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/.

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.

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.

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.

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.

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.

Ranking microbial metabolomic and genomic links in the NPLinker framework using complementary scoring functions.

Specialised metabolites from microbial sources are well-known for their wide range of biomedical applications, particularly as antibiotics. When mining paired genomic and metabolomic data sets for novel specialised metabolites, establishing links between Biosynthetic Gene Clusters (BGCs) and metabolites represents a promising way of finding such novel chemistry. However, due to the lack of detailed biosynthetic knowledge for the majority of predicted BGCs, and the large number of possible combinations, this is not a simple task. This problem is becoming ever more pressing with the increased availability of paired omics data sets. Current tools are not effective at identifying valid links automatically, and manual verification is a considerable bottleneck in natural product research. We demonstrate that using multiple link-scoring functions together makes it easier to prioritise true links relative to others. Based on standardising a commonly used score, we introduce a new, more effective score, and introduce a novel score using an Input-Output Kernel Regression approach. Finally, we present NPLinker, a software framework to link genomic and metabolomic data. Results are verified using publicly available data sets that include validated links.

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.

Pseudonocardia abyssalis sp. nov. and Pseudonocardia oceani sp. nov., two novel actinomycetes isolated from the deep Southern Ocean.

The actinomycetes strains KRD168T and KRD185T were isolated from sediments collected from the deep Southern Ocean and, in this work, they are described as representing two novel species of the genus Pseudonocardia through a polyphasic approach. Despite sharing >99 % 16S rRNA gene sequence similarity with other members of the genus, comparative genomic analysis allowed species delimitation based on average nucleotide identity and digital DNA-DNA hybridization. The KRD168T genome is characterized by a size of 6.31 Mbp and a G+C content of 73.44 mol%, while the KRD185T genome has a size of 6.82 Mbp and a G+C content of 73.98 mol%. Both strains contain meso-diaminopimelic acid as the diagnostic diamino acid, glucose as the major whole-cell sugar, MK-8(H4) as a major menaquinone and iso-branched hexadecanoic acid as a major fatty acid. Biochemical and fatty acid analyses also revealed differences between these strains and their phylogenetic neighbours, supporting their status as distinct species. The names Pseudonocardia abyssalis sp. nov. (type strain KRD168T=DSM 111918T=NCIMB 15270T) and Pseudonocardia oceani (type strain KRD185T=DSM 111919T=NCIMB 15269T) are proposed.

Dopamine is associated with prioritization of reward-associated memories in Parkinson's disease.

Patients with Parkinson's disease have reduced reward sensitivity related to dopaminergic neuron loss, which is associated with impairments in reinforcement learning. Increasingly, however, dopamine-dependent reward signals are recognized to play an important role beyond reinforcement learning. In particular, it has been shown that reward signals mediated by dopamine help guide the prioritization of events for long-term memory consolidation. Meanwhile, studies of memory in patients with Parkinson's disease have focused on overall memory capacity rather than what is versus what isn't remembered, leaving open questions about the effect of dopamine replacement on the prioritization of memories by reward and the time-dependence of this effect. The current study sought to fill this gap by testing the effect of reward and dopamine on memory in patients with Parkinson's disease. We tested the effect of dopamine modulation and reward on two forms of long-term memory: episodic memory for neutral objects and memory for stimulus-value associations. We measured both forms of memory in a single task, adapting a standard task of reinforcement learning with incidental episodic encoding events of trial-unique objects. Objects were presented on each trial at the time of feedback, which was either rewarding or not. Memory for the trial-unique images and for the stimulus-value associations, and the influence of reward on both, was tested immediately after learning and 2 days later. We measured performance in Parkinson's disease patients tested either ON or OFF their dopaminergic medications and in healthy older control subjects. We found that dopamine was associated with a selective enhancement of memory for reward-associated images, but that it did not influence overall memory capacity. Contrary to predictions, this effect did not differ between the immediate and delayed memory tests. We also found that while dopamine had an effect on reward-modulated episodic memory, there was no effect of dopamine on memory for stimulus-value associations. Our results suggest that impaired prioritization of cognitive resource allocation may contribute to the early cognitive deficits of Parkinson's disease.

Comparative Metabologenomics Analysis of Polar Actinomycetes.

Biosynthetic and chemical datasets are the two major pillars for microbial drug discovery in the omics era. Despite the advancement of analysis tools and platforms for multi-strain metabolomics and genomics, linking these information sources remains a considerable bottleneck in strain prioritisation and natural product discovery. In this study, molecular networking of the 100 metabolite extracts derived from applying the OSMAC approach to 25 Polar bacterial strains, showed growth media specificity and potential chemical novelty was suggested. Moreover, the metabolite extracts were screened for antibacterial activity and promising selective bioactivity against drug-persistent pathogens such as Klebsiella pneumoniae and Acinetobacter baumannii was observed. Genome sequencing data were combined with metabolomics experiments in the recently developed computational approach, NPLinker, which was used to link BGC and molecular features to prioritise strains for further investigation based on biosynthetic and chemical information. Herein, we putatively identified the known metabolites ectoine and chrloramphenicol which, through NPLinker, were linked to their associated BGCs. The metabologenomics approach followed in this study can potentially be applied to any large microbial datasets for accelerating the discovery of new (bioactive) specialised metabolites.

Time-resolved neural reinstatement and pattern separation during memory decisions in human hippocampus.

Mnemonic decision-making has long been hypothesized to rely on hippocampal dynamics that bias memory processing toward the formation of new memories or the retrieval of old ones. Successful memory encoding may be best optimized by pattern separation, whereby two highly similar experiences can be represented by underlying neural populations in an orthogonal manner. By contrast, successful memory retrieval is thought to be supported by a recovery of the same neural pattern laid down during encoding. Here we examined how hippocampal pattern completion and separation emerge over time during memory decisions. We measured electrocorticography activity in the human hippocampus and posterior occipitotemporal cortex (OTC) while participants performed continuous recognition of items that were new, repeated (old), or highly similar to a prior item (similar). During retrieval decisions of old items, both regions exhibited significant reinstatement of multivariate high-frequency activity (HFA) associated with encoding. Further, the extent of reinstatement of encoding patterns during retrieval was correlated with the strength (HFA power) of hippocampal encoding. Evidence for encoding pattern reinstatement was also seen in OTC on trials requiring fine-grained discrimination of similar items. By contrast, hippocampal activity showed evidence for pattern separation during these trials. Together, these results underscore the critical role of the hippocampus in supporting both reinstatement of overlapping information and separation of similar events.

Linking genomics and metabolomics to chart specialized metabolic diversity.

Microbial and plant specialized metabolites constitute an immense chemical diversity, and play key roles in mediating ecological interactions between organisms. Also referred to as natural products, they have been widely applied in medicine, agriculture, cosmetic and food industries. Traditionally, the main discovery strategies have centered around the use of activity-guided fractionation of metabolite extracts. Increasingly, omics data is being used to complement this, as it has the potential to reduce rediscovery rates, guide experimental work towards the most promising metabolites, and identify enzymatic pathways that enable their biosynthetic production. In recent years, genomic and metabolomic analyses of specialized metabolic diversity have been scaled up to study thousands of samples simultaneously. Here, we survey data analysis technologies that facilitate the effective exploration of large genomic and metabolomic datasets, and discuss various emerging strategies to integrate these two types of omics data in order to further accelerate discovery.

The association between epiblepharon and obesity: an experience at tertiary care center in Western Pennsylvania/North America.

PURPOSE: Epiblepharon is a congenital eyelid anomaly that occurs most frequently in Asian children. Recent literature has identified an association between obesity and increased rates of epiblepharon among Asian children. The purpose of our study was to determine whether obesity was also associated with epiblepharon in a non-Asian population. METHODS: The medical records of all children with a diagnosis of epiblepharon seen in the oculoplastic clinic at a single institution over a 2-year period were reviewed and included all the Caucasian children with epiblepharon. The average body mass index was calculated for all patients with epiblepharon. The rate of obesity among these children was compared with the national rate of childhood obesity in the United States as defined by the Center for Disease Control and Prevention. RESULTS: Our study included 10 Caucasian children with epiblepharon. There were 8 girls and 2 boys. The rate of obesity among non-Asian children with epiblepharon was 40%, which is substantially higher than the average rate of obesity among children in the USA. One child was overweight. CONCLUSIONS: This study suggests an association between obesity and epiblepharon in non-Asian children. Obesity likely contributes to anatomic variations in the midface and eyelids that can lead to the development of epiblepharon. Given the rising rates of childhood obesity, it is important to be aware of its association with epiblepharon in ethnic populations other than Asian.

Modulating the Use of Multiple Memory Systems in Value-based Decisions with Contextual Novelty.

With multiple learning and memory systems at its disposal, the human brain can represent the past in many ways, from extracting regularities across similar experiences (incremental learning) to storing rich, idiosyncratic details of individual events (episodic memory). The unique information carried by these neurologically distinct forms of memory can bias our behavior in different directions, raising crucial questions about how these memory systems interact to guide choice and the factors that cause one to dominate. Here, we devised a new approach to estimate how decisions are independently influenced by episodic memories and incremental learning. Furthermore, we identified a biologically motivated factor that biases the use of different memory types-the detection of novelty versus familiarity. Consistent with computational models of cholinergic memory modulation, we find that choices are more influenced by episodic memories following the recognition of an unrelated familiar image but more influenced by incrementally learned values after the detection of a novel image. Together this work provides a new behavioral tool enabling the disambiguation of key memory behaviors thought to be supported by distinct neural systems while also identifying a theoretically important and broadly applicable manipulation to bias the arbitration between these two sources of memories.

Awakening ancient polar Actinobacteria: diversity, evolution and specialized metabolite potential.

Polar and subpolar ecosystems are highly vulnerable to global climate change with consequences for biodiversity and community composition. Bacteria are directly impacted by future environmental change and it is therefore essential to have a better understanding of microbial communities in fluctuating ecosystems. Exploration of Polar environments, specifically sediments, represents an exciting opportunity to uncover bacterial and chemical diversity and link this to ecosystem and evolutionary parameters. In terms of specialized metabolite production, the bacterial order Actinomycetales, within the phylum Actinobacteria are unsurpassed, producing 10 000 specialized metabolites accounting for over 45 % of all bioactive microbial metabolites. A selective isolation approach focused on spore-forming Actinobacteria of 12 sediment cores from the Antarctic and sub-Arctic generated a culture collection of 50 strains. This consisted of 39 strains belonging to rare Actinomycetales genera including Microbacterium, Rhodococcus and Pseudonocardia. This study used a combination of nanopore sequencing and molecular networking to explore the community composition, culturable bacterial diversity, evolutionary relatedness and specialized metabolite potential of these strains. Metagenomic analyses using MinION sequencing was able to detect the phylum Actinobacteria across polar sediment cores at an average of 13 % of the total bacterial reads. The resulting molecular network consisted of 1652 parent ions and the lack of known metabolite identification supports the argument that Polar bacteria are likely to produce previously unreported chemistry.

Hippocampal representations as a function of time, subregion, and brain state.

How does the hippocampus represent interrelated experiences in memory? We review prominent yet seemingly contradictory theoretical perspectives, which propose that the hippocampus distorts experiential representations to either emphasize their distinctiveness or highlight common elements. These fundamentally different kinds of memory representations may be instantiated in the brain via conjunctive separated codes and adaptively differentiated codes on the one hand, or integrated relational codes on the other. After reviewing empirical support for these different coding schemes within the hippocampus, we outline two organizing principles which may explain the conflicting findings in the literature. First focusing on where the memories are formed and stored, we argue that distinct hippocampal regions represent experiences at multiple levels of abstraction and may transmit them to distinct cortical networks. Then focusing on when memories are formed, we identify several factors that can open and maintain specialized time windows, during which the very same hippocampal network is biased toward one coding scheme over the others. Specifically, we discuss evidence for (1) excitability-mediated integration windows, maintained by persistently elevated CREB levels following encoding of a specific memory, (2) fleeting cholinergically-mediated windows favoring memory separation, and (3) sustained dopaminergically-mediated windows favoring memory integration. By presenting a broad overview of different hippocampal coding schemes across species, we hope to inspire future empirical and modeling research to consider how factors surrounding memory formation shape the representations in which they are stored.

Lingering Cognitive States Shape Fundamental Mnemonic Abilities.

Why are people sometimes able to recall associations in exquisite detail while at other times left frustrated by the deficiencies of memory? Although this apparent fickleness of memory has been extensively studied by investigating factors that build strong memory traces, researchers know less about whether memory success also depends on cognitive states that are in place when a cue is encountered. Motivating this possibility, neurocomputational models propose that the hippocampus's capacity to support associative recollection (pattern completion) is biased by persistent neurochemical states, which can be elicited by exposure to familiarity and novelty. We investigated these models' behavioral implications by assessing how recent familiarity influences different memory-retrieval processes. We found that recent familiarity selectively benefitted associative memory (Experiment 1) and that this effect decayed over seconds (Experiment 2), consistent with the timescale of hippocampal neuromodulation. Thus, we show that basic memory computations can be shaped by a subtle, biologically motivated manipulation.

Efficacy of Amphotericin B Against Fusarium and Aspergillus in Corneal Storage Medium.

PURPOSE: The incidence of postkeratoplasty fungal infection is increasing in the United States, and our most commonly used corneal storage medium, Optisol-GS, contains antibiotics but no antifungal agents. We previously demonstrated the efficacy of amphotericin B additives in eliminating Candida albicans contaminants in Optisol-GS. The purpose of this study was to determine whether amphotericin B would also be efficacious against Fusarium solani and Aspergillus fumigatus. METHODS: Vials of Optisol-GS were supplemented with 0.255 µg/mL of amphotericin B. Half of the vials were inoculated with F. solani and half with A. fumigatus. Positive control vials were inoculated with the fungi but no amphotericin B. The vials were refrigerated, sampled, and plated at different time points. The plates were then incubated at 36°C for 48 hr after which fungal colony counts were performed. RESULTS: There was an average reduction in the growth of F. solani in the amphotericin B-supplemented vials of 44% on day 2, 79% on day 7, and 80% on day 14 when compared with the positive control vials. There was an average reduction in the growth of A. fumigatus in the amphotericin B-supplemented vials of 40% on day 2 and 14% on day 7 when compared with the positive control vials. Both amphotericin B-supplemented and control vials grew less than 2 colonies of A. fumigatus on day 14. CONCLUSIONS: This study suggests that amphotericin B additives in Optisol-GS reduce the growth of F. solani and A. fumigatus.