Calcium and avian intrapulmonary chemoreceptor response to CO2.

Intrapulmonary chemoreceptors (IPC) are highly responsive respiratory chemoreceptors that innervate the lungs of birds and diapsid reptiles. IPC are stimulated by low levels of lung Pco(2), inhibited by high levels of lung Pco(2), and their vagal afferents serve as a sensory limb for reflex adjustments of breathing depth and rate. Most IPC exhibit both phasic and tonic sensitivity to CO(2), and spike frequency adaptation (SFA) contributes to their phasic CO(2) responsiveness. To test whether CO(2) responsiveness and SFA in IPC is modulated by a Ca(2+)-linked mechanism, we quantified the role of transmembrane Ca(2+) fluxes and Ca(2+)-related channels on single-unit IPC function in response to phasic changes in inspired Pco(2). We found that 1) broad-spectrum blockade of Ca(2+) channels using cadmium or cobalt and blockade of L-type Ca(2+) channels using nifedipine increased IPC discharge; 2) activation of L-type Ca(2+) channels using BAY K 8644 reduced IPC discharge; 3) blockade of Ca(2+)-activated potassium channels using charybdotoxin (antagonist of large-conductance Ca(2+)-dependent K(+) channel) increased IPC discharge, but neither charybdotoxin nor apamin affected SFA; and 4) blockade of chloride channels, including Ca(2+)-activated chloride channels, with niflumic acid decreased IPC discharge at low Pco(2) and increased IPC discharge at high Pco(2), resulting in a net attenuation of the IPC CO(2) response. We conclude that Ca(2+) influx through L-type Ca(2+) channels has an inhibitory effect on IPC afferent discharge and CO(2) sensitivity, that spike frequency adaptation is not due to apamin- or charybdotoxin-sensitive Ca(2+)-activated K(+) channels in IPC, and that chloride channels blocked by niflumic acid help modulate IPC CO(2) responses.     

Regulation of the immune response to tumor antigen. VIII. The effects of host specific anti-I-J antibodies on the immune response to tumors of different origin

The efficiency of in vivo therapy using alloantisera produced to interact specifically with I-J subregion encoded determinants has been investigated in two etiologically distinct syngeneic tumor systems, both of which have been shown to evoke suppressor T-cell host responses. Administration of 2 μl/day of anti-I-J^k alloantisera caused a significant reduction in the growth of the P815 methylcholanthrene (MCA)-induced mastocytoma or the 1316 ultraviolet (uv) radiation-induced fibrosarcoma in the syngeneic host. Inhibition of tumor growth with anti-I-J antibody treatment occurred in normal as well as in subcarcinogenically uv-treated hosts given the uv-induced 1316 fibrosarcoma, even though the normal host is capable of spontaneously rejecting the tumor graft in the absence of external manipulation. Evidence is also provided that the effects of anti-I-J antibody treatment are not due to direct interactions with the tumor cells, or to contaminating antiviral antibody activity within the antiserum. We have previously demonstrated the reduction of tumor growth in two antigenically distinct MCA-induced tumor systems (S1509a, SAI) using similar treatments. The data presented herein thus reinforce the possibility that such means of therapy may be beneficial to the treatment of a wide variety to tumor types where suppression represents a detrimental component of the host response, and may also provide some insight into the mechanisms underlying the effects of uv radiation on the immune response to tumor antigen.     

On the origin of intracellular compartmentation and organized metabolic systems

The history of the development of the ideas and research of organized metabolic systems during last three decades is shortly reviewed. The cell cytoplasm is crowded with solutes, soluble macromolecules such as enzymes, nucleic acids, structural proteins and membranes. The high protein density within the large compartments of the cells predominantly determines the major characteristics of cellular environment such as viscosity, diffusion and inhomogeneity. The fact that the solvent viscosity of cytoplasm is not substantially different from the water is explained by intracellular structural heterogeneity: the intrinsic macromolecular density is relatively low within the interstitial voids in the cell because many soluble enzymes are apparently integral parts of the insoluble cytomatrix and are not distributed homogeneously. The molecular crowding and sieving restrict the mobility of very large solutes, binding severely restrict the mobility of smaller solutes. One of consequence of molecular crowding and hindered diffusion is the need to compartmentalize metabolic pathway to overcome diffusive barriers. Although the movement of small molecules is slowed down in the cytoplasm, the metabolism can successfully proceed and even be facilitated by metabolite channeling which directly transfers the intermediate from one enzyme to an adjacent enzyme without the need of free aqueous-phase diffusion. The enhanced probability for intermediates to be transferred from one active site to the other by sequential enzymes requires stable or transient interactions of the relevant enzymes, which associate physically in non-dissociable, static multienzyme complexes--metabolones, particles containing enzymes of a part or whole metabolic systems. Therefore, within the living cell the metabolism depends on the structural organization of enzymes forming microcompartments. Since cells contain many compartments and microenvironments, the measurement of the concentration of metabolites in whole cells or tissues gives an average cellular concentration and not that which is actually sensed by the active site of a specific enzyme. Thus, the microcompartmentation could provide a mechanism which can control metabolic pathways. Independently and in parallel to the developments described above, the ideas of compartmentation came into existence from the necessity to explain important physiological phenomena, in particular in heart research and in cardiac electrophysiology. These phenomena demonstrated the physiological importance of the biophysical and biochemical mechanisms described in this review.     

On artificial immune systems and swarm intelligence

This position paper explores the nature and role of two bio-inspired paradigms, namely Artificial Immune Systems (AIS) and Swarm Intelligence (SI). We argue that there are many aspects of AIS that have direct parallels with SI and examine the role of AIS and SI in science and also in engineering, with the primary focus being on the immune system. We explore how in some ways, algorithms from each area are similar, but we also advocate, and explain, that rather than being competitors, AIS and SI are complementary tools and can be used effectively together to solve complex engineering problems.     

Effect of baroreceptor activity on ventilatory response to chemoreceptor stimulation.

This study tested the hypothesis that ventilatory responses to chemoreceptor stimulation are affected by the level of arterial pressure and degree of baroreceptor activation. Carotid chemoreceptors were stimulated by injection of nicotine into the common carotid artery of anesthetized dogs. Arterial pressure was reduced by bleeding the animals and raised by transient occlusion of the abdominal aorta. The results indicate that ventilatory responses to chemoreceptor stimulation were augmented by hypotension and depressed by hypertension. In additional studies we excluded the possibility that the findings were produced by a direct effect of changes in arterial pressure on chemoreceptors. Both carotid bifurcations were perfused at constant flow. In one carotid bifurcation, perfusion pressure was raised to stimulate carotid sinus baroreceptors. In the other carotid bifurcation, pressure was constant and nicotine was injected to stimulate carotid chemoreceptors. Stimulation of baroreceptors on one side attenuated the ventilatory response to stimulation of contralateral chemoreceptors. This inhibition was observed before and after bilateral cervical vagotomy. We conclude that there is a major central interaction between baroreceptor and chemoreceptor reflexes so that changes in baroreceptor activity modulate ventilatory responses to chemoreceptor stimulation.     

Increased chemoreceptor output and ventilatory response to sustained hypoxia

In adult humans the ventilatory response to sustained hypoxia (VRSH) is biphasic, characterized by an initial brisk increase, due to peripheral chemoreceptor (PC) stimulation, followed by a decline attributed to central depressant action of hypoxia. To study the effects of selective stimulation of PC on the ventilatory response pattern to hypoxia, the VRSH was evaluated after pretreatment with almitrine (A), a PC stimulant. Eight subjects were pretreated with A (75 mg po) or placebo (P) on 2 days in a single-blind manner. Two hours after drug administration, they breathed, in succession, room air (10 min), O2 (5 min), room air (5 min), hypoxia [25 min, arterial O2 saturation (SaO2) = 80%], O2 (5 min), and room air (5 min). End-tidal CO2 was kept constant at the normoxic base-line values. Inspiratory minute ventilation (VI) and breathing patterns were measured over the last 2 min of each period and during minutes 3-5 of hypoxia, and nadirs in VI were assessed just before and after O2 exposure. Independent of the day, the VRSH was biphasic. With P and A pretreatment, early hypoxia increased VI 4.6 +/- 1 and 14.2 +/- 1 (SE) l/min, respectively, from values obtained during the preceding room-air period. On A day the hypoxic ventilatory decline was significantly larger than that on P day, and on both days the decline was a constant fraction of the acute hypoxic response.(ABSTRACT TRUNCATED AT 250 WORDS)     

On the origin of meiosis and sex.

The pre-karyote (the host for alpha-proteobacteria) is not assumed to have had a fusion prohibiting cell surface, and thus unlike prokaryotes could have practiced sex. A single DNA damage checkpoint control might have been the only checkpoint pathway regulating the ancient pre-karyotic cell cycle from which the modern eukaryotic cell cycle evolved. This single checkpoint would allow the cell division only when all the pre-karyote genome was completely replicated without mistakes. If the restart of DNA replication was impossible after DNA damage, the last chance to survive for this in S-phase blocked pre-karyote would be the fusion with the partner. After the fusion, recombination, and subsequent completing the replication of both haploid sets, the single DNA damage checkpoint would allow two subsequent rounds of fission. The fusion might have represented both useful repair strategy, and a mechanism of horizontal transmission of the ancestors of mitochondria. The presence/absence of these symbionts might have been a primordial form of sexual determination.     

On the mechanistic origin of damped oscillations in biochemical reaction systems

A generalized reaction scheme for the kinetic interaction of two reactants in a metabolic pathway has been examined in order to establish what minimal mechanistic patterns are required to support a damped oscillatory transient-state kinetic behaviour of such a two-component system when operating near a steady state. All potentially oscillating sub-systems inherent in this scheme are listed and briefly characterized. The list includes several mechanistic patterns that may be frequently encountered in biological system (e.g. involving feedback inhibition, feed-forward activation, substrate inhibition or product activation), but also draw attention to some hitherto unforeseen mechanisms by which the kinetic interaction of two metabolites may trigger damped oscillations. The results can be used to identify possible sources of oscillations in metabolic pathways without detailed knowledge about the explicit rate equations that apply.     

On the origin of the adaptative immune system (AIS): the hypothesis

The adaptive immune system (AIS) appears exclusively at the vertebrate ones with jaw. In parallel, the lymphoid tissu associated with the digestive tract, or GALT (gut associated lympho?d tissu), seems to play an essential part in the development of this response immune with memory. That one could find its origin in the innate immune system of the invertebrates and closer the cyclostomes (vertebrates without jaws). But the transition is brutal since the chondrychtyens (lines, sharks) do have the AIS but the cyclostomes not. Moreover, it is still enigmatic and source of speculations. The gnathostomes (vertebrate with jaw) raise ancestral and adaptive innate defences of which acquisition will be discussed here. We will also discuss the consequences of integration in the genome by rag1 and rag2 genes (recombination activating genes).