Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure.

Drug resistance in HIV type 1 (HIV-1) is a pervasive problem that affects the lives of millions of people worldwide. Although records of drug-resistant mutations (DRMs) have been extensively tabulated within public repositories, our understanding of the evolutionary kinetics of DRMs and how they evolve together remains limited. Epistasis, the interaction between a DRM and other residues in HIV-1 protein sequences, is key to the temporal evolution of drug resistance. We use a Potts sequence-covariation statistical-energy model of HIV-1 protein fitness under drug selection pressure, which captures epistatic interactions between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the acquisition of DRMs as they arise in an ensemble of drug-naive patient protein sequences. We follow the time course of 52 DRMs in the enzymes protease, RT, and integrase, the primary targets of antiretroviral therapy. The rates at which DRMs emerge are highly correlated with their observed acquisition rates reported in the literature when drug pressure is applied. This result highlights the central role of epistasis in determining the kinetics governing DRM emergence. Whereas rapidly acquired DRMs begin to accumulate as soon as drug pressure is applied, slowly acquired DRMs are contingent on accessory mutations that appear only after prolonged drug pressure. We provide a foundation for using computational methods to determine the temporal evolution of drug resistance using Potts statistical potentials, which can be used to gain mechanistic insights into drug resistance pathways in HIV-1 and other infectious agents.

DNA conformational dynamics in the context-dependent non-CG CHH methylation by plant methyltransferase DRM2.

DNA methylation provides an important epigenetic mechanism that critically regulates gene expression, genome imprinting, and retrotransposon silencing. In plants, DNA methylation is prevalent not only in a CG dinucleotide context but also in non-CG contexts, namely CHG and CHH (H = C, T, or A) methylation. It has been established that plant non-CG DNA methylation is highly context dependent, with the +1- and +2-flanking sequences enriched with A/T nucleotides. How DNA sequence, conformation, and dynamics influence non-CG methylation remains elusive. Here, we report structural and biochemical characterizations of the intrinsic substrate preference of DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2), a plant DNA methyltransferase responsible for establishing all cytosine methylation and maintaining CHH methylation. Among nine CHH motifs, the DRM2 methyltransferase (MTase) domain shows marked substrate preference toward CWW (W = A or T) motifs, correlating well with their relative abundance in planta. Furthermore, we report the crystal structure of DRM2 MTase in complex with a DNA duplex containing a flexible TpA base step at the +1/+2-flanking sites of the target nucleotide. Comparative structural analysis of the DRM2-DNA complexes provides a mechanism by which flanking nucleotide composition impacts DRM2-mediated DNA methylation. Furthermore, the flexibility of the TpA step gives rise to two alternative DNA conformations, resulting in different interactions with DRM2 and consequently temperature-dependent shift of the substrate preference of DRM2. Together, this study provides insights into how the interplay between the conformational dynamics of DNA and temperature as an environmental factor contributes to the context-dependent CHH methylation by DRM2.

De novo induction of a DNA-histone H3K9 methylation loop on synthetic human repetitive DNA in cultured tobacco cells.

Genetic modifications in plants are crucial tools for fundamental and applied research. Transgene expression usually varies among independent lines or their progeny and is associated with the chromatin structure of the insertion site. Strategies based on understanding how to manipulate the epigenetic state of the inserted gene cassette would help to ensure transgene expression. Here, we report a strategy for chromatin manipulation by the artificial tethering of epigenetic effectors to a synthetic human centromeric repetitive DNA (alphoid DNA) platform in plant Bright-Yellow-2 (BY-2) culture cells. By tethering DNA-methyltransferase (Nicotiana tabacum DRM1), we effectively induced DNA methylation and histone methylation (H3K9me2) on the alphoid DNA platform. Tethering of the Arabidopsis SUVH9, which has been reported to lack histone methyltransferase activity, also induced a similar epigenetic state on the alphoid DNA in BY-2 cells, presumably by activating the RNA-dependent DNA methylation (RdDM) pathway. Our results emphasize that the interplay between DNA and histone methylation mechanisms is intrinsic to plant cells. We also found that once epigenetic modification states were induced by the tethering of either DRM1 or SUVH9, the modification was maintained even when the direct tethering of the effector was inhibited. Our system enables the analysis of more diverse epigenetic effectors and will help to elucidate the chromatin assembly mechanisms of plant cells.

Application of molecular epidemiology in revealing HIV-1 transmission network and recombination patterns in Tianjin, China.

Using a comprehensive molecular epidemiological approach, we characterized the transmission dynamics of HIV-1 among the MSM population in Tianjin, China. Our findings revealed that 38.56% (386/1001) of individuals clustered across 109 molecular transmission clusters (TCs), with MSM aged 50 and below being the group most commonly transmitting HIV-1. Among the identified TCs, CRF01_AE predominated, followed by CRF07_BC. Notably, CRF07_BC demonstrated a higher propensity for forming large clusters compared to CRF01_AE. Birth-death skyline analyses of the two largest clusters indicated that the HIV/AIDS transmission may be at a critical point, nearly all had Re approximately 1 by now. A retrospective analysis revealed that the rapid expansion of these large clusters was primarily driven by the introduction of viruses in 2021, highlighting the crucial importance of continuous molecular surveillance in identifying newly emerging high-risk transmission chains and adapting measures to address evolving epidemic dynamics. Furthermore, we detected the transmission of drug-resistant mutations (DRMs) within the TCs, particularly in the CRF07_BC clusters (K103N, Y181C, and K101E) and CRF01_AE clusters (P225H and K219R), emphasizing the importance of monitoring to support the continued efficacy of first-line therapies and pre-exposure prophylaxis (PrEP). Recombination analyses indicated that complex recombinant patterns, associated with increased amino acid variability, could confer adaptive traits to the viruses, potentially providing a competitive advantage in certain host populations or regions. Our study highlights the potential of integrating molecular epidemiological and phylodynamic approaches to inform targeted interventions.

Regulation of Na+-K+-ATPase leads to disturbances of isoproterenol-induced cardiac dysfunction via interference of Ca2+-dependent cardiac metabolism.

Reductions in Na+-K+-ATPase (NKA) activity and expression are often observed in the progress of various reason-induced heart failure (HF). However, NKA α1 mutation or knockdown cannot cause spontaneous heart disease. Whether the abnormal NKA α1 directly contributes to HF pathogenesis remains unknown. Here, we challenge NKA α1+/- mice with isoproterenol to evaluate the role of NKA α1 haploinsufficiency in isoproterenol (ISO)-induced cardiac dysfunction. Genetic knockdown of NKA α1 accelerated ISO-induced cardiac cell hypertrophy, heart fibrosis, and dysfunction. Further studies revealed decreased Krebs cycle, fatty acid oxidation, and mitochondrial OXPHOS in the hearts of NKA α1+/- mice challenged with ISO. In ISO-treated conditions, inhibition of NKA elevated cytosolic Na+, further reduced mitochondrial Ca2+ via mNCE, and then finally down-regulated cardiac cell energy metabolism. In addition, a supplement of DRm217 alleviated ISO-induced heart dysfunction, mitigated cardiac remodeling, and improved cytosolic Na+ and Ca2+ elevation and mitochondrial Ca2+ depression in the NKA α1+/- mouse model. The findings suggest that targeting NKA and mitochondria Ca2+ could be a promising strategy in the treatment of heart disease.

Transcranial direct current stimulation over the left posterior temporal lobe modulates semantic control: Evidence from episodic memory distortions.

Evidence accumulates to show that semantic cognition requires, in addition to semantic representations, control processes that regulate the accessibility and use of semantic knowledge in a task- and time-appropriate fashion. Semantic control has been recently proposed to rely on a distributed network that includes the posterior temporal cortex. Along these lines, recent meta-analyses of neuroimaging data and studies with patients suffering from semantic aphasia have suggested that the left posterior middle temporal gyrus (pMTG) is critically involved whenever situational context must constrain semantic retrieval. In the present experiment, we used transcranial direct current stimulation over the left posterior temporal lobe in an attempt to interfere with semantic control while participants performed a DRM task, a procedure for inducing conceptually-based false recognition that is contingent on both activation and control processes. Paralleling findings with patients suffering from brain damage restricted to the temporoparietal cortex, anodal stimulation (relative to sham stimulation) resulted in increased false recognition but intact true recognition. These findings fit well with the idea that the left pMTG is a key component of a semantic control network, the alteration of which results in memory performance that is affected by the intrusion of contextually-inappropriate semantic information.

Effects of emotional ambiguity and emotional intensity on true and false memory.

Whereas the effects of emotional intensity (the perceived strength of an item's valence or arousal) have long been studied in true- and false-memory research, emotional ambiguity (the uncertainty that attaches to perceived emotional intensity) has only been studied recently. Available evidence suggests that emotional ambiguity has reliable effects on true memory that are distinct from those of emotional intensity. However, those findings are mostly restricted to recall, and the effects of emotional ambiguity on false memory remain unexplored. The current study addressed both limitations by measuring the effects of emotional ambiguity and emotional intensity on true and false recognition. In two experiments, we manipulated valence ambiguity and valence intensity (Experiment 1) and arousal ambiguity and arousal intensity (Experiment 2) of Deese/Roediger/McDermott lists. Multiple linear regression analyses were conducted for Experiment 1, Experiment 2, and the combined data of the experiments to separate the effects of emotional ambiguity and emotional intensity. Our results showed that both valence ambiguity and arousal ambiguity improved true recognition, and the effects of valence ambiguity remained robust even when controlling for valence intensity, arousal intensity, and arousal ambiguity. More importantly, for both valence and arousal, there was an interaction between ambiguity and intensity in false memory. Specifically, we found that valence ambiguity increased false recognition with positive valence, while arousal ambiguity amplified the effect of arousal intensity on false recognition. Our results are discussed in the context of the emotional ambiguity hypothesis and fuzzy-trace theory.

False memory-guided eye movements: insights from a DRM-Saccade paradigm.

The Deese-Roediger and McDermott (DRM) paradigm and visually guided saccade tasks are both prominent research tools in their own right. This study introduces a novel DRM-Saccade paradigm, merging both methodologies. We used rule-based saccadic eye movements whereby participants were presented with items at test and were asked to make a saccade to the left or right of the item to denote a recognition or non-recognition decision. We measured old/new recognition decisions and saccadic latencies. Experiment 1 used a pro/anti saccade task to a single target. We found slower saccadic latencies for correct rejection of critical lures, but no latency difference between correct recognition of studied items and false recognition of critical lures. Experiment 2 used a two-target saccade task and also measured corrective saccades. Findings corroborated those from Experiment 1. Participants adjusted their initial decisions to increase accurate recognition of studied items and rejection of unrelated lures but there were no such corrections for critical lures. We argue that rapid saccades indicate cognitive processing driven by familiarity thresholds. These occur before slower source-monitoring is able to process any conflict. The DRM-Saccade task could effectively track real-time cognitive resource use during recognition decisions.

False recall is associated with larger caudate in males but not in females.

After learning semantically related words, some people are more likely than others to incorrectly recall unstudied but semantically related lures (i.e., Deese-Roediger-McDermott [DRM] false recall). Previous studies have suggested that neural activity in subcortical regions (e.g., the caudate) is involved in false memory, and that there may be sex differences in the neural basis of false memory. However, sex-specific associations between subcortical volumes and false memory are not well understood. This study investigated whether sex modulates the associations between subcortical volumes and DRM false recall in 400 healthy college students. Volumes of subcortical regions including the caudate, accumbens, amygdala, hippocampus, pallidum, putamen and thalamus were obtained from structural magnetic resonance images and measured using FreeSurfer. The results showed that males had lower true and false recall but larger subcortical volumes than females. Interestingly, higher false recall was associated with a larger caudate in males, but not in females. This association was significant after controlling for age and intracranial volume. This study provides new evidence on the neural basis of false recall. It suggests that the caudate plays a role in false recall in young men, and that future studies of the neural correlates of false memory should consider sex differences.

"I heard it before or not": time-course of ERP response and behavioural correlates associated with false recognition memory.

Electrophysiological and behavioural correlates of true and false memories were examined in the Deese/Roediger-McDermont (DRM) paradigm. A mass univariate approach for analysing event-related potentials (ERP) in the temporal domain was used to examine the electrophysiological effects associated with this paradigm precisely (point-by-point) and without bias (data-driven). Behaviourally, true and false recognition did not differ, and the predicted DRM effect was observed, as false recognition of critical lures (i.e., new words semantically related to studied words) was higher than false alarms of new (unrelated) words. Neurally, an expected old/new effect was observed during the time-range of the late positive component (LPC) over left centro-parietal scalp electrodes. Furthermore, true recognition also evoked larger LPC amplitudes than false recognition over both left centro-parietal and fronto-central scalp electrodes. However, we did not observe LPC-related differences between critical lures and new words, nor between correct rejections of critical lures and new words. In contrast, correct rejections of critical lures were accompanied by higher activation of a sustained positive slow wave (SPSW) in right fronto-central electrodes beyond 1200 ms. This result reveals a key role of post-retrieval processes in recognition. Results are discussed in light of theoretical approaches to false memory in the DRM paradigm.

Investigating a bias account of emotional false memories using a criterion warning and force choice restrictions at retrieval.

Here, we add to the debate as to whether false recognition of emotional stimuli is more memory-based or more bias-based. Emotional false memory findings using the DRM paradigm have been marked by higher false alarms to negatively arousing compared to neutral critical lure items. Explanation for these findings has mainly focused on false memory-based accounts. However, here we address the question of whether a response bias for emotional stimuli can, at least in part, explain this phenomenon. In Experiment 1, we used a criterion warning, previously shown to increase more conservative responding and reduce false recognition. Experiment 2, we employed a two-alternative-forced choice test, which minimises the role of criterion setting. In both experiments, we compared false alarms to negative and neutral critical lures. We observed a significant decrease in false recognition rates for both negative and neutral critical lures under the conditions of forced choice restriction and criterion warning. However, despite these conditions, negative items, compared to their neutral counterparts, still consistently provoked a higher degree of false recognition. The discussion that follows presents an exploration of both memory-based accounts and criterion-setting explanations for the enhanced emotional false memory finding.

The barriers to uptake of disaster risk management science in urban planning: A political economy analysis.

There is increasing effort in science to support disaster risk management (DRM) and climate change adaptation in urban environments. It is now common for research calls and projects to reference coproduction methods and science uptake goals. This paper identifies lessons for researchers, research funders, and research users wishing to enable useful, useable, and used science based on the perspectives of research users in urban planning from low- and middle-income countries. DRM-supporting science is viewed by policy actors as: complicated and poorly communicated; presenting inadequate, partial, and outdated information; misaligned with policy cycles; and costly to access and inadequately positioned to overcome the policy barriers that hinder integration of DRM into urban planning. Addressing these specific concerns points to more systematic collection and organisation of data and enhancement of supporting administrative structures to facilitate better sight of human vulnerability and its link to development decision-making and wider processes of urban risk creation.

From vector spaces to DRM lists: False Memory Generator, a software for automated generation of lists of stimuli inducing false memories.

The formation of false memories is one of the most widely studied topics in cognitive psychology. The Deese-Roediger-McDermott (DRM) paradigm is a powerful tool for investigating false memories and revealing the cognitive mechanisms subserving their formation. In this task, participants first memorize a list of words (encoding phase) and next have to indicate whether words presented in a new list were part of the initially memorized one (recognition phase). By employing DRM lists optimized to investigate semantic effects, previous studies highlighted a crucial role of semantic processes in false memory generation, showing that new words semantically related to the studied ones tend to be more erroneously recognized (compared to new words less semantically related). Despite the strengths of the DRM task, this paradigm faces a major limitation in list construction due to its reliance on human-based association norms, posing both practical and theoretical concerns. To address these issues, we developed the False Memory Generator (FMG), an automated and data-driven tool for generating DRM lists, which exploits similarity relationships between items populating a vector space. Here, we present FMG and demonstrate the validity of the lists generated in successfully replicating well-known semantic effects on false memory production. FMG potentially has broad applications by allowing for testing false memory production in domains that go well beyond the current possibilities, as it can be in principle applied to any vector space encoding properties related to word referents (e.g., lexical, orthographic, phonological, sensory, affective, etc.) or other type of stimuli (e.g., images, sounds, etc.).

Cannabis increases susceptibility to false memory.

With the growing global acceptance of cannabis and its widespread use by eyewitnesses and suspects in legal cases, understanding the popular drug's ramifications for memory is a pressing need. In a double-blind, randomized, placebo-controlled trial, we examined the acute and delayed effects of Δ9-tetrahydrocannabinol (THC) intoxication on susceptibility to false memory in 64 healthy volunteers. Memory was tested immediately (encoding and retrieval under drug influence) and 1 wk later (retrieval sober). We used three different methods (associative word lists and two misinformation tasks using virtual reality). Across all methods, we found evidence for enhanced false-memory effects in intoxicated participants. Specifically, intoxicated participants showed higher false recognition in the associative word-list task both at immediate and delayed test than controls. This yes bias became increasingly strong with decreasing levels of association between studied and test items. In a misinformation task, intoxicated participants were more susceptible to false-memory creation using a virtual-reality eyewitness scenario and virtual-reality perpetrator scenario. False-memory effects were mostly restricted to the acute-intoxication phase. Cannabis seems to increase false-memory proneness, with decreasing strength of association between an event and a test item, as assessed by different false-memory paradigms. Our findings have implications for how and when the police should interview suspects and eyewitnesses.

False memories formation is increased in individuals with insomnia.

Previous studies suggest that sleep can influence false memories formation. Specifically, acute sleep loss has been shown to promote false memories production by impairing memory retrieval at subsequent testing. Surprisingly, the relationship between sleep and false memories has only been investigated in healthy subjects but not in individuals with insomnia, whose sleep is objectively impaired compared to healthy subjects. Indeed, this population shows several cognitive impairments involving prefrontal functioning that could affect source monitoring processes and contribute to false memories generation. Moreover, it has been previously reported that subjects with insomnia differentially process sleep-related versus neutral stimuli. Therefore, the aim of the present study was to compare false memories production between individuals with insomnia symptoms and good sleepers, and to evaluate the possible influence of stimulus category (neutral versus sleep-related) in the two groups. The results show that false memories are globally increased in participants reporting insomnia symptoms compared to good sleepers. A reduction in source monitoring ability was also observed in the former group, suggesting that an impairment of this executive function could be especially involved in false memories formation. Moreover, our data seem to confirm that false memories production in individuals with insomnia symptoms appears significantly modulated by stimulus category.

Conceptual metaphors influence memory automatically: Evidence from a divided attention false memory task.

Previous research has found that reading a list of ostensibly unrelated expressions based on the same underlying conceptual metaphor can evoke false recognition on a memory task for new expressions that use the same metaphor, the so-called conceptual metaphor false memory effect. We examined the automaticity of this effect by dividing participants' attention with a concurrent task. In Study 1, attention was manipulated while participants read the lists of expressions, whereas in Study 2, attention was manipulated both when they read the lists and when they were engaged in the later recognition memory test. Across both studies, the conceptual metaphor false memory effect was observed when conscious processing was limited by dividing attention. These data support the argument that conceptual metaphors are automatically activated when metaphorical expressions are read.

How rich are false memories in a naturalistic context in healthy aging?

The recall of factual and contextual information is a core characteristic of episodic memory sensitive to aging effects. The innovative aim of the present study was to assess in a naturalistic context the quantity and quality of correct and false free recalls among younger and older adults considering feature binding (What-Where-When-Details) and recollection (Remembering vs. Knowing). Thanks to virtual reality, we designed a multimodal environment simulating a lively town in which we implemented a variant of a DRM task rich in sets of semantically related items (e.g., fruits on a market stall). We asked 30 young and 30 older participants to navigate in the virtual environment, paying attention to the items, and then recall as many items and as much contextual information as possible and indicate the presence of recollection. As expected, older adults produced fewer correct recall but more intrusions than younger adults, and their correct recall was more deficient in binding and recollection. In both age groups, false recall was associated with the correct context inferred from a related set of items. However, the intrusions produced by older adults were highly recollected compared to those of the younger adults, and they were associated with false item-related contextual information.

Effects of visual imagery on false memories in DRM and misinformation paradigms.

This study examined the possibility that moderators of false memories in the Deese-Roediger-McDermott (DRM) paradigm affect the occurrence of false memories in the misinformation paradigm. More precisely, the purpose was to determine to what extent an imaging instruction modulates false memories in the DRM and misinformation paradigms. A sample of young adults was assigned to the DRM or the misinformation tasks, either in control conditions or in conditions including an imaging instruction. Findings revealed that an imaging instruction decreases false memories in DRM whereas there is no evidence about imaging effects in the misinformation task. These observations tally with previous studies, reporting a weak or no correlation between false memories in these paradigms, and are discussed in the light of current theories.

Structure and Mechanism of Plant DNA Methyltransferases.

DNA methylation is an important epigenetic mark conserved in eukaryotes from fungi to animals and plants, where it plays a crucial role in regulating gene expression and transposon silencing. Once the methylation mark is established by de novo DNA methyltransferases, specific regulatory mechanisms are required to maintain the methylation state during chromatin replication, both during meiosis and mitosis. Plant DNA methylation is found in three contexts; CG, CHG, and CHH (H = A, T, C), which are established and maintained by a unique set of DNA methyltransferases and are regulated by plant-specific pathways. DNA methylation in plants is often associated with other epigenetic modifications, such as noncoding RNA and histone modifications. This chapter focuses on the structure, function, and regulatory mechanism of plant DNA methyltransferases and their crosstalk with other epigenetic pathways.

Generative processing and emotional false memories: a generation "cost" for negative false memory formation but only after delay.

Previous research shows that manipulations (e.g. levels-of-processing) that facilitate true memory often increase susceptibility to false memory. An exception is the generation effect. Using the Deese/Roediger-McDermott (DRM) paradigm, Soraci et al. found that generating rather than reading list items led to an increase in true but not false memories. They argued that generation led to enhanced item-distinctiveness that drove down false memory production. In the current study, we investigated the effects of generative processing on valenced stimuli and after a delayed retention interval to examine factors that may lead to a generation effect that increases false memories. At the immediate test, false recognition rates for both negative and neutral valanced critical lures were similar across read and generate conditions. However, after a one-week delay, we saw a valence differentiation, with a generation effect for false recognition but only for negative stimuli. The roles of item-specific and relational processing during encoding and their interaction with long-term retention are discussed.