New design strategies for ultra-specific CRISPR-Cas13a-based RNA detection with single-nucleotide mismatch sensitivity.

An increasingly pressing need for clinical diagnostics has required the development of novel nucleic acid-based detection technologies that are sensitive, fast, and inexpensive, and that can be deployed at point-of-care. Recently, the RNA-guided ribonuclease CRISPR-Cas13 has been successfully harnessed for such purposes. However, developing assays for detection of genetic variability, for example single-nucleotide polymorphisms, is still challenging and previously described design strategies are not always generalizable. Here, we expanded our characterization of LbuCas13a RNA-detection specificity by performing a combination of experimental RNA mismatch tolerance profiling, molecular dynamics simulations, protein, and crRNA engineering. We found certain positions in the crRNA-target-RNA duplex that are particularly sensitive to mismatches and establish the effect of RNA concentration in mismatch tolerance. Additionally, we determined that shortening the crRNA spacer or modifying the direct repeat of the crRNA leads to stricter specificities. Furthermore, we harnessed our understanding of LbuCas13a allosteric activation pathways through molecular dynamics and structure-guided engineering to develop novel Cas13a variants that display increased sensitivities to single-nucleotide mismatches. We deployed these Cas13a variants and crRNA design strategies to achieve superior discrimination of SARS-CoV-2 strains compared to wild-type LbuCas13a. Together, our work provides new design criteria and Cas13a variants to use in future easier-to-implement Cas13-based RNA detection applications.

Migraine inhibitor olcegepant reduces weight loss and IL-6 release in SARS-CoV-2-infected older mice with neurological signs.

COVID-19 can cause neurological symptoms such as fever, dizziness, and nausea. However, such neurological symptoms of SARS-CoV-2 infection have been hardly assessed in mouse models. In this study, we infected two commonly used wild-type mouse lines (C57BL/6J and 129/SvEv) and a 129S calcitonin gene-related peptide (αCGRP) null-line with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including fever, dizziness, and nausea. We then evaluated whether a CGRP receptor antagonist, olcegepant, a "gepant" antagonist used in migraine treatment, could mitigate acute neuroinflammatory and neurological signs of SARS-COV-2 infection. First, we determined whether CGRP receptor antagonism provided protection from permanent weight loss in older (>18 m) C57BL/6J and 129/SvEv mice. We also observed acute fever, dizziness, and nausea in all older mice, regardless of treatment. In both wild-type mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels with virtually no IL-6 release in mice lacking αCGRP. These findings suggest that migraine inhibitors such as those blocking CGRP receptor signaling protect against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection, which may have repercussions for related pandemic or endemic coronavirus outbreaks.IMPORTANCECoronavirus disease (COVID-19) can cause neurological symptoms such as fever, headache, dizziness, and nausea. However, such neurological symptoms of severe acute respiratory syndrome CoV-2 (SARS-CoV-2) infection have been hardly assessed in mouse models. In this study, we first infected two commonly used wild-type mouse lines (C57BL/6J and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological symptoms including fever and nausea. Furthermore, we showed that the migraine treatment drug olcegepant could reduce long-term weight loss and IL-6 release associated with SARS-CoV-2 infection. These findings suggest that a migraine blocker can be protective for at least some acute SARS-CoV-2 infection signs and raise the possibility that it may also impact long-term outcomes.

Isolating the effects of visual imagery on prospective memory.

Two experiments investigated the role of visual imagery in prospective memory (PM). In experiment 1, 140 participants completed a general knowledge quiz which included a PM task of writing a letter "X" next to any questions that referred to space. Participants either visualised themselves performing this task, verbalised an implementation intention about the task, did both, or did neither. Performance on the PM task was enhanced in both conditions involving visual imagery but not by implementation intentions alone. In experiment 2, 120 participants imagined themselves writing a letter "X" next to questions about space, or in a bizarre imagery condition imagined themselves drawing an alien next to those questions. Relative to the control condition, PM was significantly enhanced when participants imagined writing a letter "X" next to the target questions, but not by the bizarre imagery task. The findings indicate that the robust effects of imagery observed in retrospective memory also extend to PM.

The effect of survival processing on memory for pictures depends on how memory is tested.

ABSTRACTTwo experiments investigated the effects of survival processing on memory for pictures of objects. In experiment 1, participants were presented with 32 pictures of common objects and rated them for their relevance to a survival scenario, a moving home scenario, or for pleasantness. In a surprise recall test, participants in the survival condition recalled more of the verbal labels of the objects than participants in the moving and pleasantness conditions. In experiment 2, participants rated 64 pictures of objects in survival, moving home, or pleasantness conditions. Memory for visual detail was assessed using a forced-choice recognition test in which participants had to decide which of two highly similar pictures was the one they rated at study. In contrast to the results of experiment 1, correct recognition scores were highest in the pleasantness condition and lowest in the survival condition. This pattern suggests that survival processing enhances memory for objects but not for precise visual detail. The findings are consistent with the view that rating objects for their survival value directs attention to the potential uses of the objects. They also emphasise the importance of the match between encoding and retrieval processes in the survival processing paradigm.

A Live Attenuated Influenza Vaccine Elicits Enhanced Heterologous Protection When the Internal Genes of the Vaccine Are Matched to Those of the Challenge Virus.

Influenza A virus (IAV) causes significant morbidity and mortality, despite the availability of viral vaccines. The efficacy of live attenuated influenza vaccines (LAIVs) has been especially poor in recent years. One potential reason is that the master donor virus (MDV), on which all LAIVs are based, contains either the internal genes of the 1960 A/Ann Arbor/6/60 or the 1957 A/Leningrad/17/57 H2N2 viruses (i.e., they diverge considerably from currently circulating strains). We previously showed that introduction of the temperature-sensitive (ts) residue signature of the AA/60 MDV into a 2009 pandemic A/California/04/09 H1N1 virus (Cal/09) results in only 10-fold in vivo attenuation in mice. We have previously shown that the ts residue signature of the Russian A/Leningrad/17/57 H2N2 LAIV (Len LAIV) more robustly attenuates the prototypical A/Puerto Rico/8/1934 (PR8) H1N1 virus. In this work, we therefore introduced the ts signature from Len LAIV into Cal/09. This new Cal/09 LAIV is ts in vitro, highly attenuated (att) in mice, and protects from a lethal homologous challenge. In addition, when our Cal/09 LAIV with PR8 hemagglutinin and neuraminidase was used to vaccinate mice, it provided enhanced protection against a wild-type Cal/09 challenge relative to a PR8 LAIV with the same attenuating mutations. These findings suggest it may be possible to improve the efficacy of LAIVs by better matching the sequence of the MDV to currently circulating strains.IMPORTANCE Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines. Among current influenza vaccines, the live attenuated influenza vaccine (LAIV) is unique in its ability to elicit T-cell immunity to the conserved internal proteins of the virus. Despite this, LAIV has shown limited efficacy in recent years. One possible reason is that the conserved, internal genes of all current LAIVs derive from virus strains that were isolated between 1957 and 1960 and that, as a result, do not resemble currently circulating influenza viruses. We have therefore developed and tested a new LAIV, based on a currently circulating pandemic strain of influenza. Our results show that this new LAIV elicits improved protective immunity compared to a more conventional LAIV.

The effect of dysphoria on the relationship between autobiographical memories and the self.

Two experiments investigated the bi-directional relationship between episodic autobiographical memories (ABMs) and semantic self-images in dysphoric and nondysphoric individuals. Participants in Experiment 1 generated positive and negative "I am" statements, which were then used to cue specific ABMs. Nondysphoric participants generated similar numbers of ABMs to positive and negative cues, suggesting both positive and negative self-images are supported by clusters of specific ABMs. The same was observed in dysphoric participants, but phenomenological ratings showed that they rated positive ABMs as less vivid, and negative ABMs more central to their life story, than the nondysphoric group. Participants in Experiment 2 retrieved positive or negative ABMs and then generated "I am" self-statements. Retrieving positive ABMs increased the positivity of self-statements in the nondysphoric but not the dysphoric group. These findings suggest the interaction between ABMs and self-images functions to promote a positive view of the self, but this is disrupted in dysphoria.

Cidofovir Diphosphate Inhibits Adenovirus 5 DNA Polymerase via both Nonobligate Chain Termination and Direct Inhibition, and Polymerase Mutations Confer Cidofovir Resistance on Intact Virus.

Human adenovirus (AdV) can cause fatal disease in immune-suppressed individuals, but treatment options are limited, in part because the antiviral cytidine analog cidofovir (CDV) is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, nonnephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. Therefore, we have examined the effect of CDVpp on DNA synthesis by a purified adenovirus 5 (AdV5) DNA polymerase (Pol). CDVpp was incorporated into nascent DNA strands and promoted a nonobligate form of chain termination (i.e., AdV5 Pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 Pol. At elevated concentrations, CDVpp inhibited AdV5 Pol in a manner consistent with both chain termination and direct inhibition of Pol activity. Finally, a recombinant AdV5 was constructed, containing Pol mutations (V303I and T87I) that were selected following an extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated 50% effective concentration (EC50) for BCV and a 1.9-fold increased EC50 for CDV; thus, these results confirmed that viral resistance to BCV and CDV can be attributed to mutations in the viral Pol. These findings show that the anti-AdV5 activity of CDV and BCV is mediated through the viral DNA Pol and that their antiviral activity may occur via both (nonobligate) chain termination and (at high concentration) direct inhibition of AdV5 Pol activity.

Putting false memories into context: the effects of odour contexts on correct and false recall.

False memories created by the Deese/Roediger-McDermott (DRM) paradigm are often accompanied by contextual information. Yet, research investigating the effects of context on false memories is surprisingly scarce. We used the context-dependent memory (CDM) model to construct same versus different context conditions using odours as contexts and DRM lists as to-be-remembered stimuli. Experiment 1 showed that levels of correct recall were higher in the same-context condition than in the changed-context condition, but no effects of context were observed in false recall. Experiment 2 used different odours and a longer retention interval and showed that context-dependent memory effects were found for both true and false memory. For true memory, context reinstatement improved memory, whilst simultaneously reducing false memory. Theoretical and forensic implications of these findings are discussed.

Natural Seminal Amyloids as Targets for Development of Synthetic Inhibitors of HIV Transmission.

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.

Hydrophobic Nanoparticles Reduce the ß-Sheet Content of SEVI Amyloid Fibrils and Inhibit SEVI-Enhanced HIV Infectivity.

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 ß-sheet secondary structural characteristics. Herein, we show that polymers containing hydrophobic side chains can interact with SEVI and reduce its ß-sheet content by ∼45% compared with the ß-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.

Direct and generative retrieval of autobiographical memories: The roles of visual imagery and executive processes.

Two experiments used a dual task methodology to investigate the role of visual imagery and executive resources in the retrieval of specific autobiographical memories. In Experiment 1, dynamic visual noise led to a reduction in the number of specific memories retrieved in response to both high and low imageability cues, but did not affect retrieval times. In Experiment 2, irrelevant pictures reduced the number of specific memories but only in response to low imageability cues. Irrelevant pictures also increased response times to both high and low imageability cues. The findings are in line with previous work suggesting that disrupting executive resources may impair generative, but not direct, retrieval of autobiographical memories. In contrast, visual distractor tasks appear to impair access to specific autobiographical memories via both the direct and generative retrieval routes, thereby highlighting the potential role of visual imagery in both pathways.

Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders.

Leucine-rich repeat kinase 2 (LRRK2) is the single most common genetic cause of both familial and sporadic Parkinson's disease (PD), both of which share pathogenetic and neurologic similarities with human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND). Pathologic LRRK2 activity may also contribute to neuroinflammation, because microglia lacking LRRK2 exposed to proinflammatory stimuli have attenuated responses. Because microglial activation is a hallmark of HIV-1 neuropathology, we have investigated the role of LRRK2 activation using in vitro and in vivo models of HAND. We hypothesize that LRRK2 is a key modulator of microglial inflammatory responses, which play a pathogenic role in both HAND and PD, and that these responses may cause or exacerbate neuronal damage in these diseases. The HIV-1 Tat protein is a potent neurotoxin produced during HAND that induces activation of primary microglia in culture and long-lasting neuroinflammation and neurotoxicity when injected into the CNS of mice. We found that LRRK2 inhibition attenuates Tat-induced pS935-LRRK2 expression, proinflammatory cytokine and chemokine expression, and phosphorylated p38 and Jun N-terminal kinase signaling in primary microglia. In our murine model, cortical Tat injection in LRRK2 knock-out (KO) mice results in significantly diminished neuronal damage, as assessed by microtubule-associated protein 2 (MAP2), class III ß-tubulin TUJ1, synapsin-1, VGluT, and cleaved caspase-3 immunostaining. Furthermore, Tat-injected LRRK2 KO animals have decreased infiltration of peripheral neutrophils, and the morphology of microglia from these mice were similar to that of vehicle-injected controls. We conclude that pathologic activation of LRRK2 regulates a significant component of the neuroinflammation associated with HAND.

Neomycin Sulfate Improves the Antimicrobial Activity of Mupirocin-Based Antibacterial Ointments.

In the midst of the current antimicrobial pipeline void, alternative approaches are needed to reduce the incidence of infection and decrease reliance on last-resort antibiotics for the therapeutic intervention of bacterial pathogens. In that regard, mupirocin ointment-based decolonization and wound maintenance practices have proven effective in reducing Staphylococcus aureus transmission and mitigating invasive disease. However, the emergence of mupirocin-resistant strains has compromised the agent's efficacy, necessitating new strategies for the prevention of staphylococcal infections. Herein, we set out to improve the performance of mupirocin-based ointments. A screen of a Food and Drug Administration (FDA)-approved drug library revealed that the antibiotic neomycin sulfate potentiates the antimicrobial activity of mupirocin, whereas other library antibiotics did not. Preliminary mechanism of action studies indicate that neomycin's potentiating activity may be mediated by inhibition of the organism's RNase P function, an enzyme that is believed to participate in the tRNA processing pathway immediately upstream of the primary target of mupirocin. The improved antimicrobial activity of neomycin and mupirocin was maintained in ointment formulations and reduced S. aureus bacterial burden in murine models of nasal colonization and wound site infections. Combination therapy improved upon the effects of either agent alone and was effective in the treatment of contemporary methicillin-susceptible, methicillin-resistant, and high-level mupirocin-resistant S. aureus strains. From these perspectives, combination mupirocin-and-neomycin ointments appear to be superior to that of mupirocin alone and warrant further development.

A Single Mutation at PB1 Residue 319 Dramatically Increases the Safety of PR8 Live Attenuated Influenza Vaccine in a Murine Model without Compromising Vaccine Efficacy.

The live attenuated influenza vaccine (LAIV) is preferentially recommended for use in most children yet remains unsafe for the groups most at risk. Here we have improved the safety of a mouse-adapted live attenuated influenza vaccine containing the same attenuating amino acid mutations as in human LAIV by adding an additional mutation at PB1 residue 319. This results in a vaccine with a 20-fold decrease in protective efficacy and a 10,000-fold increase in safety.

Development of a mouse-adapted live attenuated influenza virus that permits in vivo analysis of enhancements to the safety of live attenuated influenza virus vaccine.

The live attenuated influenza virus vaccine (LAIV) is preferentially recommended for use in persons 2 through 49 years of age but has not been approved for children under 2 or asthmatics due to safety concerns. Therefore, increasing safety is desirable. Here we describe a murine LAIV with reduced pathogenicity that retains lethality at high doses and further demonstrate that we can enhance safety in vivo through mutations within NS1. This model may permit preliminary safety analysis of improved LAIVs.

Adaptive false memory: Imagining future scenarios increases false memories in the DRM paradigm.

Previous research has shown that rating words for their relevance to a future scenario enhances memory for those words. The current study investigated the effect of future thinking on false memory using the Deese/Roediger-McDermott (DRM) procedure. In Experiment 1, participants rated words from 6 DRM lists for relevance to a past or future event (with or without planning) or in terms of pleasantness. In a surprise recall test, levels of correct recall did not vary between the rating tasks, but the future rating conditions led to significantly higher levels of false recall than the past and pleasantness conditions did. Experiment 2 found that future rating led to higher levels of false recognition than did past and pleasantness ratings but did not affect correct recognition. The effect in false recognition was, however, eliminated when DRM items were presented in random order. Participants in Experiment 3 were presented with both DRM lists and lists of unrelated words. Future rating increased levels of false recognition for DRM lures but did not affect correct recognition for DRM or unrelated lists. The findings are discussed in terms of the view that false memories can be associated with adaptive memory functions.

A dysphoric's TALE: The relationship between the self-reported functions of autobiographical memory and symptoms of depression.

Autobiographical memory (AM) is believed to serve self, social and directive functions; however, little is known regarding how this triad of functions operates in depression. Using the Thinking About Life Experiences questionnaire [Bluck, S., & Alea, N. (2011). Crafting the TALE: Construction of a measure to assess the functions of autobiographical remembering. Memory, 19, 470-486.; Bluck, S., Alea, N., Habermas, T., & Rubin, D. C. (2005). A TALE of three functions: The self-reported uses of autobiographical memory. Social Cognition, 23, 91-117.], two studies explored the relationship between depressive symptomology and the self-reported frequency and usefulness of AMs for self, social and directive purposes. Study 1 revealed that thinking more frequently but talking less frequently about past life events was significantly associated with higher depression scores. Recalling past events more frequently to maintain self-continuity was also significantly associated with higher depressive symptomology. However, results from Study 2 indicated that higher levels of depression were also significantly associated with less-frequent useful recollections of past life events for self-continuity purposes. Taken together, the findings suggest atypical utilisations of AM to serve self-continuity functions in depression and can be interpreted within the wider context of ruminative thought processes.

Eyewitness memory: The impact of a negative mood during encoding and/or retrieval upon recall of a non-emotive event.

The police often appeal for eyewitnesses to events that were unlikely to have been emotive when observed. An eyewitness, however, may be in a negative mood whilst encoding or retrieving such events as mood can be influenced by a range of personal, social, and environmental factors. For example, bad weather can induce a negative mood. This experiment compared the impact of negative and neutral moods during encoding and/or retrieval upon eyewitness recall of a non-emotive event. A negative mood during encoding had no impact upon the number of correct details recalled (provided participants were in a neutral mood at retrieval) but a negative mood during retrieval impaired the number of correct details recalled (provided participants were in a neutral mood at encoding). A negative mood at both time points enhanced the number of correct details recalled, demonstrating a mood-dependent memory enhancement. The forensic implications of these findings are discussed.

Influenza A virus attenuation by codon deoptimization of the NS gene for vaccine development.

UNLABELLED: Influenza viral infection represents a serious public health problem that causes contagious respiratory disease, which is most effectively prevented through vaccination to reduce transmission and future infection. The nonstructural (NS) gene of influenza A virus encodes an mRNA transcript that is alternatively spliced to express two viral proteins, the nonstructural protein 1 (NS1) and the nuclear export protein (NEP). The importance of the NS gene of influenza A virus for viral replication and virulence has been well described and represents an attractive target to generate live attenuated influenza viruses with vaccine potential. Considering that most amino acids can be synthesized from several synonymous codons, this study employed the use of misrepresented mammalian codons (codon deoptimization) for the de novo synthesis of a viral NS RNA segment based on influenza A/Puerto Rico/8/1934 (H1N1) (PR8) virus. We generated three different recombinant influenza PR8 viruses containing codon-deoptimized synonymous mutations in coding regions comprising the entire NS gene or the mRNA corresponding to the individual viral protein NS1 or NEP, without modifying the respective splicing and packaging signals of the viral segment. The fitness of these synthetic viruses was attenuated in vivo, while they retained immunogenicity, conferring both homologous and heterologous protection against influenza A virus challenges. These results indicate that influenza viruses can be effectively attenuated by synonymous codon deoptimization of the NS gene and open the possibility of their use as a safe vaccine to prevent infections with these important human pathogens. IMPORTANCE: Vaccination serves as the best therapeutic option to protect humans against influenza viral infections. However, the efficacy of current influenza vaccines is suboptimal, and novel approaches are necessary for the prevention of disease cause by this important human respiratory pathogen. The nonstructural (NS) gene of influenza virus encodes both the multifunctional nonstructural protein 1 (NS1), essential for innate immune evasion, and the nuclear export protein (NEP), required for the nuclear export of viral ribonucleoproteins and for timing of the virus life cycle. Here, we have generated a recombinant influenza A/Puerto Rico/8/1934 (H1N1) (PR8) virus containing a codon-deoptimized NS segment that is attenuated in vivo yet retains immunogenicity and protection efficacy against homologous and heterologous influenza virus challenges. These results open the exciting possibility of using this NS codon deoptimization methodology alone or in combination with other approaches for the future development of vaccine candidates to prevent influenza viral infections.

Episodic elaboration: Investigating the structure of retrieved past events and imagined future events.

Five experiments investigated the cognitive processes involved in the elaboration of past and future events. A production listing procedure was used, in which participants listed details of each event in forwards chronological order, backwards chronological order, or free order. For both past and future events, forwards and free ordering conditions were reliably faster than backwards order. Production rates between past and future temporal directions did not differ in Experiments 1a, 1b, and 3. However, in Experiment 2, the elaboration of future events was faster than the elaboration of past events. This pattern can be explained by the findings of Experiment 4, in which production rates were faster for likely events than for unlikely events but only in the future condition. Overall, the findings suggest that the elaboration of future, but not past, events, is facilitated when constructed around current goals.