Multi-omics analysis of antagonistic interactions among free-living Pseudonocardia from diverse ecosystems.

Actinomycetes are a phylogenetically diverse bacterial group which are widely distributed across terrestrial and aquatic ecosystems. Within this order, the genus Pseudonocardia and their specialised metabolites have been the focus of previous ecological studies due to their antagonistic interactions with other microorganisms and their mutualistic interactions with insects. However, the chemical ecology of free-living Pseudonocardia remains understudied. This study applies a multi-omics approach to investigate the chemical ecology of free-living actinomycetes from the genus Pseudonocardia. In a comparative genomics analysis, it was observed that the biosynthetic gene cluster family distribution was influenced mainly by phylogenetic distance rather than the geographic or ecological origin of strains. This finding was also observed in the mass spectrometry-based metabolomic profiles of nine Pseudonocardia species isolated from marine sediments and two terrestrial species. Antagonist interactions between these 11 species were examined, and matrix-assisted laser desorption/ionisation-mass spectrometry imaging was used to examine in situ chemical interactions between the Southern Ocean strains and their phylogenetically close relatives. Overall, it was demonstrated that phylogeny was the main predictor of antagonistic interactions among free-living Pseudonocardia. Moreover, two features at m/z 441.15 and m/z 332.20 were identified as metabolites related to these interspecies interactions.

Proactive interference of visual working memory chunks implicates long-term memory.

Visual working memory (VWM) is a limited cognitive resource that can be functionally expanded through chunking (Miller, 1956). For example, participants can hold an increasing number of colours in mind as they learn to chunk reliably paired combinations (Brady et al., 2009). We investigated whether this benefit is mediated through the in situ compression of VWM representations (Brady et al., 2009) or the offloading of chunks to long-term memory (LTM; Huang & Awh, 2018; Ngiam et al., 2019) by asking if a vulnerability of LTM - proactive interference - influences VWM performance. We adapted previous designs using deterministic (Experiment 1, N = 60) and probabilistic pairings (Experiments 2 and 3, N = 64 and 80, respectively), to include colour pairings that swapped in sequence along with pairings that were consistent in sequence. Generally, participants reported colours from consistent pairs more accurately than from swapping pairs, which we designed to drive interference in LTM (Experiments 1 and 2). The error profiles also pointed to proactive interference between swapping pairs in all three experiments. Moreover, participants who had explicit awareness of frequent colour pairings had higher VWM accuracy, and their errors reflected more proactive interference than their unaware counterparts (Experiment 3). This pattern of long-term proactive interference in a VWM task lends support for accounts of VWM chunking that propose LTM offloading.

Polygenic risk for depression and anterior and posterior hippocampal volume in children and adolescents.

BACKGROUND: Depression has frequently been associated with smaller hippocampal volume. The hippocampus varies in function along its anterior-posterior axis, with the anterior hippocampus more strongly associated with stress and emotion processing. The goals of this study were to examine the associations among parental history of anxiety/depression, polygenic risk scores for depression (PGS-DEP), and anterior and posterior hippocampal volumes in children and adolescents. To examine specificity to PGS-DEP, we examined associations of educational attainment polygenic scores (PGS-EA) with anterior and posterior hippocampal volume. METHODS: Participants were 350 3- to 21-year-olds (46 % female). PGS-DEP and PGS-EA were computed based on recent, large-scale genome-wide association studies. High-resolution, T1-weighted magnetic resonance imaging (MRI) data were acquired, and a semi-automated approach was used to segment the hippocampus into anterior and posterior subregions. RESULTS: Children and adolescents with higher polygenic risk for depression were more likely to have a parent with a history of anxiety/depression. Higher polygenic risk for depression was significantly associated with smaller anterior but not posterior hippocampal volume. PGS-EA was not associated with anterior or posterior hippocampal volumes. LIMITATIONS: Participants in these analyses were all of European ancestry. CONCLUSIONS: Polygenic risk for depression may lead to smaller anterior but not posterior hippocampal volume in children and adolescents, and there may be specificity of these effects to PGS-DEP rather than PGS-EA. These findings may inform the earlier identification of those in need of support and the design of more effective, personalized treatment strategies. DECLARATIONS OF INTEREST: none. DECLARATIONS OF INTEREST: None.

Fluctuations in Sustained Attention Explain Moment-to-Moment Shifts in Children's Memory Formation.

Why do children's memories often differ from adults' after the same experience? Whereas prior work has focused on children's immature memory mechanisms to answer this question, here we focus on the costs of attentional lapses for learning. We track sustained attention and memory formation across time in 7- to 10-year-old children and adults (n = 120) to show that sustained attention causally shapes the fate of children's individual memories. Moreover, children's attention lapsed twice as frequently as adults', and attention fluctuated with memory formation more closely in children than adults. In addition, although attentional lapses impaired memory for expected events in both children and adults, they impaired memory for unexpected events in children only. Our work reveals that sustained attention is an important cognitive factor that controls access to children's long-term memory stores. Our work also raises the possibility that developmental differences in cognitive performance stem from developmental shifts in the ability to sustain attention.

Antibiotics from rare actinomycetes, beyond the genus Streptomyces.

Throughout the golden age of antibiotic discovery, Streptomyces have been unsurpassed for their ability to produce bioactive metabolites. Yet, this success has been hampered by rediscovery. As we enter a new stage of biodiscovery, omics data and existing scientific repositories can enable informed choices on the biodiversity that may yield novel antibiotics. Here, we focus on the chemical potential of rare actinomycetes, defined as bacteria within the order Actinomycetales, but not belonging to the genus Streptomyces. They are named as such due to their less-frequent isolation under standard laboratory practices, yet there is increasing evidence to suggest these biologically diverse genera harbour considerable biosynthetic and chemical diversity. In this review, we focus on examples of successful isolation and genera that have been the focus of more concentrated biodiscovery efforts, we survey the representation of rare actinomycete taxa, compared with Streptomyces, across natural product data repositories in addition to its biosynthetic potential. This is followed by an overview of clinically useful drugs produced by rare actinomycetes and considerations for future biodiscovery efforts. There is much to learn about these underexplored taxa, and mounting evidence suggests that they are a fruitful avenue for the discovery of novel antimicrobials.

Artificial intelligence for natural product drug discovery.

Developments in computational omics technologies have provided new means to access the hidden diversity of natural products, unearthing new potential for drug discovery. In parallel, artificial intelligence approaches such as machine learning have led to exciting developments in the computational drug design field, facilitating biological activity prediction and de novo drug design for molecular targets of interest. Here, we describe current and future synergies between these developments to effectively identify drug candidates from the plethora of molecules produced by nature. We also discuss how to address key challenges in realizing the potential of these synergies, such as the need for high-quality datasets to train deep learning algorithms and appropriate strategies for algorithm validation.

Time separating spatial memories does not influence their integration in humans.

Humans can navigate through similar environments-like grocery stores-by integrating across their memories to extract commonalities or by differentiating between each to find idiosyncratic locations. Here, we investigate one factor that might impact whether two related spatial memories are integrated or differentiated: Namely, the temporal delay between experiences. Rodents have been shown to integrate memories more often when they are formed within 6 hours of each other. To test if this effect influences how humans spontaneously integrate spatial memories, we had 131 participants search for rewards in two similar virtual environments. We separated these learning experiences by either 30 minutes, 3 hours, or 27 hours. Memory integration was assessed three days later. Participants were able to integrate and simultaneously differentiate related memories across experiences. However, neither memory integration nor differentiation was modulated by temporal delay, in contrast to previous work. We further showed that both the levels of initial memory reactivation during the second experience and memory generalization to novel environments were comparable across conditions. Moreover, perseveration toward the initial reward locations during the second experience was related positively to integration and negatively to differentiation-but again, these associations did not vary by delay. Our findings identify important boundary conditions on the translation of rodent memory mechanisms to humans, motivating more research to characterize how even fundamental memory mechanisms are conserved and diverge across species.

What sticks after statistical learning: The persistence of implicit versus explicit memory traces.

Statistical learning is a powerful mechanism that extracts even subtle regularities from our information-dense worlds. Recent theories argue that statistical learning can occur through multiple mechanisms-both the conventionally assumed automatic process that precipitates unconscious learning, and an attention-dependent process that brings regularities into conscious awareness. While this view has gained popularity, there are few empirical dissociations of the hypothesized implicit and explicit forms of statistical learning. Here we provide strong evidence for this dissociation in two ways. First, we show in healthy adults (N = 60) that implicit and explicit traces have divergent consolidation trajectories, with implicit knowledge of structure strengthened over a 24-h period, while precise explicit representations tend to decay. Second, we demonstrate that repeated testing strengthens the retention of explicit representations but that implicit statistical learning is uninfluenced by testing. Together these dissociations provide much needed support for the reconceptualization of statistical learning as a multi-component construct.

Comparing visual memories to similar visual inputs risks lasting memory distortion.

Maintaining perceptual experiences in visual working memory (VWM) allows us to flexibly accomplish various tasks, but some tasks come at a price. For example, comparing VWM representations to novel perceptual inputs can induce inadvertent memory distortions. If these distortions can persist, they may explain why everyday memories often become unreliable after people perform perceptual comparisons (e.g., eyewitness testimony). Here, we conducted two experiments to assess the consequences of perceptual comparisons using real-world objects that were temporarily maintained in VWM (n = 32) or recalled from visual long-term memory back into VWM (n = 30). In each experiment, young adults reported systematic memory distortions following perceptual comparisons. These distortions increased in magnitude with the delay between encoding and comparisons and were preserved when memories were retrieved again a day later. These findings suggest that perceptual comparisons play a mechanistic role in everyday memory distortions, including situations where memory accuracy is vital. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Pay attention and you might miss it: Greater learning during attentional lapses.

Attentional lapses have been found to impair everything from basic perception to learning and memory. Yet, despite the well-documented costs of lapses on cognition, recent work suggests that lapses might unexpectedly confer some benefits. One potential benefit is that lapses broaden our learning to integrate seemingly irrelevant content that could later prove useful-a benefit that prior research focusing only on goal-relevant memory would miss. Here, we measure how fluctuations in sustained attention influence the learning of seemingly goal-irrelevant content that competes for attention with target content. Participants completed a correlated flanker task in which they categorized central targets (letters or numbers) while ignoring peripheral flanking symbols that shared hidden probabilistic relationships with the targets. We found that across participants, higher rates of attentional lapses correlated with greater learning of the target-flanker relationships. Moreover, within participants, learning was more evident during attentional lapses. These findings address long-standing theoretical debates and reveal a benefit of attentional lapses: they expand the scope of learning and decisions beyond the strictly relevant.

MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters.

With an ever-increasing amount of (meta)genomic data being deposited in sequence databases, (meta)genome mining for natural product biosynthetic pathways occupies a critical role in the discovery of novel pharmaceutical drugs, crop protection agents and biomaterials. The genes that encode these pathways are often organised into biosynthetic gene clusters (BGCs). In 2015, we defined the Minimum Information about a Biosynthetic Gene cluster (MIBiG): a standardised data format that describes the minimally required information to uniquely characterise a BGC. We simultaneously constructed an accompanying online database of BGCs, which has since been widely used by the community as a reference dataset for BGCs and was expanded to 2021 entries in 2019 (MIBiG 2.0). Here, we describe MIBiG 3.0, a database update comprising large-scale validation and re-annotation of existing entries and 661 new entries. Particular attention was paid to the annotation of compound structures and biological activities, as well as protein domain selectivities. Together, these new features keep the database up-to-date, and will provide new opportunities for the scientific community to use its freely available data, e.g. for the training of new machine learning models to predict sequence-structure-function relationships for diverse natural products. MIBiG 3.0 is accessible online at https://mibig.secondarymetabolites.org/.

Aging shifts the relative contributions of episodic and semantic memory to decision-making.

Healthy aging is accompanied by well-characterized shifts in memory systems: episodic memory tends to decline with age while semantic memory remains relatively intact, with some knowledge domains strengthening. Beyond reflecting on the past, these distinct memory systems often guide decisions about the future. Yet how such age-related memory shifts influence simple value-based choices remain understudied. Here, younger (18-24 years) and older (61-75 years) adults completed a card game in which they could use task-relevant episodic memories to maximize the number of points they earned. Critically, they could also use task-irrelevant semantic memories to guide their choices. Both younger and older adults successfully used episodic memory to make decisions, but older adults did so less reliably than younger adults. Further, while younger adults strategically suppressed task-irrelevant semantic memories when a relevant episodic memory could be used, older adults used semantic memory to guide their decisions regardless of the relevance of episodic memory. We provide evidence that declining inhibitory control may play a role in how older adults arbitrate between competing memory sources when making decisions. These effects are consistent with the literature on age-related shifts in memory and cognitive control systems and add to a growing body of work on how episodic memories inform reinforcement learning and value-based decision-making. Our findings highlight how patterns of age-related memory differences can have consequences for value-based choices, which has implications for other types of decision-making, from the economic to the mundane. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

ActinoBase: tools and protocols for researchers working on Streptomyces and other filamentous actinobacteria.

Actinobacteria is an ancient phylum of Gram-positive bacteria with a characteristic high GC content to their DNA. The ActinoBase Wiki is focused on the filamentous actinobacteria, such as Streptomyces species, and the techniques and growth conditions used to study them. These organisms are studied because of their complex developmental life cycles and diverse specialised metabolism which produces many of the antibiotics currently used in the clinic. ActinoBase is a community effort that provides valuable and freely accessible resources, including protocols and practical information about filamentous actinobacteria. It is aimed at enabling knowledge exchange between members of the international research community working with these fascinating bacteria. ActinoBase is an anchor platform that underpins worldwide efforts to understand the ecology, biology and metabolic potential of these organisms. There are two key differences that set ActinoBase apart from other Wiki-based platforms: [1] ActinoBase is specifically aimed at researchers working on filamentous actinobacteria and is tailored to help users overcome challenges working with these bacteria and [2] it provides a freely accessible resource with global networking opportunities for researchers with a broad range of experience in this field.

A corollary discharge mediates saccade-related inhibition of single units in mnemonic structures of the human brain.

Despite the critical link between visual exploration and memory, little is known about how neuronal activity in the human mesial temporal lobe (MTL) is modulated by saccades. Here, we characterize saccade-associated neuronal modulations, unit-by-unit, and contrast them to image onset and to occipital lobe neurons. We reveal evidence for a corollary discharge (CD)-like modulatory signal that accompanies saccades, inhibiting/exciting a unique population of broad-/narrow-spiking units, respectively, before and during saccades and with directional selectivity. These findings comport well with the timing, directional nature, and inhibitory circuit implementation of a CD. Additionally, by linking neuronal activity to event-related potentials (ERPs), which are directionally modulated following saccades, we recontextualize the ERP associated with saccades as a proxy for both the strength of inhibition and saccade direction, providing a mechanistic underpinning for the more commonly recorded saccade-related ERP in the human brain.

Overcoming drug resistance, the natural way.

Colistin is an antibiotic of last resort for treating Gram-negative bacterial infections, but resistance is spreading rapidly. In a recent issue of Nature, Wang et al. use genome mining to identify and synthesize a natural variant that bypasses colistin resistance and offers new hope for tackling antimicrobial resistance.

Changes in Hospital Discharges with Alcohol-Related Liver Disease in a Gastroenterology and General Medical Unit Following the Introduction of Minimum Unit Pricing of Alcohol: The GRI Q4 Study.

AIMS: Minimum unit price (MUP) of 50 pence per unit of alcohol was introduced in Scotland on the 1 May 2018. We assessed alcohol-related liver disease (ArLD) discharges from Glasgow Royal Infirmary (GRI) before and after the introduction of MUP. METHODS: Medical records of all patients discharged from Gastroenterology wards at GRI in the fourth quarter (Q4) of the years 2015-2019 were reviewed. All patients with ArLD were identified, and detailed hospitalization data were collected retrospectively. Active drinking, severity scores, presence of alcoholic hepatitis (AH) and 90-day mortality and readmission rates were assessed. RESULTS: There were fewer ArLD discharges per quarter after MUP than before (mean 80.3 pre-MUP; mean 68 post-MUP), and the proportion of active drinkers was lower post-MUP (64.7 vs. 70.5%). There was a significant fall in the mean number of weekly discharges of individual patients who were actively drinking (4.0 ± 2.0 pre-MUP, 2.8 ± 1.5 post-MUP, P = 0.01). There were no differences in the proportion of patients presenting with ascites, encephalopathy or AH; however, there was a reduction in presentations with acute upper gastrointestinal bleeding from 15.8% pre-MUP to 7.4% post-MUP (P = 0.02; odds ratio 0.42). Severity of liver disease remained unchanged. The 90-day mortality and readmission rates were not significantly different. CONCLUSION: Since the introduction of MUP there has been a reduction in the absolute numbers of patients discharged with ArLD and the number of individual patients involved at GRI. The pattern of clinical presentation was largely unaffected with overall ArLD severity, readmission rates and 90-day mortality similar pre- and post-MUP.

OpenMaze: An open-source toolbox for creating virtual navigation experiments.

Incorporating 3D virtual environments into psychological experiments offers an innovative solution for balancing experimental control and ecological validity. Their flexible application to virtual navigation experiments, however, has been limited because accessible development tools best support only a subset of desirable task design features. We created OpenMaze, an open-source toolbox for the Unity game engine, to overcome this barrier. OpenMaze offers researchers the ability to conduct a wide range of first-person spatial navigation experiment paradigms in fully customized 3D environments. Crucially, because all experiments are defined using human-readable configuration files, our toolbox allows even those with no prior coding experience to build bespoke tasks. OpenMaze is also compatible with a variety of input devices and operating systems, broadening its possible applications. To demonstrate its advantages and limitations, we review and contrast other available software options before providing an overview of our design objectives and walking the reader through the process of building an experiment in OpenMaze.

The Natural Products Atlas 2.0: a database of microbially-derived natural products.

Within the natural products field there is an increasing emphasis on the study of compounds from microbial sources. This has been fuelled by interest in the central role that microorganisms play in mediating both interspecies interactions and host-microbe relationships. To support the study of natural products chemistry produced by microorganisms we released the Natural Products Atlas, a database of known microbial natural products structures, in 2019. This paper reports the release of a new version of the database which includes a full RESTful application programming interface (API), a new website framework, and an expanded database that includes 8128 new compounds, bringing the total to 32 552. In addition to these structural and content changes we have added full taxonomic descriptions for all microbial taxa and have added chemical ontology terms from both NP Classifier and ClassyFire. We have also performed manual curation to review all entries with incomplete configurational assignments and have integrated data from external resources, including CyanoMetDB. Finally, we have improved the user experience by updating the Overview dashboard and creating a dashboard for taxonomic origin. The database can be accessed via the new interactive website at https://www.npatlas.org.

Single-Trajectory Multiple-Target Deep Brain Stimulation for Parkinsonian Mobility and Cognition.

BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is an emerging target to potentially treat cognitive dysfunction. OBJECTIVES: The aim of this study is to achieve feasibility and safety of globus pallidus pars interna (GPi) and NBM DBS in advanced PD with cognitive impairment. METHODS: We performed a phase-II double-blind crossover pilot trial in six participants to assess safety and cognitive measures, the acute effect of NBM stimulation on attention, motor and neuropsychological data at one year, and neuroimaging biomarkers of NBM stimulation. RESULTS: NBM DBS was well tolerated but did not improve cognition. GPi DBS improved dyskinesia and motor fluctuations (P = 0.04) at one year. NBM stimulation was associated with reduced right frontal and parietal glucose metabolism (P < 0.01) and increased low- and high-frequency power and functional connectivity. Volume of tissue activated in the left NBM was associated with stable cognition (P < 0.05). CONCLUSIONS: Simultaneous GPi and NBM stimulation is safe and improves motor complications. NBM stimulation altered neuroimaging biomarkers but without lasting cognitive improvement. © 2021 International Parkinson and Movement Disorder Society.