1. This study demonstrates plasticity of the vestibuloocular reflex (VOR) in chickens and compares it to that of other species and to that of newly hatched chicks. Adaptive changes in the VOR were induced by subjecting the animals to combinations of visual and vestibular stimuli that simulated the effect of the VOR being either too low in gain or reversed in phase. 2. The VOR of chickens resembles that of mammals, but the curve of phase lead versus frequency seems shifted toward higher frequencies. The VOR of newly hatched chicks has extremely low gain (less than 0.1). 3. In both the older and newly hatched animals, the VOR gain increased substantially after 2 h in an environment in which the imposed en bloc rotations produced increased retinal image slip in the normal directions. Similarly, 2 h of reversed retinal image slip produced decreased VOR gain and, in some cases, reversal fo the phase of the VOR. The gain changes were largest at the "training" frequency. The phase changes were in the direction of increased phase lead. Changes in the gains of the optokinetic responses and of the combination of VOR and optokinetic responses were also seen, especially in the newly hatched animals. 4. The newly hatched birds showed the largest VOR changes in the increased-gain situation, whereas the older birds showed the largest changes in the reversed-phase situation, as assessed by the changes in the average retinal slip velocity experienced. These results may well not be a consequence of differences in age, per se, but of differences in average retinal slip experienced in the two experimental situations at the start of the trial because of the lower VOR gain of the newly hatched animals. There seems to be no dramatic difference in VOR plasticity between newly hatched and older birds. 5. Our results with reversed visual motion are substantially different from those obtained in similar studies on rabbits, suggesting that these two species use different error signals to control the adaptive adjustment of the VOR.
25 26 KEY WORDS: Streptococcus pneumoniae, infection tolerance, autophagy, pneumolysin, pore-27 forming toxin, cholesterol dependent cytolysin, cation-π interaction 28 2 ABSTRACT 29 The opportunistic pathogen Streptococcus pneumoniae has dual lifestyles: one of an asymptomatic 30 colonizer in the human nasopharynx and the other of a deadly pathogen invading sterile host 31 compartments. The latter triggers an overwhelming inflammatory response, partly driven via pore 32 forming activity of the cholesterol dependent cytolysin (CDC), pneumolysin. Although 33 pneumolysin-induced inflammation drives person-to-person transmission from nasopharynx, the 34 primary reservoir for pneumococcus, it also contributes to high mortality rates, creating a 35 bottleneck that hampers widespread bacterial dissemination, thus acting as a double-edged sword. 36 Serotype 1 ST306, a widespread pneumococcal clone, harbours a non-hemolytic variant of 37 pneumolysin (Ply-NH). Performing crystal structure analysis of Ply-NH, we identified Y150H and 38 T172I as key substitutions responsible for loss of its pore forming activity. We uncovered a novel 39 inter-molecular cation-π interaction, governing formation of the transmembrane β-hairpins (TMH) 40 in the pore state of Ply, which can be extended to other CDCs. H150 in Ply-NH disrupts this 41 interaction, while I172 provides structural rigidity to domain-3, through hydrophobic interactions, 42 inhibiting TMH formation. Loss of pore forming activity enabled improved cellular invasion and 43 autophagy evasion, promoting an atypical intracellular lifestyle for pneumococcus, a finding that 44 was corroborated in in vivo infection models. Attenuation of inflammatory responses and tissue 45 damage promoted tolerance of Ply-NH-expressing pneumococcus in the lower respiratory tract. 46 Adoption of this altered lifestyle may be necessary for ST306 due to its limited nasopharyngeal 47 157 pneumolysin (Ply-H; 5CR6 and 4QQA) (16, 22). Superposition of Ply-NH structure with the 158 recently reported structures of Ply-H (5CR6 and 4QQA) (16, 22) produced root mean square 159 deviation (r.m.s.d.) of 2.4 and 1.2 Å, respectively, over 471 Cα atoms. Superposition of specific 160 domains, D1-3 of Ply-NH and Ply-H (5CR6) yielded r.m.s.d. of 0.75 Å and alignment of only D4 161
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