O-glycosylation of the Plasmodium sporozoite surface proteins CSP and TRAP was recently identified, but the role of this modification in the parasite life cycle and its relevance to vaccine design remain unclear. Here, we identify the Plasmodium protein O-fucosyltransferase (POFUT2) responsible for O-glycosylating CSP and TRAP. Genetic disruption of POFUT2 in Plasmodium falciparum results in ookinetes that are attenuated for colonizing the mosquito midgut, an essential step in malaria transmission. Some POFUT2-deficient parasites mature into salivary gland sporozoites although they are impaired for gliding motility, cell traversal, hepatocyte invasion, and production of exoerythrocytic forms in humanized chimeric liver mice. These defects can be attributed to destabilization and incorrect trafficking of proteins bearing thrombospondin repeats (TSRs). Therefore, POFUT2 plays a similar role in malaria parasites to that in metazoans: it ensures the trafficking of Plasmodium TSR proteins as part of a non-canonical glycosylation-dependent endoplasmic reticulum protein quality control mechanism.

We tested the hypotheses that: (1) anxiety regarding the possibility of falling alters the attentional demands of gait; and (2) this alteration in the attentional requirements of gait occurs independently of gait pattern accommodations. Sixteen younger and 15 older adults participated in this study. Subjects walked at a self-determined velocity along a 7.2-m walkway under four conditions of postural threat; the walking conditions varied depending on the width constraints of the walkway (60 cm vs 15 cm) and the height of the walking surface (0 cm vs 60 cm). Attentional demands of locomotion in each condition of testing were assessed using the dual-task methodology, in which participants verbally responded to an auditory cue as quickly as possible while continuing to walk. Our findings revealed that: (1) participants were successful in verbally responding to the auditory cue without modifying their gait pattern; (2) reaction times increased for all subjects when walking in the condition of greatest postural threat; (3) the attentional demands for locomotion varied with the phase of the gait cycle for younger adults but not for older adults; (4) the phase-dependent effect for younger adults disappeared in the condition of greatest postural threat, while reaction time scores for older adults systematically increased; and (5) increases in reaction time persisted despite significant changes in gait kinematics. Our findings confirm that anxiety increases the attentional demands for locomotion and provide further explanation for age-dependent increases in the attentional demands of gait. Furthermore, our findings confirm that fall-related anxiety predicates an increase in the allocation of attention to locomotor control that is independent of gait pattern adjustments.

DEDICATIONI dedicate this thesis to my Poppa, John Joseph Lacey. You have taught me the meaning of dignity.iii ABSTRACTThe effects of postural threat and the potential consequences of obstacle contact on the obstacle negotiation kinematics among younger and older adults were examined. Seventeen older (OA; 7 males, 10 females; mean age, 68.94 ± 4.85) and fifteen younger adults (YA; 5 males, 10 females; mean age, 22.53 ± 2.77) negotiated virtual and real obstacles while walking at a self-determined velocity along a 7.2m walkway under 4 different conditions of postural threat. Postural threat was manipulated by varying the width (0.60m versus 0.15m) and height (floor versus elevated (0.00m versus 0.60m)) of the walkway. Postural threat altered crossing kinematics for all subjects. Specifically, age-related differences emerged with increasing postural threat, however die changes observed among older adults were considerably different from those of younger adults. Additionally, there was an effect for the potential consequences of obstacle contact, however, no age-related differences emerged. These results revealed an effect for postural threat and obstacle characteristics on the negotiation strategies of younger and older adults. Both postural threat and obstacle characteristics elicit conservative crossing kinematics in younger and older adults. Specifically, these findings illustrate age-dependent differences in obstacle negotiation strategies and that postural threat affects older adults differently than younger adults whereas the potential consequences of obstacle contact affects younger and older adults equally. iv ACKNOWLEDGEMENTSWe did it! This thesis would not have been possible without die support of my family and friends. I would like to show my appreciation to everyone who encouraged and stood by me during the creation of this thesis.

The task of obstacle negotiation, from precrossing through obstacle crossing, is attentionally demanding for elderly persons, and fall risk, due to a compromised availability of attentional resources, does occur prior to obstacle crossing in this age group.

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