Miracle-dz/UniFAR-FTUs huggingface dataset:
Fast and flexible design of novel proteins using graph neural networks

Protein structure and function is determined by the arrangement of the linear sequence of amino acids in 3D space. Despite substantial advances, precisely designing sequences that fold into a predetermined shape (the “protein design” problem) remains difficult. We show that a deep graph neural network, ProteinSolver, can solve protein design by phrasing it as a constraint satisfaction problem (CSP). To sidestep the considerable issue of optimizing the network architecture, we first develop a network that is accurately able to solve the related and straightforward problem of Sudoku puzzles. Recognizing that each protein design CSP has many solutions, we train this network on millions of real protein sequences corresponding to thousands of protein structures. We show that our method rapidly designs novel protein sequences and perform a variety of in silico and in vitro validations suggesting that our designed proteins adopt the predetermined structures. One Sentence Summary A neural network optimized using Sudoku puzzles designs protein sequences that adopt predetermined structures.
Discrete neural clusters encode orientation, curvature and corners in macaque V4

As an intermediate stage of the ventral visual pathway, V4 plays a crucial role in transforming basic orientation information into higher-ordered object representations. However, the neural mechanisms underlying the encoding of simple, complex and intermediate features in V4 remain poorly understood. Using two-photon calcium imaging in awake macaques, we recorded the responses of large populations of V4 neurons to thousands of natural images. To understand these high-dimensional data sets, we performed dimensional reduction analysis on the neuronal population responses. We found orthogonal dimensions encoding orientation and more complex features, with curves and corners represented separately. These distinct feature dimensions were encoded by spatially clustered subpopulations of neurons organized in iso-orientation and curvature domains. Using synthetic stimuli, we confirmed that curvature and corner selective neurons in V4 were tuned to integral features rather than combinations of local orientation compartments. Our results show that curves and corners are encoded by neurons clustered into functional domains separate from orientation. This functionally specific population architecture may serve to facilitate local computations that expedite more complex shape and object representations at higher levels of the ventral pathway.
Drosophila histone locus body assembly and function involves multiple interactions

The histone locus body (HLB) assembles at replication-dependent (RD) histone loci and concentrates factors required for RD histone mRNA biosynthesis. The D. melanogaster genome has a single locus comprised of ∼100 copies of a tandemly arrayed repeat unit containing one copy of each of the 5 RD histone genes. To determine sequence elements required for D. melanogaster HLB formation and histone gene expression, we used transgenic gene arrays containing 12 copies of the histone repeat unit that functionally complement loss of the ∼200 endogenous RD histone genes. A 12x histone gene array in which all H3-H4 promoters were replaced with H2a-H2b promoters does not form an HLB or express high levels of RD histone mRNA in the presence of the endogenous histone genes. In contrast, this same transgenic array is active in HLB assembly and RD histone gene expression in the absence of the endogenous RD histone genes and rescues the lethality caused by homozygous deletion of the RD histone locus. The HLB formed in the absence of endogenous RD histone genes on the mutant 12x array contains all known factors present in the wild type HLB including CLAMP, which normally binds to GAGA repeats in the H3-H4 promoter. These data suggest that multiple protein-protein and/or protein-DNA interactions contribute to HLB formation, and that the large number of endogenous RD histone gene copies sequester available factor(s) from attenuated transgenic arrays, thereby preventing HLB formation and gene expression.
Whole genome sequencing of Plasmodium vivax isolates reveals frequent sequence and structural polymorphisms in erythrocyte binding genes

Plasmodium vivax malaria is much less common in Africa than the rest of the world because the parasite relies primarily on the Duffy antigen/chemokine receptor (DARC) to invade human erythrocytes, and the majority of Africans are Duffy negative. Recently, there has been a dramatic increase in the reporting of P. vivax cases in Africa, with a high number of them being in Duffy negative individuals, potentially indicating P. vivax has evolved an alternative invasion mechanism that can overcome Duffy negativity. Here, we analyzed single nucleotide polymorphism (SNP) and copy number variation (CNV) in Whole Genome Sequence (WGS) data from 44 P. vivax samples isolated from symptomatic malaria patients in southwestern Ethiopia, where both Duffy positive and Duffy negative individuals are found. A total of 236,351 SNPs were detected, of which 21.9% was nonsynonymous and 78.1% was synonymous mutations. The largest number of SNPs were detected on chromosomes 9 (33,478 SNPs; 14% of total) and 10 (28,133 SNPs; 11.9%). There were particularly high levels of polymorphism in erythrocyte binding gene candidates including reticulocyte binding protein 2c (RBP2c), merozoite surface protein 1 (MSP1), and merozoite surface protein 3 (MSP3.5, MSP3.85 and MSP3.9). Thirteen genes related to immunogenicity and erythrocyte binding function were detected with significant signals of positive selection. Variation in gene copy number was also concentrated in genes involved in host-parasite interactions, including the expansion of the Duffy binding protein gene (PvDBP) on chromosome 6 and several PIR genes. Based on the phylogeny constructed from the whole genome sequences, the expansion of these genes was an independent process among the P. vivax lineages in Ethiopia. We further inferred transmission patterns of P. vivax infections among study sites and showed various levels of gene flow at a small geographical scale. The genomic features of P. vivax provided baseline data for future comparison with those in Duffy-negative individuals, and allowed us to develop a panel of informative Single Nucleotide Polymorphic markers diagnostic at a micro-geographical scale.
Dynamics of gaze control during prey capture in freely moving mice

Many studies of visual processing are conducted in unnatural conditions, such as head- and gaze-fixation. As this radically limits natural exploration of the visual environment, there is much less known about how animals actively use their sensory systems to acquire visual information in natural, goal-directed contexts. Recently, prey capture has emerged as an ethologically relevant behavior that mice perform without training, and that engages vision for accurate orienting and pursuit. However, it is unclear how mice target their gaze during such natural behaviors, particularly since, in contrast to many predatory species, mice have a narrow binocular field and lack foveate vision that would entail fixing their gaze on a specific point in the visual field. Here we measured head and bilateral eye movements in freely moving mice performing prey capture. We find that the majority of eye movements are compensatory for head movements, thereby acting to stabilize the visual scene. During head turns, however, these periods of stabilization are interspersed with non-compensatory saccades that abruptly shift gaze position. Analysis of eye movements relative to the cricket position shows that the saccades do not preferentially select a specific point in the visual scene. Rather, orienting movements are driven by the head, with the eyes following in coordination to sequentially stabilize and recenter the gaze. These findings help relate eye movements in the mouse to other species, and provide a foundation for studying active vision during ethological behaviors in the mouse.
Equine strongyle communities are constrained by horse sex and species dipersal-1 fecundity trade-off 2

13 Equine strongyles are a major health issue. Large strongyles can cause death of horses while 14 cyathostomins (small strongyles) have shown increased resistance to anthelmintics 15 worldwide. Description of strongyle communities have accumulated but little is known about 16 the diversity of these communities and underpinning environmental factors. 17 This study analysed the diversity of strongyle communities in 48 horses from Poland. 18 Strongyle species fell into two groups, contrasted by their prevalence and relative abundance. 19 Seven horses were necessary to sample at least 90% of strongyle community diversity, 20 providing a minimal cut-off to implement sampling trial in the field. Strongyle communities 21 entertained a network of mostly positive interactions and species co-occurrence was found 22 more often than expected by chance. In addition, species fecundity and prevalence were 23 negatively correlated (r=-0.78), suggesting functional trade-offs between species dispersal 24 abilities and fecundity. This functional trade-off may underpin species coexistence. Horse sex 25 was also a significant constraint shaping strongyle communities. Indeed, mares generally 26 displayed more similar strongyle communities than stallions (p=0.004) and Cylicostephanus 27 calicatus was more abundant in stallions suggesting sex-specific interactions (p=0.02). 28 While niche partitioning is likely to explain some of the positive interactions between equine 29 strongyle species, coexistence may also result from a functional trade-off between dispersal 30 ability and fecundity. There is significant evidence that horse sex drives strongylid 31 community structure, which may require differential control strategies between mares and 32 stallions. 33 34
Bridging parametric and nonparametric measures of species interactions unveils new insights of non-equilibrium dynamics

A central theme in ecological research is to understand how species interactions contribute to community dynamics. Species interactions are the basis of parametric (model-driven) and nonpara-metric (model-free) approaches in theoretical and empirical work. However, despite their different interpretations across these approaches, these measures have occasionally been used interchangeably, limiting our opportunity to use their differences to gain new insights about ecological systems. Here, we revisit two of the most used measures across these approaches: species interactions measured as constant direct effects (typically used in parametric approaches) and local aggregated effects (typically used in nonparametric approaches). We show two fundamental properties of species interactions that cannot be revealed without bridging these definitions. First, we show that the local aggregated intraspecific effect summarizes all potential pathways through which one species impacts itself, which are likely to be negative even without any constant direct self-regulation mechanism. This property has implications for the long-held debate on how communities can be stabilized when little evidence of self-regulation has been found among higher-trophic species. Second, we show that a local aggregated interspecific effect between two species is correlated with the constant direct interspecific effect if and only if the population dynamics do not have any higher-order direct effects. This other property provides a rigorous methodology to detect direct higher-order effects in the field and experimental data. Overall, our findings illustrate a practical route to gain further insights about non-equilibrium ecological dynamics and species interactions.
Risk Factor Assessment of Hospice Patients Readmitted within 7 Days of Acute Care Hospital Discharge

Factors surrounding readmission rates for hospice patients within seven days are still relatively unknown. The present study specifically investigates the seven-day readmission rate of patients newly discharged to hospice, and the predictive factors associated with readmission for this population. In a retrospective case-control study, we seek to identify potential predictors by comparing the characteristics of patients discharged to hospice and readmitted within one week to patients who were not readmitted. Cases (n = 46) were patients discharged to home hospice and readmitted to the hospital within seven days. Controls (n = 117) were patients discharged to home hospice and not readmitted to the hospital within seven days. Significant risk factors for readmission within seven days were found to be: age (p < 0.01), race (p < 0.001), language (p < 0.001), and insurance (p < 0.001). Further study of these predictors may identify opportunities for interventions that address patient and family concerns that may lead to readmission.
High-order interdependencies in the aging brain

Brain interdependencies can be studied either from a structural/anatomical perspective (“structural connectivity”, SC) or by considering statistical interdependencies (“functional connectivity”, FC). Interestingly, while SC is typically pairwise (white-matter fibers start in a certain region and arrive at another), FC is not; however, most FC analyses focus only on pairwise statistics and neglect high-order interactions. A promising tool to study high-order interdependencies is the recently proposed O-Information, which can quantify the intrinsic statistical synergy and redundancy in groups of three or more interacting variables. In this paper we used the O-Information to investigate how high-order statistical interdependencies are affected by age. For this, we analised functional magnetic resonance imaging (fMRI) data at rest obtained from 164 healthy participants, ranging from 10 to 80 years old. Our results show that older subjects (age ranging from 60 to 80 years) exhibit a higher predominance of redundant dependencies than younger subjects; moreover, this effect seems to be pervasive, taking place at all interaction orders. Additionally, we found that these effects are highly heterogeneous across brain regions, and suggest the existence of a “redundancy core” formed by the prefrontal and motor cortices – thus involving functions such as working memory, executive and motor functions. Our methodology to assess high-order interdependencies in fMRI data has unlimited applications. The code to calculate these metrics is freely available.
Resting-State Connectivity of Auditory and Reward Systems in Alzheimer’s Disease and Mild Cognitive Impairment

Music-based interventions have become increasingly widely adopted for dementia and related disorders. Previous research shows that music engages reward-related regions through functional connectivity with the auditory system. Here we characterize intrinsic connectivity of the auditory and reward systems in healthy aging, mild cognitive impairment (MCI) - a predementia phase of cognitive dysfunction, and Alzheimer’s disease (AD). Using resting-state fMRI data from the Alzheimer’s Database Neuroimaging Initiative, we tested functional connectivity within and between auditory and reward systems in older adults with MCI, AD, and age-matched healthy controls (N=105). Seed-based correlations were assessed from regions of interest (ROIs) in the auditory network, i.e. anterior superior temporal gyrus (aSTG), posterior superior temporal gyrus (pSTG), Heschl’s Gyrus, and reward network (i.e., nucleus accumbens, caudate, putamen, and orbitofrontal cortex [OFC]). AD individuals were lower in both within-network and between-network functional connectivity in the auditory network and reward networks compared to MCI and healthy controls. Furthermore, graph theory analyses showed that MCI individuals had higher clustering, local efficiency, degrees, and strengths than both AD individuals and healthy controls. Together, the auditory and reward systems show preserved within- and between-network connectivity in MCI relative to AD. These results suggest that music-based interventions have the potential to make an early difference in individuals with MCI, due to the preservation of functional connectivity in reward-related regions and between auditory and reward networks at that initial stage of neurodegeneration.
Communication Through Coherence by Means of Cross-frequency Coupling

The theory of communication through coherence (CTC) posits the synchronization of brain oscillations as a key mechanism for information sharing and perceptual binding. In a parallel literature, hippocampal theta activity (4 – 10 Hz) has been shown to modulate the appearance of neocortical fast gamma oscillations (100 – 150 Hz), a phenomenon known as cross-frequency coupling (CFC). Even though CFC has also been previously associated with information routing, it remains to be determined whether it directly relates to CTC. In particular, for the theta-fast gamma example at hand, a critical question is to know if the phase of the theta cycle influences gamma synchronization across the neocortex. To answer this question, we designed a new screening method for detecting the modulation of the cross-regional high-frequency synchronization by the phase of slower oscillations. Upon applying the method, we found that the long-distance synchronization of neocortical fast gamma during REM sleep depends on the instantaneous phase of the theta rhythm. These results show that CFC is likely to aid long-range information transfer by facilitating the cross-regional synchronization of faster rhythms, thus consistent with classical CTC views.
Amplitude modulation encoding in auditory cortex: Comparisons between the primary and middle lateral belt regions

In macaques, the middle lateral auditory cortex (ML) is a belt region adjacent to primary auditory cortex (A1) and believed to be at a hierarchically higher level. Although ML single-unit responses have been studied for several auditory stimuli, the ability of ML cells to encode amplitude modulation (AM) – an ability which has been widely studied in A1 – has not yet been characterized. Here we compare the responses of A1 and ML neurons to amplitude modulated (AM) noise in awake macaques. While several of the basic properties of A1 and ML responses to AM noise are similar, we found several key differences. ML neurons do not phase lock as strongly, are less likely to phase lock, and are more likely to respond in a non-synchronized fashion than A1 cells, consistent with a temporal-to-rate transformation as information ascends the auditory hierarchy. ML neurons tend to have lower temporally (phase-locking) based best modulation frequencies than A1. At the level of ML, neurons that decrease firing rate with increasing modulation depth become more common than in A1. In both A1 and ML we find a prevalent class of neurons with excitatory rate responses at lower modulation frequencies and suppressed rate responses relative to the unmodulated carrier at middle modulation frequencies.
On the ecology and distribution of steelhead (Oncorhynchus mykiss) in California’s Eel River

Preservation of life-history and other phenotypic complexity is central to the resilience of Pacific salmon stocks. Steelhead (Oncorhynchus mykiss) express a diversity of life history strategies such as the propensity to migrate (anadromy/residency) and the timing and state of maturation upon return to freshwater (run-timing), providing an opportunity to study adaptive phenotypic complexity. Historically, the Eel River supported upwards of one million salmon and steelhead, but the past century has seen dramatic declines of all salmonids in the watershed. Here we investigate life history variation in Eel River steelhead by using Rapture sequencing, on thousands of individuals, to genotype the region diagnostic for run-timing (GREB1L) and the region strongly associated with residency/anadromy (OMY5) in the Eel River and other locations, as well as determine patterns of overall genetic differentiation. Our results provide insight into many conservation related issues. For example, we found distinct segregation between winter and summer-run steelhead correlated with flow dependent barriers in major forks of the Eel; that summer-run steelhead inhabited the upper Eel prior to construction of an impassable dam, and that both life-history and overall genetic diversity have been maintained in the resident trout population above; and no evidence of the summer-run allele in the South Fork Eel, indicating that summer run-timing cannot be expected to arise from standing genetic variation in this and other populations that lack the summer-run phenotype. The results presented in this study provide valuable information for designing future restoration and management strategies for O. mykiss in Northern California and beyond.
Software for Detecting Heterogeneous Evolutionary Processes across Aligned Sequence Data

Most model-based molecular phylogenetic methods assume that the sequences diverged on a tree under homogeneous conditions. If evolution occurred under these conditions, then it is unlikely that the sequences would become compositionally heterogeneous. Conversely, if the sequences are compositionally heterogeneous, then it is unlikely that they have evolved under homogeneous conditions. We present methods to detect and analyse heterogeneous evolution in aligned sequence data and to examine—visually and numerically—its effect on phylogenetic estimates. The methods are implemented in three programs, allowing users to better examine under what conditions their phylogenetic data may have evolved.
Testing the Two-Step Model of Plant Root Microbiome Acquisition Under Multiple Plant Species and Soil Sources

The two-step model for plant root microbiomes considers soil as the primary microbial source. Active selection of the plant’s bacterial inhabitants results in a biodiversity decrease towards roots. We collected in situ ruderal plant roots and their soils and used these soils as the main microbial input for single genotype tomatoes grown in a greenhouse. We massively sequenced the 16S rRNA and shotgun metagenomes of the soils, in situ plants, and tomato roots. Tomato roots did follow the two-step model, while ruderal plants did not. Ruderal plants and their soils are closer than tomato and its soil, based on protein comparisons. We calculated a metagenomic tomato root core of 51 bacterial genera and 2,762 proteins, which could be the basis for microbiome-oriented plant breeding programs. The tomato and ruderal metagenomic differences are probably due to plant domestication trade-offs, impacting plant-microbe interactions.