Miracle-dz/UniFAR-FTUs huggingface dataset:
Hippocampal cells integrate past memory and present perception for the future

The ability to use stored information in a highly flexible manner is a defining feature of the declarative memory system. However, the neuronal mechanisms underlying this flexibility are poorly understood. To address this question, we recorded single-unit activity from the hippocampus of two non-human primates performing a newly devised task requiring the monkeys to retrieve long-term item-location association memory and then use it flexibly in different circumstances. We found that hippocampal neurons signaled both mnemonic information representing the retrieved location and perceptual information representing the external circumstance. The two signals were combined at a single-neuron level to construct goal-directed information by three sequentially occurring neuronal operations (e.g., convergence, transference, targeting) in the hippocampus. Thus, flexible use of knowledge may be supported by the hippocampal constructive process linking memory and perception, which may fit the mnemonic information into the current situation to present manageable information for a subsequent action.
A fast and efficient smoothing approach to Lasso regression and an application in statistical genetics: polygenic risk scores for chronic obstructive pulmonary disease (COPD)

High dimensional linear regression problems are often fitted using Lasso approaches. Although the Lasso objective function is convex, it is not differentiable everywhere, making the use of gradient descent methods for minimization not straightforward. To avoid this technical issue, we apply Nesterov smoothing to the original (unsmoothed) Lasso objective function. We introduce a closed-form smoothed Lasso which preserves the convexity of the Lasso function, is uniformly close to the unsmoothed Lasso, and allows us to obtain closed-form derivatives everywhere for efficient and fast minimization via gradient descent. Our simulation studies are focused on polygenic risk scores using genetic data from a genome-wide association study (GWAS) for chronic obstructive pulmonary disease (COPD). We compare accuracy and runtime of our approach to the current gold standard in the literature, the FISTA algorithm. Our results suggest that the proposed methodology provides estimates with equal or higher accuracy than the FISTA algorithm while having the same asymptotic runtime scaling. The proposed methodology is implemented in the R-package smoothedLasso , available on the Comprehensive R Archive Network (CRAN).
Computer vision for pattern detection in chromosome contact maps

Chromosomes of all species studied so far display a variety of higher-order organisational features, such as self-interacting domains or loops. These structures, which are often associated to biological functions, form distinct, visible patterns on genome-wide contact maps generated by chromosome conformation capture approaches such as Hi-C. Here we present Chromosight, an algorithm inspired from computer vision that can detect patterns in contact maps. Chromosight has greater sensitivity than existing methods on synthetic simulated data, while being faster and applicable to any type of genomes, including bacteria, viruses, yeasts and mammals. Our method does not require any prior training dataset and works well with default parameters on data generated with various protocols. Chromatin loops bridging distant loci within chromosomes can be detected by a variety of techniques such as Hi-C. Here the authors present Chromosight, an algorithm applied on mammalian, bacterial, viral and yeast genomes, able to detect various types of pattern in chromosome contact maps, including chromosomal loops.
Temporal resource continuity increases predator abundance in a metapopulation model: insights for conservation and biocontrol

The amount of habitat in a landscape is an important metric for evaluating the effects of land cover and land use on biodiversity and ecosystem services, yet it fails to capture complex temporal dimensions of resource availability that could be consequential for species population dynamics. If ephemeral resources across multiple habitat patches are synchronously available, resource gaps could be detrimental to population growth. In contrast, asynchronously available resources create a mosaic of temporally complementary resources that mobile organisms can track across the landscape. Knowledge is especially lacking on the relevance of temporal complementation for tri-trophic interactions and biological pest control. Here we use a spatially-explicit predator-prey metapopulation model to test the effect of different spatiotemporal resource patterns on insect predators and their prey. We examined prey and predator responses in model landscapes that varied in both the amount and temporal variability of basal vegetation resources. Further, we examined cases where prey comprised either a single generalist species or two specialist species that use different resources available either early or late in the growing season. We found that predators and generalist prey benefitted from lower temporal variance of basal resources, which increased both of their landscape-scale abundances. However, increasing the amount of basal resources also increased the variability of generalist prey populations, resulting in a negative correlation between basal resource amount and predator abundance. Specialist prey, on the other hand, did not benefit from less temporally variable in basal resources, since they were restricted by habitat type while also suffering greater predation. Predators feeding on specialists achieved greater prey suppression in landscapes with less temporally variable resources. Our simulations demonstrate the joint importance of landscape-scale temporal dynamics of resources and resource amount in understanding how landscape heterogeneity influences biodiversity and ecosystem services such as the biological control of agricultural pests.
Express saccades during a countermanding task

Express saccades are unusually short latency, visually guided saccadic eye movements. They are most commonly observed when the fixation spot disappears at a consistent, short interval before a target spot appears at a repeated location. The saccade countermanding task includes no fixation-target gap, variable target presentation times, and the requirement to withhold saccades on some trials. These testing conditions should discourage production of express saccades. However, two macaque monkeys performing the saccade countermanding task produced consistent, multimodal distributions of saccadic latencies. These distributions consisted of a longer mode extending from 200 ms to as much as 600 ms after target presentation and another consistently less than 100 ms after target presentation. Simulations revealed that by varying express saccade production, monkeys could earn more reward. If express saccades were not rewarded, they were rarely produced. The distinct mechanisms producing express and longer saccade latencies were revealed further by the influence of regularities in the duration of the fixation interval preceding target presentation on saccade latency. Temporal expectancy systematically affected the latencies of regular but not of express saccades. This study highlights that cognitive control can integrate information across trials and strategically elicit intermittent very short latency saccades to acquire more reward.
Varmole: a biologically drop-connect deep neural network model for prioritizing disease risk variants and genes

Population studies such as GWAS have identified a variety of genomic variants associated with human diseases. To further understand potential mechanisms of disease variants, recent statistical methods associate functional omic data (e.g., gene expression) with genotype and phenotype and link variants to individual genes. However, how to interpret molecular mechanisms from such associations, especially across omics is still challenging. To address this, we develop an interpretable deep learning method, Varmole to simultaneously reveal genomic functions and mechanisms while predicting phenotype from genotype. In particular, Varmole embeds multi-omic networks into a deep neural network architecture and prioritizes variants, genes and regulatory linkages via drop-connect without needing prior feature selections. Varmole is available as a Python package on GitHub at https://github.com/daifengwanglab/Varmole.
Age-and reserve-related increases in fronto-parietal and anterior hippocampal activity during episodic encoding predict subsequent memory

Remembering associations between encoded items and their contextual setting is a feature of episodic memory. Although this ability deteriorates with age in general, there is substantial variability in how older individuals perform on episodic memory tasks. This variability may stem from genetic and/or environmental factors related to reserve, allowing some individuals to compensate for age-related decline through differential recruitment of brain regions. In this fMRI study, we tested predictions related to reserve and compensation in a large adult lifespan sample (N=154). We used multivariate Behaviour Partial Least Squares (B-PLS) analysis to examine how age, retrieval accuracy, and a proxy measure of reserve, impacted brain activity patterns during spatial and temporal context encoding and retrieval. Reserve modulated age-related compensatory brain responses in ventral visual, temporal, and fronto-parietal regions during memory encoding as a function of task demands. Activity in inferior parietal, medial temporal, and ventral visual regions were strongly impacted by age at encoding and retrieval, but were also related to individual differences in reserve. Our findings are consistent with the concepts of reserve and compensation and suggest that reserve may mitigate age-related decline by modulating compensatory brain responses in the aging brain.
Heme A-containing oxidases evolved in the ancestors of iron oxidizing bacteria

The origin of oxygen respiration in bacteria has long intrigued biochemists, microbiologists and evolutionary biologists. The earliest enzymes that consume oxygen to extract energy did not evolve in the same lineages of photosynthetic bacteria that released oxygen on primordial earth, leading to the great oxygenation event (GOE). A widespread type of such enzymes is proton pumping cytochrome c oxidase (COX) that contains heme A, a unique prosthetic group for these oxidases. Here we show that the most ancestral proteins for the biosynthesis of heme A are present in extant acidophilic Fe2+-oxidizing Proteobacteria. Acidophilic Fe2+-oxidizers lived on emerged land around the time of the GOE, as suggested by the earliest geochemical evidence for aerobic respiration on paleoproterozoic earth. The gene for heme A synthase in acidophilic Fe2+-oxidizing Proteobacteria is associated with the COX gene cluster for iron oxidation. Compared to many other soil bacteria, the COX subunits encoded by this gene cluster are early diverging. Our data suggest that the ancient bacterial lineage which first evolved heme A-containing COX was related to the ancestors of present acidophilic Fe2+-oxidizers such as Acidiferrobacter and Acidithiobacillus spp. The copper leaching activity of such bacteria might have constituted a key ecological factor to promote COX evolution.
Arrayed CRISPRi and quantitative imaging describe the morphotypic landscape of essential mycobacterial genes

Mycobacterium tuberculosis possesses a large number of genes of unknown or merely predicted function, undermining fundamental understanding of pathogenicity and drug susceptibility. To address this challenge, we developed a high-throughput functional genomics approach combining inducible CRISPR-interference and image-based analyses of morphological features and sub-cellular molecular localizations in the related non-pathogen, M. smegmatis. Applying automated imaging and analysis to an arrayed library of 272 essential gene knockdown mutants, we derive robust, quantitative descriptions of bacillary morphologies consequent on gene silencing. Leveraging statistical-learning, we demonstrate that functionally related genes cluster by morphotypic similarity and that this information can be used to infer gene function. Exploiting this observation, we reveal a previously unknown restriction-modification system, and identify filamentation as a defining mycobacterial response to histidine starvation. Our results support the application of large-scale image-based analyses for mycobacterial functional genomics, simultaneously establishing the utility of this approach for drug mechanism-of-action studies.
Emergence of RBD mutations from circulating SARS-CoV-2 strains with enhanced structural stability and higher human ACE2 receptor affinity of the spike protein

Abstract Spike protein receptor binding domain (RBD) of SARS-CoV-2 is the critical determinant of viral tropism and infectivity. Genomes of global SARS-CoV-2 strains were analyzed, yielding 32 RBD mutant strains clustering into 10 mutation types under high positive selection pressure. Three mutation types circulating in Wuhan, Shenzhen, Hong Kong, and France, displayed enhanced structural stability along with higher human ACE2 receptor affinity of the spike protein, indicating these mutants may have acquired increased infectivity to humans.
Age-Related Differences in Auditory Cortex Activity During Spoken Word Recognition

Understanding spoken words requires the rapid matching of a complex acoustic stimulus with stored lexical representations. The degree to which the brain networks supporting spoken word recognition are affected by adult aging remains poorly understood. In the current study we used fMRI to measure the brain responses to spoken words in two conditions: an attentive listening condition, in which no response was required, and a repetition task. Listeners were 29 young adults (aged 19–30 years) and 32 older adults (aged 65–81 years) without self-reported hearing difficulty. We found largely similar patterns of activity during word perception for both young and older adults, centered on bilateral superior temporal gyrus. As expected, the repetition condition resulted in significantly more activity in areas related to motor planning and execution (including premotor cortex and supplemental motor area) compared to the attentive listening condition. Importantly, however, older adults showed significantly less activity in probabilistically-defined auditory cortex than young adults when listening to individual words in both the attentive listening and repetition tasks. Age differences in auditory cortex activity were seen selectively for words (no age differences were present for 1-channel vocoded speech, used as a control condition), and could not be easily explained by accuracy on the task, movement in the scanner, or hearing sensitivity (available on a subset of participants). These findings indicate largely similar patterns of brain activity for young and older adults when listening to words in quiet, but suggest less recruitment of auditory cortex by the older adults.
A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with 3 cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse, compared to a new HSF2BP knock-out mouse showed that it behaves as a hypomorphic allele. HSF2BP-S167L females show reduced fertility with small litter sizes. To obtain mechanistic insights, we identified C19ORF57/MIDAP as a strong interactor and stabilizer of HSF2BP by forming a higher-order macromolecular structure involving BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L mutation showed a strongly decreased expression of both MIDAP and HSF2BP at the recombination nodules. Although HSF2BP-S167L does not affect heterodimerization between HSF2BP and MIDAP, it promotes a lower expression of both proteins and a less proficient activity in replacing RPA by the recombinases RAD51/DMC1, thus leading to a lower frequency of cross-overs. Our results provide insights into the molecular mechanism of two novel actors of meiosis underlying non-syndromic ovarian insufficiency. Summary Felipe-Medina et al. describe a missense variant in the meiotic gene HSF2BP in a consanguineous family with Premature Ovarian Insufficiency, and characterize it as an hypormorphic allele, that in vivo impairs its dimerization with a novel meiotic actor, MIDAP/ C19ORF57, and affect recombination at double-strand DNA breaks.
Choices change the temporal weighting of decision evidence

Decisions do not occur in isolation, but are embedded in sequences of other decisions, often pertaining to the same source of evidence. Here, we characterized the impact of intermittent choices on the accumulation of a protracted stream of decision-relevant evidence towards a final decision. Human participants performed two versions, based on perceptual or numerical evidence, of a decision task that required two successive judgments at different times during the evidence stream: an intermittent response consisting of a binary choice, and a continuous estimation at the end of the evidence stream. In a control condition, subjects executed a choice-independent motor response instead of binary choice as the intermittent response. In both, perceptual and numerical tasks, the intermittent choice reduced the sensitivity of subsequent evidence, and flipped the relative temporal weighting of early and late evidence in the final estimation judgment. The individual extent of the choice-induced overall (non-selective) sensitivity reduction predicted the extent of the selective down-weighting of subsequent evidence inconsistent with the initial choice, a form of confirmation bias. In sum, active decisions about a protracted evidence stream profoundly alter the dynamics of evidence accumulation, consistent with an active, modulatory mechanism triggered by the choice.
Brain Activity Reveals Multiple Motor-Learning Mechanisms in a Real-World Task

Many recent studies found signatures of motor learning in neural Beta oscillations (13– 30Hz), and specifically in the post-movement Beta rebound (PMBR). All these studies were in controlled laboratory-tasks in which the task designed to induce the studied learning mechanism. Interestingly, these studies reported opposing dynamics of the PMBR magnitude over learning for the error-based and reward-based tasks (increase versus decrease, respectively). Here we explored the PMBR dynamics during real-world motor-skill-learning in a billiards task using mobile-brain-imaging. Our EEG recordings highlight the opposing dynamics of PMBR magnitudes (increase versus decrease) between different subjects performing the same task. The groups of subjects, defined by their neural dynamics, also showed behavioural differences expected for different learning mechanisms. Our results suggest that when faced with the complexity of the real-world different subjects might use different learning mechanisms for the same complex task. We speculate that all subjects combine multi-modal mechanisms of learning, but different subjects have different predominant learning mechanisms.
Plasmidome analysis of carbapenem-resistant Enterobacteriaceae isolated in Vietnam

Carbapenem-resistant Enterobacteriaceae (CRE) represent a serious threat to public health due to limited management of severe infections and high mortality. The rate of resistance of Enterobacteriaceae isolates to major antimicrobials, including carbapenems, is much higher in Vietnam than in Western countries, but the reasons remain unknown due to the lack of genomic epidemiology research. A previous study suggested that carbapenem resistance genes, such as the carbapenemase gene bla NDM-1 , spread via plasmids among Enterobacteriaceae in Vietnam. In this study, we performed detection and molecular characterization of bla NDM-1 -carrying plasmids in CRE isolated in Vietnam, and identified several possible cases of horizontal transfer of plasmids both within and among species of bacteria. Twenty-five carbapenem-resistant isolates from Enterobacteriaceae clinically isolated in a reference medical institution in Hanoi were sequenced on Illumina short-read sequencers, and 12 isolates harboring bla NDM-1 were sequenced on an Oxford Nanopore Technologies long-read sequencer to obtain complete plasmid sequences. Most of the plasmids co-carried genes conferring resistance to clinically relevant antimicrobials, including third-generation cephalosporins, aminoglycosides, and fluoroquinolones, in addition to bla NDM-1 , leading to multidrug resistance of their bacterial hosts. These results provide insight into the genetic basis of CRE in Vietnam, and could help control nosocomial infections.
ICEs Are the Main Reservoirs of the Ciprofloxacin-Modifying crpP Gene in Pseudomonas aeruginosa

The ciprofloxacin-modifying crpP gene was recently identified in a plasmid isolated from a clinical Pseudomonas aeruginosa clinical isolate. Homologues of this gene were also identified in Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. We set out to explore the mobile genetic elements involved in the acquisition and spread of this gene in publicly available and complete genomes of Pseudomonas. The crpP gene was identified only in P. aeruginosa, in more than half of the complete chromosomes (61.9%, n=133/215) belonging to 52 sequence types, of which the high-risk clone ST111 was the most frequent. We identified 136 crpP-harboring ICEs, with 93.4% belonging to the mating-pair formation G (MPFG) family. The ICEs were integrated at the end of a tRNALys gene and were all flanked by highly conserved 45-bp direct repeats. The core ICEome contains 26 genes (2.2% of all genes), which are present in 99% or more of the crpP-harboring ICEs. The most frequently encoded traits on these ICEs include replication, transcription, intracellular trafficking and cell motility. Our work reveals that ICEs are the main vectors promoting the dissemination of the ciprofloxacin-modifying crpP gene in P. aeruginosa. Author Notes All supporting data has been provided within the article or through supplementary data files. Supplementary material is available with the online version of this article. Impact Statement A high proportion of Pseudomonas aeruginosa clinical isolates are resistant to ciprofloxacin. Resistance to this antibiotic is often mediated by chromosomal mutations, but recently horizontally transferred genes have been identified. We assessed the repartition of the ciprofloxacin-modifying crpP gene among Pseudomonas genomes and we characterized the mobile elements associated with its acquisition. We found that this gene is prevalent in P. aeruginosa and frequently associated with integrative and conjugative elements (ICEs). Importantly, we also identified highly conserved direct repeats that can be used to accurately delimit crpP-carrying ICEs in P. aeruginosa genomes. Data Summary All the bacterial genomes scanned in this study have been deposited previously in the National Center for Biotechnology Information genome database and are listed on the supplementary tables. The newick files used to create the trees in Figures 1 and 4 are deposited on figshare at https://figshare.com/projects/ICEs_are_the_main_reservoirs_of_the_ciprofloxacin-modifying_crpP_gene_in_Pseudomonas_aeruginosa/79308.