Anti-interleukin-1 and anti-tumor necrosis factor-alpha synergistically inhibit adjuvant arthritis in Lewis rats

Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play dominant roles in mediating the progression of many inflammatory joint diseases, including rheumatoid arthritis in humans, collagen-induced arthritis in mice and rats, and adjuvant arthritis in rats. Blockade of either cytokine partially controls these diseases. The present study investigated the value of combination anti-cytokine therapy in arthritis: the efficacy of IL-1 receptor antagonist (IL-1ra) and 30 kDa polyethylene glycol (PEG)-conjugated soluble TNF receptor type I (PEG sTNF-RI) given together was assessed in Lewis rats with adjuvant arthritis. Administration of either IL-1ra or PEG sTNF-RI partially alleviated joint inflammation, loss of bone mineral density, and loss of body weight. In contrast, combination of these anti-cytokine treatments exhibited a synergistic capacity to inhibit these changes, even when combining doses of IL-1ra and PEG sTNF-RI that did not affect lesion severity when used alone. Statistical analysis of these adjuvant arthritis data using the isobologram method proved that IL-1ra and PEG sTNF-RI were clearly synergistic in inhibiting inflammation, loss of bone mineral density, loss of body weight, and histopathologic parameters of inflammation and joint destruction. These results suggest that treating autoimmune arthritic diseases with combinations of anti-IL-1 and anti-TNF molecules will achieve superior efficacy compared to the use of a single class of anti-cytokine agent and may allow for dose reductions that could prove useful in minimizing potential side effects.     

HBsAg uptake by macrophages in vitro: an immunofluorescence study.

The uptake of HBsAg by in vitro cultured macrophages was studied by immunofluorescence method. Intracytoplasmic fluorescent particles appeared 3 h after the contact with HBsAg-positive serum, while after 24-48 h only a few cells contained these particles, which are probably destroyed within the cytoplasm.     

Lysosomal multienzyme complex: pros and cons of working together

The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and their importance in tissue differentiation and remodeling. In lysosomes, the degradation of complex, macromolecular substrates requires the synergistic action of multiple hydrolases that usually work in a stepwise fashion. This catalytic machinery explains the existence of lysosomal enzyme complexes that can be dynamically assembled and disassembled to efficiently and quickly adapt to the pool of substrates to be processed or degraded, adding extra tiers to the regulation of the individual protein components. An example of such a complex is the one composed of three hydrolases that are ubiquitously but differentially expressed: the serine carboxypeptidase, protective protein/cathepsin A (PPCA), the sialidase, neuraminidase-1 (NEU1), and the glycosidase β-galactosidase (β-GAL). Next to this ‘core’ complex, the existence of sub-complexes, which may contain additional components, and function at the cell surface or extracellularly, suggests as yet unexplored functions of these enzymes. Here we review how studies of basic biological processes in the mouse models of three lysosomal storage disorders, galactosialidosis, sialidosis, and GM1-gangliosidosis, revealed new and unexpected roles for the three respective affected enzymes, Ppca, Neu1, and β-Gal, that go beyond their canonical degradative activities. These findings have broadened our perspective on their functions and may pave the way for the development of new therapies for these lysosomal storage disorders.     

Glutamate synthase: a complex iron-sulfur flavoprotein

Glutamate synthase is a complex iron-sulfur flavoprotein that forms l-glutamate from l-glutamine and 2-oxoglutarate. It participates with glutamine synthetase in ammonia assimilation processes. The known structural and biochemical properties of glutamate synthase from Azospirillum brasilense, a nitrogen-fixing bacterium, will be discussed in comparison to those of the ferredoxin-dependent enzyme from photosynthetic tissues and of the eukaryotic reduced pyridine nucleotide-dependent form of glutamate synthase in order to gain insight into the mechanism of the glutamate synthase reaction. Sequence analyses also revealed that the small subunit of bacterial glutamate synthase may be the prototype of a novel class of flavin adenine dinucleotide- and iron-sulfur-containing oxidoreductase widely used as an enzyme subunit or domain to transfer reducing equivalents from NAD(P)H to an acceptor protein or protein domain. Received 10 November 1998, received after revision 10 December 1998; accepted 10 December 1998     

Neurotrophins and their receptors: signaling trios in complex biological systems

The neurotrophins, a class of four related growth factors, utilize a dual receptor system consisting of Trk receptor tyrosine kinases and the structurally unrelated p75(NTR) to modulate diverse and sometimes opposing biological actions. The identification of novel ligands for p75(NTR), unconventional mechanisms for Trk activation and unique signaling intermediates further underscores the complex nature of neurotrophin: receptor interactions, as well as their functions within and outside of the nervous systems. This review summarizes recent surprises of how ligand-receptor pairing may affect diverse developmental events, regulate response to injury and extend their influence on memory and learning.     

Rana esculenta complex: An experimental analysis of lethality and hybridogenesis

Summary Experiments designed to analyze the lethality and hybridogenesis in the European green frog complex have yielded the following results: 1. As a rule the inter-se cross ofRana esculenta is lethal, but several crosses have produced fully viable progeny. The frequency of such break-through crosses appears to be related to parental population structure. 2. Parabiotic joining of lethal to viable embryos indicates that manifestation of the lethal effect is autonomous. There is, however, a 16–18% increase in the life span of the lethal partner. 3. Studies of LDH isozyme patterns revealed that thelessonae-specific alleles coding for the B^a and B^c subunits can be passed to the F₁ progeny from a parental female or male of theesculenta phenotype. This demonstrates that there is no total elimination of thelessonae genome in theesculenta germ cells. 4. Immunologically, offspring from the inter-se cross ofR. esculenta show a closer relationship to theridibunda than to theesculenta phenotype. Variations of antigenic protein patterns suggest the possibility of chromosomal recombination betweenlessonae andridibunda in theesculenta hybrid. These results are confirmed by two-dimensional electrophoretic analysis of proteins in the oocytes of the three frog phenotypes.This work was supported by grants from the Swiss National Science Foundation and the Georges and Antoine Claraz Schenkung.