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Amyloids refer to a class of protein or peptide aggregates that are heterogeneous in size, morphology, and composition, and are implicated to play a central role in many neurodegenerative and systemic diseases. The strong correlation between biological activity and extent of aggregation of amyloidogenic proteins and peptides has led to an explosion of research efforts to target these materials with synthetic molecules or engineered antibodies to try to attenuate their function in disease pathology. Although many of these efforts to attenuate amyloid function have shown great promise in laboratory settings, the vast majority of work has been focused on targeting amyloids associated with neurologic diseases, which has been met with significant additional challenges that preclude clinical evaluation. Only recently have researchers started applying their efforts toward neutralizing the activity of amyloids associated with non-neurologic diseases. For instance, small peptides present in high abundance in human semen have been found to aggregate into amyloid-like fibrils, with in vitro experiments indicating that these amyloid fibrils could potentially increase the rate of infection of pathogens such as HIV by over 400 000-fold during sexual contact. Mechanistic investigations of naturally occurring seminal amyloid species such as Semen-derived Enhancer of Virus Infection (SEVI) and related natural peptide aggregates suggest that these materials interact strongly with virus particles and cell surfaces, facilitating viral attachment and internalization into cells and, thus, possibly promoting sexual transmission of disease. Such amyloid mediators in HIV transmission represent an attractive target for development of chemical approaches to attenuate their biological activity. For instance, the activity of seminal amyloids in genital fluids potentially allows for topical delivery of amyloid-targeting molecules, which could minimize common problems with systemic toxicity or permeability across biological barriers. In addition, molecules that target these amyloid mediators in viral attachment could potentially work synergistically with current antiviral agents to reduce the rate of HIV transmission. This Account will briefly summarize some of the key evidence in support of the capability of SEVI to enhance viral infection, and will highlight examples, many from our group, of recent efforts aimed at inhibiting its activity using synthetic small molecules, oligomeric peptides, and polymeric materials. We present various chemical strategies that have shown promise for neutralizing the role of SEVI in HIV transmission including the development of aggregation inhibitors of SEVI fibril formation, small molecule amyloid binders that modulate the charge or structure of SEVI, and synthetic molecules that form bioresistive coatings on SEVI and inhibit its interaction with the virus or cell surface. We discuss some unique challenges that hamper translation of these molecular strategies toward clinical evaluation, and propose several opportunities for researchers to address these challenges.

Semen-derived enhancer of virus infection (SEVI) fibrils are naturally abundant amyloid aggregates found in semen that facilitate viral attachment and internalization of human immunodeficiency virus (HIV) in cells, thereby increasing the probability of infection. Mature SEVI fibrils are composed of aggregated peptides exhibiting high β-sheet secondary structural characteristics. Herein, we show that polymers containing hydrophobic side chains can interact with SEVI and reduce its β-sheet content by ∼45% compared with the β-sheet content of SEVI in the presence of polymers with hydrophilic side chains, as estimated by polarization modulation-infrared reflectance absorption spectroscopy measurements. A nanoparticle (NP) formulation of this hydrophobic polymer reduced SEVI-mediated HIV infection in TMZ-bl cells by 60% compared with the control treatment. Although these NPs lacked specific amyloid-targeting groups, thus requiring high concentrations to observe biological activity, the use of hydrophobic interactions to alter the secondary structure of amyloids represents a useful approach to neutralizing the SEVI function. These results could, therefore, have general implications in the design of novel materials that can modify the activity of amyloids associated with a variety of other neurological and systemic diseases.

Three experiments investigated the relationship between future thinking and false memories. In Experiment 1, participants remembered familiar events (e.g., a holiday) from their past, imagined planning the same events in the future, or took part in a control condition in which they visualized typical events. They then rated a series of schema-related and schema-unrelated nouns for how likely they were to be encountered within those events. In a surprise recognition test, participants in the future condition falsely recognized more schema-related items than participants in the past and control conditions. No reliable effects of rating condition were observed in correct recognition. Experiment 2 found the same pattern when participants imagined unfamiliar events (e.g., taking part in a bank robbery) from past or future perspectives. Participants in Experiment 3 remembered a past or imagined a future holiday and were then instructed to generate items that someone might take on a holiday. Participants in the future condition generated more nonstudied items and fewer studied items relative to participants in the past condition. The findings of Experiments 1 and 2 indicate that simulating future events enhances the activation of related items that gives rise to false memories. The findings of Experiment 3 suggest that these activation processes play an adaptive role in guiding the planning of future events.

Previous research by the authors found that mental toughness, as measured by the Mental Toughness Questionnaire 48 (MTQ48; Clough, P.J., Earle, K., & Sewell, D. [2002]. Mental toughness: the concept and its measurement. In I. Cockerill (Ed.), Solutions in sport psychology [pp. 32-43]. London: Thomson Publishing), was significantly associated with performance on the list-method directed forgetting task. The current study extends this finding to the item-method directed forgetting task in which the instruction to Remember or Forget is given after each item in the study list. A significant positive association was found between the correct recognition of Remember words and the emotional control subscale of the MTQ48. No significant associations were observed with other measures of mental toughness or personality. The findings are discussed in terms of the relationship between mental toughness and cognitive control.

The semen-derived enhancer of virus infection (SEVI) is a natural amyloid material that has been shown to substantially increase viral attachment and infectivity of HIV in cells. We previously reported that synthetic monomeric and oligomeric amyloid-targeting molecules could form protein-resistive coatings on SEVI and inhibit SEVI- and semen-mediated enhancement of HIV infectivity. While oligomeric amyloid-binding compounds showed substantial improvement in apparent binding to SEVI compared to monomeric compounds, we observed only a modest correlation between apparent binding to SEVI and activity for reducing SEVI-mediated HIV infection. Here, we synthesized amyloid-binding polyacrylate-based polymers and polymeric nanoparticles of comparable size to HIV virus particles (∼150 nm) to assess the effect of sterics on the inhibition of SEVI-mediated enhancement of HIV infectivity. We show that these polymeric materials exhibit excellent capability to reduce SEVI-mediated enhancement of HIV infection, with the nanoparticles exhibiting the greatest activity (IC50 value of ∼4 μg/mL, or 59 nM based on polymer) of any SEVI-neutralizing agent reported to date. The results support that the improved activity of these nanomaterials is likely due to their increased size (diameters = 80-200 nm) compared to amyloid-targeting small molecules and that steric interactions may play as important a role as binding affinity in inhibiting viral infection mediated by SEVI amyloids. In contrast to the previously reported SEVI-neutralizing, amyloid-targeting molecules (which required concentrations at least 100-fold above the Kd to observe activity), the approximate 1:1 ratio of apparent Kd to IC50 for activity of these polymeric materials suggests the majority of polymer molecules that are bound to SEVI contribute to the inhibition of HIV infectivity enhanced by SEVI. Such size-related effects on physical inhibition of protein-protein interactions may open further opportunities for the use of targeted nanomaterials in disease intervention.

Previous research demonstrating that positive episodic simulation enhances future expectancies has relied on explicit expectancy measures. The current study investigated the effects of episodic simulation on implicit expectancies. Using the Future Thinking Implicit Relational Assessment Procedure (FT-IRAP), participants made true/false decisions to indicate whether or not they expected positive/negative outcomes after adopting orientations consistent or inconsistent with an optimistic disposition. The outcome measure, DIRAP, was based on response time differences between consistent and inconsistent blocks. Participants then engaged in either positive simulation training, in which they imagined positive future events, or a neutral visualisation task before repeating the FT-IRAP twice following 10-minute intervals. Positive simulation training increased DIRAP scores for don't-expect-negative trials–boosting participants' readiness to affirm that negative events were unlikely to happen to them. Although findings did not generalise across all trial types, they show potential for positive simulation training to enhance implicit future expectancies. [ABSTRACT FROM AUTHOR]

The effect of list length on children's false memories was investigated using list and story versions of the Deese/Roediger-McDermott procedure. Short (7 items) and long (14 items) sequences of semantic associates were presented to children aged 6, 8, and 10 years old either in lists or embedded within a story that emphasized the list theme. Subsequent tests of recognition memory revealed different effects of length for lists and stories across development. Longer lists produced more false alarms to critical lures for 8- and 10-year-olds only, and longer stories produced more false alarms to critical lures for 6-year-olds only. These results demonstrate that increasing the number of items presented at study increases false recognition for younger as well as older children when the theme of the items is made salient. (Contains 2 figures and 1 table.)

Recent literature has argued that whereas remembering the past and imagining the future make use of shared cognitive substrates, simulating future events places heavier demands on executive resources. These propositions were explored in 3 experiments comparing the impact of imagery and concurrent task demands on speed and accuracy of past event retrieval and future event simulation. Results provide support for the suggestion that both past and future episodes can be constructed through 2 mechanisms: a noneffortful "direct" pathway and a controlled, effortful "generative" pathway. However, limited evidence emerged for the suggestion that simulating of future, compared with retrieving past, episodes places heavier demands on executive resources; only under certain conditions did it emerge as a more error prone and lengthier process. The findings are discussed in terms of how retrieval and simulation make use of the same cognitive substrates in subtly different ways. (Contains 3 tables.)