Mitotic regulation: the fine tuning of separase activity

Mitotic progression requires the dissolution of cohesion between sister chromatids. Cohesion is dissolved by an essential protease known as separase. Separase is highly conserved throughout evolution and is subjected to multiple levels of regulation. Here we discuss recent studies that unravel several key mechanisms for regulating separase activity.     

Promoter knock-in: a novel rational method for the fine tuning of genes

Background  

Metabolic engineering aims at channeling the metabolic fluxes towards a desired compound. An important strategy to achieve this is the modification of the expression level of specific genes. Several methods for the modification or the replacement of promoters have been proposed, but most of them involve time-consuming screening steps. We describe here a novel optimized method for the insertion of constitutive promoters (referred to as "promoter knock-in") whose strength can be compared with the native promoter by applying a promoter strength predictive (PSP) model.     

Noise cancellation: viral fine tuning of the cellular environment for its own genome replication

Productive replication of DNA viruses elicits host cell DNA damage responses, which cause both beneficial and detrimental effects on viral replication. In response to the viral productive replication, host cells attempt to attenuate the S-phase cyclin-dependent kinase (CDK) activities to inhibit viral replication. However, accumulating evidence regarding interactions between viral factors and cellular signaling molecules indicate that viruses utilize them and selectively block the downstream signaling pathways that lead to attenuation of the high S-phase CDK activities required for viral replication. In this review, we describe the sophisticated strategy of Epstein-Barr virus to cancel such "noisy" host defense signals in order to hijack the cellular environment.     

Diversity emergence and dynamics during primary immune response: a shape space,physical space model

A computational model of the dynamics of diversity among T-cell receptors and MHC: peptide complex molecules is presented. We propose a method by which individual immune systems may evolve effcient or ineffcient states as a result of T-cell receptor crossreactivity as well as genetic variation among pathogens. By combining shape space and physical space models, valuable insight is obtained into how immune system-wide state is, in large part, determined by localised space dynamics. In the model, system-wide state also informs local dynamics, especially in the lymphatic system during primary immune response. The process by which similar initial infection conditions across individuals may result in highly variable end states (a phenomenon observed in the clinical context) is modelled. Our results show that activity alone is not a good indicator of infection suppression or removal. In this work, we postulate that successful viral clearance is characterised by broad T-cell receptor activation (in shape space), and results in low average concentration levels of activated cytotoxic lymphocyte cells.     

A functional analysis of T-DNA gene 6b: the fine tuning of cytokinin effects on shoot development

Summary The physiological function in planta of T-DNA gene 6b was studied under various experimental conditions. For this purpose the coding region of gene 6b was cloned behind the 1-promoter of the TR-DNA to enhance expression of the gene product in transformed plant cells. Expression of the recombinant gene in leaf discs of Nicotiana tabacum altered the capacity for shoot formation of the discs, induced by exogenous (i.e. BAP in the growth medium or agrobacterial trans-zeatin produced under control of gene tzs) or endogenous cytokinins (i.e. isopentenyladenosine produced under control of T-DNA gene 4). The data obtained indicate a reduction of cytokinin activity within the plant cells by the product of T-DNA gene 6b.Abbreviations AMP adenosine-5-monophosphate - BAP 6-benzylaminopurine     

Leptin and the immune system: how nutritional status influences the immune response

Several observations suggest the presence of an interaction between immune and the endocrine systems. Leptin is an adipocyte-derived hormone, that belongs structurally to the long-chain helical cytokine family such as interleukin-2 (IL-2), interleukin-12 (IL-12), growth hormone (GH), and signals by a class I cytokine receptor (Ob-R). This cytokine represents an important link between fat mass on the one side and the regulation of energy balance and reproductive function on the other. Indeed, obese leptin-deficient ob/ob mice display low body temperature, hyperphagia, infertility and evidence of immune defects with lymphoid organ atrophy, mainly affecting thymic size and cellularity. Acute starvation, associated with decreased leptin levels, causes thymic atrophy and reduces the delayed type hypersensitivity (DTH) reaction to antigens in normal mice, resembling that observed in ob/ob mice. Leptin replacement reverses the immunosuppressive effects of acute starvation in mice. Leptin differentially affects the in vitro proliferation and cytokine production by naive and memory T cells, increasing IL-2 secretion and proliferation of naive T cells, while inducing IFN-g production in memory T cells with little effect on their proliferation. Presence of leptin seems to be necessary for the induction and maintenance of the pro-inflammatory Th1 immune response. These findings support the hypothesis that leptin plays a key role in linking nutritional state to the T cell function. According to this view, leptin might represent an important target for immune intervention in a variety of pathophysiological conditions.     

Recent advances in cryptosporidiosis: the immune response

An increased understanding of host immune responses to Cryptosporidium parvum which are responsible for clearance of primary infection and resistance to reinfection, and characterization of the parasite molecules to which they are directed, are essential for discovery of effective active and passive immunization strategies against cryptosporidiosis. In this article, recent advances in knowledge of humoral and cellular immune responses to C. parvum, their antigen specificities, and mechanisms of protection are briefly reviewed.     

Maturation of the immune response: a computational model

Experimental studies of the effect on antibody affinity of antigen dose and time after immunization show that average affinity increases progressively with time after immunization, and that this increase is greater at lower doses of antigen. In this paper we describe a polyclonal computer model of the immune system that yields all the essential phenomena of affinity maturation, including dose-dependency. Our main findings are (1) the dose-dependency relationship is not produced when typical assumptions regarding B-cell populations and binding reactions are employed, and (2) it is possible to reproduce this dependency by assuming two classes of lymphocytes: generalists and specialists. Generalists have a low threshold for response and produce antibody of low effectiveness, whereas specialists have a high threshold for response, and produce highly effective antibody. We make an analogy between the generalists and a pioneer species in ecological succession, and suggest how the generalists may contribute to a more effective defense against real infections.     

Peripheral auditory tuning for fine frequency analysis by the CF-FM bat,Rhinolophus ferrumequinum

Summary For echolocation,Rhinolophus ferrumequinum emits orientation sounds, each of which consists of a long constant-frequency (CF) component and short frequency-modulated (FM) components. The CF component is about 83 kHz and is used for Doppler-shift compensation. In this bat, single auditory nerve fibers and cochlear nuclear neurons tuned at about 83 kHz show low threshold and very sharp filter characteristics. The slopes of their tuning curves ranged between 1,000 and 3,500 dB/octave and their Q-10 dB values were between 20 and 400, 140 on the average (Figs. 3–5). The peripheral auditory system is apparently specialized for the reception and fine frequency analysis of the CF component in orientation sounds and Doppler-shift compensated echoes. This specialization is not due to suppression or inhibition comparable to lateral inhibition, but due to the mechanical specialization of the cochlea. Peripheral auditory neurons with the best frequency between 77 and 87 kHz showed not only on-responses, but also off-responses to tonal stimuli (Figs. 1, 2, and 6). The off-responses with a latency comparable to that of N₁-off were not due to a rebound from either suppression or inhibition, but probably due to a mechanical transient occurring in the cochlea at the cessation of a tone burst.We thank Alexander von Humboldt Stiftung, Deutsche Forschungsgemeinschaft (Grant No. Ne146/6-8), Stiftung Volkswagenwerk (Grant No. 111858), and American National Science Foundation (Grant No. 40018 and BMS 75-17077) for their support for our cooperative work.     

Chaperonins and the immune response

Chaperonins are a major target of the immune response to bacteria. Infection, or immunization, with bacteria induces a strong antibody response to chaperonins, and the same proteins also provide a focus for activation of T lymphocyte subsets--including CD4, CD8 and gamma-delta T cells. The high degree of sequence conservation between prokaryotic and eukaryotic chaperonins makes them candidate antigens for models of autoimmunity based on molecular mimicry, and it is possible that the immune response to chaperonins has both protective and pathogenic potential. The interactions between chaperonins and the immune response are reviewed in this article, primarily from the perspective of intracellular bacterial infection.