Parasite treatment affects maternal investment in sons.

Parasitism can be a major constraint on host condition and an important selective force. Theoretical and empirical evidence shows that maternal condition affects relative investment in sons and daughters; however, the effect of parasitism on sex ratio in vertebrates is seldom considered. We demonstrate experimentally that parasitism constrains the ability of mothers to rear sons in a long-lived seabird, the European shag Phalacrocorax aristotelis. The effect contributes to the decline in offspring survival as the breeding season progresses and hence has important population-level consequences for this, and potentially other, seasonal breeders.

The Arp2/3 complex is essential for the actin-based motility of Listeria monocytogenes.

Actin polymerisation is thought to drive the movement of eukaryotic cells and some intracellular pathogens such as Listeria monocytogenes. The Listeria surface protein ActA synergises with recruited host proteins to induce actin polymerisation, propelling the bacterium through the host cytoplasm [1]. The Arp2/3 complex is one recruited host factor [2] [3]; it is also believed to regulate actin dynamics in lamellipodia [4] [5]. The Arp2/3 complex promotes actin filament nucleation in vitro, which is further enhanced by ActA [6] [7]. The Arp2/3 complex also interacts with members of the Wiskott-Aldrich syndrome protein (WASP) [8] family - Scar1 [9] [10] and WASP itself [11]. We interfered with the targeting of the Arp2/3 complex to Listeria by using carboxy-terminal fragments of Scar1 that bind the Arp2/3 complex [11]. These fragments completely blocked actin tail formation and motility of Listeria, both in mouse brain extract and in Ptk2 cells overexpressing Scar1 constructs. In both systems, Listeria could initiate actin cloud formation, but tail formation was blocked. Full motility in vitro was restored by adding purified Arp2/3 complex. We conclude that the Arp2/3 complex is a host-cell factor essential for the actin-based motility of L. monocytogenes, suggesting that it plays a pivotal role in regulating the actin cytoskeleton.

Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex.

The Arp2/3 complex, a stable assembly of two actin-related proteins (Arp2 and Arp3) with five other subunits, caps the pointed end of actin filaments and nucleates actin polymerization with low efficiency. WASp and Scar are two similar proteins that bind the p21 subunit of the Arp2/3 complex, but their effect on the nucleation activity of the complex was not known. We report that full-length, recombinant human Scar protein, as well as N-terminally truncated Scar proteins, enhance nucleation by the Arp2/3 complex. By themselves, these proteins either have no effect or inhibit actin polymerization. The actin monomer-binding W domain and the p21-binding A domain from the C terminus of Scar are both required to activate Arp2/3 complex. A proline-rich domain in the middle of Scar enhances the activity of the W and A domains. Preincubating Scar and Arp2/3 complex with actin filaments overcomes the initial lag in polymerization, suggesting that efficient nucleation by the Arp2/3 complex requires assembly on the side of a preexisting filament-a dendritic nucleation mechanism. The Arp2/3 complex with full-length Scar, Scar containing P, W, and A domains, or Scar containing W and A domains overcomes inhibition of nucleation by the actin monomer-binding protein profilin, giving active nucleation over a low background of spontaneous nucleation. These results show that Scar and, likely, related proteins, such as the Cdc42 targets WASp and N-WASp, are endogenous activators of actin polymerization by the Arp2/3 complex.

Cholinergic deafferentation enhances rat hippocampal pyramidal neuron responsiveness to locally applied nicotine.

We tested whether cholinergic denervation of the hippocampus of young rats would result in an enhancement of CA1 pyramidal cell responsiveness to nicotine. Electrolytic lesions of the medial septal area were performed in young male Fisher 344 rats. One month later the rats were anesthetized with pentobarbital and nicotine was locally applied to CA1 pyramidal neurons using pressure microejection. The dose of nicotine required to excite the pyramidal neurons was significantly lower for cells recorded from rats with septal lesions. However, no changes in hippocampal cytisine or alpha-bungarotoxin binding were found.

Neuropeptide processing in pathophysiology.

Neuropeptides (peptides synthesized and secreted by neurons) perform many functions in the central nervous system as neurotransmitters, neuromodulators and neurotrophic factors. Neuropeptides are important regulators of amine neurotransmitter release, and can be identified as playing important roles in several pathological states. Neuropeptides are synthesized as protein precursors that are processed enzymatically to yield the biologically active peptides. Many neuropeptides having defined roles are further processed enzymatically to yield fragments having totally different actions. Examples discussed are substance P, adrenocorticotrophic hormone, endorphins and vasopressin.

The effectiveness of directed multisensory stimulation versus non-directed stimulation in comatose CHI patients: pilot study of a single subject design.

In view of the difficulties in finding control groups in sensory stimulation research, a single case methodology was explored. A pilot study was conducted on six comatose CHI patients in a neurosurgical intensive care unit. Each patient was given alternating weeks of directed multisensory stimulation (SDS) and non-directed stimulation (NDS) for half an hour a day in an ABAB single subject design. Eye movement, motor and vocal response to stimulation were recorded using the Sensory Stimulation Assessment Measure (Rader Scale). Comparisons of eye movement and motor responses on the Rader Scale appeared to indicate a greater degree of responsiveness to the SDS as compared with the NDS treatment. Overall improvement levels on the GCS, Rancho Scale and Western Neurosensory Stimulation Profile are discussed. The results are interpreted as indicative of the potential value of using single case methodology in this population, and future research directions are also discussed.

The substance P fragment SP(1-7) stimulates motor behavior and nigral dopamine release.

Earlier studies have shown that the undecapeptide substance P (SP) alters motor behavior and dopamine metabolism following injection into the substantia nigra (SN) in rat, even though the SN appears largely devoid of SP-specific (NK-1) receptors. In this report, intra-nigral injections of the amino-terminal SP fragment SP(1-7) enhanced rearing, sniffing and locomotor activity, and increased the nigral DOPAC-to-DA ratio. In addition, SP(1-7) increased 3H-DA release from the SN in vitro. These findings suggest that some of the effects of nigral SP on motor behavior and dopamine release are mediated by amino-terminal fragments of SP.

Cardiovascular effects of substance P peptides in the nucleus of the solitary tract.

Microinjection of the neuropeptide substance P (SP) into the baroreceptor portions of the nucleus of the solitary tract (NTS) caused a dose-dependent decrease in blood pressure (BP) and heart rate (HR), consistent with the putative role for SP as a transmitter in the baroreceptor reflex arc. In contrast, SP elevated BP and HR when microinjected into the adjacent area postrema. Structure-activity studies of effects of SP in the NTS revealed that an aminoterminal heptapeptide fragment of SP could fully reproduce the depressor and bradycardic effects of SP. In contrast, a carboxyterminal hexapeptide fragment of SP significantly elevated both BP and HR. The structural requirements for aminoterminal fragment effects were quite specific in terms of peptide length and sensitivity to D-amino acid substitutions. These findings are consistent with a role for SP as a baroreceptor reflex transmitter and suggest, furthermore, that this action is mediated by the aminoterminal region of SP.

The role of enzymatic processing in the biological actions of substance P.

There is considerable evidence that substance P (SP) is a neurotransmitter in the CNS. Current findings suggest that the effects of synaptically released SP are terminated by enzymatic breakdown, primarily by endopeptidase 3.4.24.11 (endo 24.11). The products of cleavage by endo 24.11 include the amino-terminal fragment SP(1-7). Evidence suggests that SP is involved in mediating baroreceptor reflex activity in the nucleus of the solitary tract (NTS). Microinjection of SP into the NTS lowered blood pressure and heart rate. Microinjection of SP(1-7) into the NTS reproduced the effects of SP on both heart rate and blood pressure. Intra-NTS injection of phosphoramidon, an inhibitor of endo 24.11 activity, completely blocked the effects of a subsequent injection of SP. This blocking effect of phosphoramidon was unaltered by pretreatment with the opiate inhibitor naloxone. In contrast, phosphoramidon failed to block the depressor and bradycardic effects of SP(1-7). The implications of these findings regarding the role of endo 24.11 in the metabolism of SP are discussed.

Nigral 5-HT and substance P-induced enhancement of passive avoidance retention.

Peripheral, posttraining injection of substance P (SP) has been shown to facilitate the retention of aversive and appetitive learning tasks, suggesting that SP may play a role in information processing. In addition, SP may modulate the release of nigrostriatal monoamines, which have also been linked with avoidance learning. This paper examines the interaction between SP and nigrostriatal monoamines by observing the behavioral effects of neurochemical lesions on SP-induced avoidance retention, and by measuring changes in nigrostriatal monoamine activity and receptor regulation following avoidance training and SP injection. In Expt. 1, 5,7-dihydroxytryptamine lesions of the substantia nigra, but not the caudate, attenuated the retention-enhancing effects of posttraining SP injection. Further, 6-hydroxydopamine lesions of the substantia nigra produced a deficit in avoidance conditioning that was reversed by posttraining SP injection. Expts. 2 and 3 demonstrated that although passive avoidance training and posttraining SP injections did not significantly alter nigral 5-hydroxytryptamine (5-HT) activity, SP increased 5-HT1 receptor density. It was concluded that SP may affect avoidance retention by modulating nigral 5-HT activity.

Effects of substance P and neurokinin A (substance K) on motor behavior: unique effect of substance P attributable to its amino-terminal sequence.

The effects of intraventricular injections of the neuropeptides substance P (SP) and neurokinin A (NK-A; also called substance K) on spontaneous motor behavior were examined in mice. SP and NK-A were essentially equipotent at enhancing grooming and scratching behavior, and at reducing sniffing behavior. However, SP significantly enhanced hindlimb rearing behavior, while NK-A reduced this behavior. The effects of 3 other tachykinins, physalaemin, eledoisin and kassinin, were comparable to those of NK-A, including the reduction in rearing. Thus, SP is unique among tachykinins in its potentiation of rearing behavior. It was further demonstrated that carboxy-terminal SP fragments with tachykinin activity on smooth muscle resemble NK-A, and not SP, in their effects on motor behavior. In contrast, amino-terminal SP fragments, devoid of tachykinin-like activity, reproduced the one motor effect unique to SP, enhanced rearing, while lacking those actions common to all tachykinins. The structural requirements for enhanced rearing behavior by amino-terminal fragments were quite specific, in terms of chain length and sensitivity to D-amino acid substitutions, with the natural amino-terminal hexa- and heptapeptides being most active. The implications of these findings are discussed in light of recent observations that these same amino-terminal SP fragments are produced in vivo as metabolites of SP.

Modulation of blood pressure by substance P: opposite effects of N- and C- terminal fragments on anesthetized rats.

Considerable evidence suggests that substance P (SP) may be a transmitter mediating the depressor effects of baroreceptor reflex activation within the brainstem, yet intracerebroventricular administration of SP is reported to result in a pronounced pressor effect. In this study, SP injected into the 4th cerebral ventricle produced a biphasic effect; a brief decrease in blood pressure followed by a lengthy increase. Similar injections of a carboxy-terminal fragment of SP produced only a pressor effect of long duration. Injection of an amino-terminal SP fragment produced only a brief, rapid depressor effect. These results suggest that the amino-terminal sequence of SP may be involved in mediating the depressor effects of baroreceptor activation.

Myocardium and cortex cerebri xenografts transplanted into the anterior chamber of the eye of athymic rats: a morphologic and electrophysiologic profile.

Heart atria and cortex cerebri from fetal rabbits (E14 and E18, respectively) were grafted into the anterior eye chamber of anesthetized athymic nude rats and allowed to mature for 2-11 weeks. All grafts received a rich vascular supply from the host iris. Atrial transplants survived well but showed no significant growth while cortex grafts increased in size an average of 320%. Spontaneous action potentials were recorded from cellular elements in both tissues and, in the case of the atria, were accompanied by observable contractions. Functional cholinergic innervation from the autonomic ground plexus of the iris was elicited in both types of grafts by phasic retinal illumination. No evidence of immunologic rejection was found by histological analysis. Taken together, these data suggest that athymic rats may provide an appropriate host environment to study transplants of the central nervous and peripheral tissue from immunologically otherwise incompatible mammalian species.

Age and strain differences in some behavioral effects of intracranial substance P.

Intracerebroventricular (ICV) injections of substance P (SP) induce a vigorous reciprocal hindlimb scratching (RHS) syndrome, accompanied by extensive grooming behavior. There is a significant (approximately 1000X) difference in responsiveness to SP, as measured by RHS and grooming, in mice as a function of genetic strain (Swiss/Webster, C57 or DBA) and age. There was considerable specificity in the ability of drugs to increase responsiveness in the least responsive type of mouse (aged DBA/2J). Responding in old DBAs was enhanced by high doses of naloxone, suggesting the involvement of opioid peptides. Significant enhancement of responding by alpha-methyl tyrosine and propranolol, but not by phenoxybenzamine or haloperidol, indicated that beta-adrenergic systems are also involved. Similar manipulations of serotonergic systems were without effect.

Novel analgesic peptides.

Several different classes of peptides have been found to confer antinociception upon treated animals. The now-classical enkephalins, endorphins and dynorphin have been much studied. This paper reviews enkephalins of atypical structure as well as a group of peptides which evoke antinociception apparently by stimulating release of opioid peptides. Among the latter are kyotorphin, substance P, bradykinin and neurotensin.

Modulation of isolation-induced fighting by N- and C-terminal analogs of substance P: evidence for multiple recognition sites.

Substance P (SP) significantly reduced fighting in mice made aggressive by prolonged isolation. The N-terminal heptapeptide fragment SP (1-7) also reduced fighting. The C-terminal fragment SP(4-11) was without activity, while the shorter C-terminal fragment analog less than E-SP(7-11) significantly increased isolation-induced fighting. The aggression-enhancing effect of less than E-SP(7-11) was antagonized by naloxone, which by itself had no significant effect. The aggression-reducing effect of SP(1-11) was significantly enhanced by naloxone, while the effect of SP(1-7) was unchanged. These results demonstrate that a behavioral effect of SP may be duplicated by an N-terminal fragment of the SP molecule, and that peptide fragments or analogs of the N- and C-terminal portions of the SP molecule can exert opposing effects on a specific behavior. These findings represent a structure/activity relationship that is strikingly different from any previously described for SP. The differing effects of naloxone on N- and C-terminal fragment analogs suggest that these two effects may be mediated by different mechanisms.

Prevention of stress-induced analgesia by substance P.

It has been shown that a variety of stressful procedures, such as immobilization and footshock, can induce a significant degree of analgesia in mice. In addition, it has been shown that for some, but not all, stressful treatments, the analgesic effect is mediated via endogenous opioids. This report describes the effects of substance P, administered systemically, on both opioid-mediated immobilization-induced analgesia and non-opioid footshock-induced analgesia. Substance P completely blocked the opioid-mediated form of stress-induced analgesia while having no effect on the non-opioid form. Exogenous substance P appears to interact with endogenous opioid pain-suppressing systems.