Miracle-dz/UniFAR-FTUs huggingface dataset:
Parental neural responsivity to infants’ visual attention: how mature brains scaffold immature brains during social interaction

Almost all attention and learning - in particular, most early learning – takes place in social settings. But little is known of how our brains support dynamic social interactions. We recorded dual-EEG from infants and parents during solo play and joint play. During solo play, fluctuations in infants’ Theta power significantly forward-predicted their subsequent attentional behaviours. But this forwards-predictiveness was lower during joint play than solo play, suggesting that infants’ endogenous neural control over attention is greater during solo play. Overall, however, infants were more attentive to the objects during joint play. To understand why, we examined how adult brain activity related to infant attention. We found that parents’ Theta power closely tracked and responded to changes in their infants’ attention. Further, instances in which parents showed greater neural responsivity were associated with longer sustained attention by infants. Our results offer new insights into how one partner influences another during social interaction.
An empirical examination of sample size effects on population demographic estimates in birds using single nucleotide polymorphism (SNP) data

Sample size is a critical aspect of study design in population genomics research, yet few empirical studies have examined the impacts of small sample sizes. We used datasets from eight diverging bird lineages to make pairwise comparisons at different levels of taxonomic divergence (populations, subspecies, and species). Our data are from loci linked to ultraconserved elements (UCEs) and our analyses used one SNP per locus. All individuals were genotyped at all loci (McLaughlin et al. 2020). We estimated population demographic parameters (effective population size, migration rate, and time since divergence) in a coalescent framework using Diffusion Approximation for Demographic Inference (δaδi; Gutenkunst et al. 2009), an allele frequency spectrum (AFS) method. Using divergence-with-gene-flow models optimized with full datasets, we subsampled at sequentially smaller sample sizes from full datasets of 6 – 8 diploid individuals per population (with both alleles called) down to 1:1, and then we compared estimates and their changes in accuracy. Accuracy was strongly affected by sample size, with considerable differences among estimated parameters and among lineages. Effective population size parameters (ν) tended to be underestimated at low sample sizes (fewer than 3 diploid individuals per population, or 6:6 haplotypes in coalescent terms). Migration (m) was fairly consistently estimated until ≤ 2 individuals per population, and no consistent trend of over- or underestimation was found in either time since divergence (T) or Θ (4Nrefμ). Lineages that were taxonomically recognized above the population level (subspecies and species pairs; i.e., deeper divergences) tended to have lower variation in scaled root mean square error (SMRSE) of parameter estimation at smaller sample sizes than population-level divergences, and many parameters were estimated accurately down to 3 diploid individuals per population. Shallower divergence levels (i.e., populations) often required at least 5 individuals per population for reliable demographic inferences using this approach. Although divergence levels might be unknown at the outset of study design, our results provide a framework for planning appropriate sampling and for interpreting results if smaller sample sizes must be used.
Deletion of Autophagy gene ATG1 and Glyoxylate cycle Regulator encoding gene UCC1 together leads to Synthetic Growth Defects and Sensitivity to Genotoxic agents in Saccharomyces cerevisiae

Atg1 of S. cerevisiae is a key component of autophagy encoded by ATG1 gene, involved in the process of degradation of cytosolic components through autophagy. UCC1, an F-box encoding gene is involved in the negative regulation of glyoxylate pathway via degradation of Cit2 enzyme by ubiquitin proteasome system. We investigated the genetic interaction between ATG1 and UCC1 using the gene deletion approach. The atg1Δucc1Δ cells showed the synthetic growth defects with abnormal budding and sensitivity to genotoxic and oxidative stress agents. Based on the observations, we report that ATG1 and UCC1 interact genetically to regulate the cell growth fitness and function in parallel pathway in cellular response to the genotoxic stress agents. The present investigation also revealed the cross talks among autophagy, ubiquitin proteasome system, and glyoxylate pathways.
Neuroblast sensory quiescence depends of vascular cytoneme contacts and sensory neuronal differentiation requires initiation of blood flow

In many organs, stem cell function depends on the communication with their niche partners. Cranial sensory neurons develop in close proximity to blood vessels, however whether vasculature is an integral component of their niches is yet unknown. Here, two separate, novel roles for vasculature in cranial sensory neurogenesis in zebrafish are uncovered. The first involves precise spatiotemporal endothelial-neuroblast cytoneme contacts and Dll4-Notch signalling to restrain neuroblast proliferation. Secondly, we find that blood flow onset triggers a transcriptional response to modify neuroblast metabolic status and is required for sensory neuron differentiation. In contrast, no role of sensory neurogenesis in vascular development is found, suggesting a unidirectional signalling from vasculature to sensory neuroblasts. Altogether, we demonstrate that the cranial vasculature constitutes a hitherto unrecognized niche component of the sensory ganglia that regulates the pace of their growth and differentiation dynamics. ♦ Vasculature is part of the cranial sensory ganglia niche and regulates neurogenesis. ♦ Cytoneme contacts between endothelial cells and sensory neuroblasts are required for neuroblast quiescence. ♦ Endothelial Dll4 and neuroblast Notch1 signal to regulate the growth of cranial sensory ganglia. ♦ Initiation of blood flow triggers a transcriptional metabolic switch and sensory neuronal differentiation.
Bacteroides thetaiotaomicron-infecting bacteriophage isolates inform sequence-based host range predictions

Our emerging view of the gut microbiome largely focuses on bacteria and less is known about other microbial components such as of bacteriophages (phages). Though phages are abundant in the gut, very few phages have been isolated from this ecosystem. Here, we report the genomes of 27 phages from the United States and Bangladesh that infect the prevalent human gut bacterium Bacteroides thetaiotaomicron. These phages are mostly distinct from previously sequenced phages with the exception of two, which are crAss-like phages. We compare these isolates to existing human gut metagenomes, revealing similarities to previously inferred phages and additional unexplored phage diversity. Finally, we use host tropisms of these phages to identify alleles of phage structural genes associated with infectivity. This work provides a detailed view of the gut’s “viral dark matter” and a framework for future efforts to further integrate isolation- and sequencing-focused efforts to understand gut-resident phages.
Poisson poisoning as the mechanism of action of the microtubule-targeting agent colchicine

Microtubule-directed anti-cancer drugs, such as paclitaxel, vinblastine, and colchicine, disrupt cell mitosis through suppression of microtubule dynamics (“kinetic stabilization”). However, while the molecular mechanisms of paclitaxel and vinblastine act as pseudo- and true-kinetic stabilizers, respectively, the molecular mechanism of colchicine has remained enigmatic since it requires explanation of both the slow kinetics of the drug and suppression of microtubule dynamics. In this work, we applied an integrated multi-scale modeling-experimental approach to systematically characterize the microtubule targeting agent (MTA) colchicine. We found that colchicine stabilizes microtubule dynamics significantly both in vivo and in vitro in a time and concentration-dependent manner. Molecular modeling results suggest that tubulin’s binding pocket is accessible to the drug for only 15% of the simulation trajectory time in straight and 82% in curved conformation on average, confirming that colchicine mainly binds to free tubulin. Molecular dynamics simulations show that there are conformational changes at longitudinal and lateral residues of GTP-tubulin-colchicine compared to a lattice tubulin structure, explaining why further incorporation of tubulin dimers to a tubulin-colchicine complex at a protofilament tip is unfavorable. Thermokinetic modeling of microtubule assembly shows that colchicine bound at fractions as low as ∼0.008 to free tubulin can poison the ends of protofilaments with a Poisson distribution and thus, reduce the microtubule growth rate, while stabilizing the tubulin lateral bond and reducing the microtubule shortening rate, i.e. true kinetic stabilization. This study suggests new strategies for colchicine administration to improve the therapeutic window in the treatment of cancer and inflammatory diseases. Significance Statement Colchicine is an ancient microtubule targeting agent (MTA) known to attenuate microtubule (MT) dynamics but its cancer treatment efficacy is often limited by lack of a detailed understanding of the drug’s mechanism of action. The primary goal of this study was to perform a multi-scale systematic analysis of molecular mechanism of action of colchicine. The analysis indicates that unlike paclitaxel and vinblastine, colchicine poisons the ends of protofilaments of MTs at low fractions bound to tubulin, in a time-dependent manner. Our results suggest new insights into improvement of the clinical administration of colchicine and new colchicine-site inhibitors.
Molecular mechanism of the pH-dependent calcium affinity in langerin

The C-type lectin receptor langerin plays a vital role in the mammalian defense against invading pathogens. Its function hinges on the affinity to its co-factor Ca2+ which in turn is regulated by the pH. We studied the structural consequences of protonating the allosteric pH-sensor histidine H294 by molecular dynamics simulations (total simulation time: about 120 µs) and Markov models. We discovered a mechanism in which the signal that the pH has dropped is transferred to the Ca2+-binding site without transferring the initial proton. Instead, protonation of H294 unlocks a conformation in which a protonated lysine side-chain forms a hydrogen bond with a Ca2+-coordinating aspartic acid. This destabilizes Ca2+ in the binding pocket, which we probed by steered molecular dynamics. After Ca2+-release, the proton is likely transferred to the aspartic acid and stabilized by a dyad with a nearby glutamic acid, triggering a conformational transition and thus preventing Ca2+-rebinding.
SnToxA, SnTox1 and SnTox3 originated in Parastagonospora nodorum in the Fertile Crescent

The center of origin of the globally distributed wheat pathogen Parastagnospora nodorum has remained uncertain because only a small number of isolates from the Fertile Crescent, a region in the Middle East where wheat was domesticated from wild grasses, were included in earlier population genetic and phylogeographic studies. We isolated and genetically analyzed 193 P. nodorum strains from three naturally infected wheat fields distributed across Iran, a country located within the Fertile Crescent, using eleven neutral microsatellite loci. Compared to previous studies that included populations from North America, Europe, Africa, Australia and China, the populations from Iran had the highest genetic diversity globally and also exhibited greater population structure over smaller spatial scales, patterns typically associated with a species’ center of origin. Genes encoding the necrotrophic effectors SnToxA, SnTox1 and SnTox3 were found at a high frequency in the Iranian population. By sequencing 96 randomly chosen Iranian strains, we detected new alleles for all three effector genes. Analyses of allele diversity showed that all three effector genes had higher diversity in Iran than in any population included in previous studies, with Iran acting as a hub for the effector diversity that was found in other global populations. Taken together, these findings support the hypothesis that P. nodorum originated either within or nearby the Fertile Crescent with a genome that already encoded all three necrotrophic effectors during its emergence as a pathogen on wheat. Our findings also suggest that P. nodorum was the original source of the ToxA genes discovered in the wheat pathogens Phaeosphaeria avenaria f. sp. tritici 1, Pyrenophora tritici-repentis and Bipolaris sorokiniana.
Mucosal microbiota and metabolome along the intestinal tracts reveals location specific relationship

The intestinal microbiota has been recognized as an important component for maintaining human health. The perturbation to its structure has been implicated in many diseases, such as obesity and cancers. The microbiota is highly metabolically active and plays a role in many metabolic pathways absent from the human host. Altered microbiota metabolism has also been linked to obesity, cardiovascular disease, and colorectal cancer. However, there is a gap in the current knowledge of how the microbiota interacts with its host. Here we performed an integrated analysis between the mucosal-associated microbiota and the mucosal tissue metabolomics in healthy non-human primates (NHPs) to investigate these relationships.We found that the overall microbiota composition is influenced by both the tissue location as well as the host individual. The NHPs intestinal microbiota predominantly comprised of members of the phyla Firmicutes, Bacteroidetes, and Proteobacteria. The large intestines contain more Spirochaetes, Tenericutes, and Lentisphaera phyla members. The small intestinal tissues have no significantly different microbiota compositions, while the cecum and distal colon differ greatly in the microbiota compositions. The metabolomics profile reveals a total of 140 metabolites with different concentration between the small and large intestines. The correlations between microbiota and tissue metabolites showed a dense and interconnected network in the small intestines while a sparse network in the large intestines.Our analysis revealed an intricate global relationship between the microbiota and the host tissue metabolome that is mainly driven by the distal colon. Most importantly, we found location specific microbiota-metabolite correlations that have potential implications for studying host-microbiota metabolic interactions.
A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet

The hypothalamus is the central regulator of energy homeostasis. Hypothalamic neuronal circuits are disrupted upon overfeeding, and play a role in the development of metabolic disorders. While mouse models have been extensively employed for understanding the mechanisms of hypothalamic dysfunction, functional magnetic resonance imaging (fMRI) on hypothalamic nuclei has been challenging. We implemented a robust glucose-induced fMRI paradigm that allows to repeatedly investigate hypothalamic responses to glucose. This approach was used to test the hypothesis that hypothalamic nuclei functioning is impaired in mice exposed to a high-fat and high-sucrose diet (HFHSD) for seven days. The blood oxygen level-dependent (BOLD) fMRI signal was measured from brains of mice under light isoflurane anaesthesia, during which a 2.6 g/kg glucose load was administered. The mouse hypothalamus responded to glucose but not saline administration with a biphasic BOLD fMRI signal reduction. Relative to controls, HFHSD-fed mice showed attenuated or blunted responses in arcuate nucleus, lateral hypothalamus, ventromedial nucleus and dorsomedial nucleus, but not in paraventricular nucleus. In sum, we have developed an fMRI paradigm that is able to determine dysfunction of glucose-sensing neuronal circuits within the mouse hypothalamus in a non-invasive manner.
SARS‐CoV‐2, an evolutionary perspective of interaction with human ACE2 reveals undiscovered amino acids necessary for complex stability

The emergence of SARS-CoV-2 has resulted in more than 200,000 infections and nearly 9,000 deaths globally so far. This novel virus is thought to have originated from an animal reservoir, and acquired the ability to infect human cells using the SARS-CoV cell receptor hACE2. In the wake of a global pandemic it is essential to improve our understanding of the evolutionary dynamics surrounding the origin and spread of a novel infectious disease. One way theory predicts selection pressures should shape viral evolution is to enhance binding with host cells. We first assessed evolutionary dynamics in select betacoronavirus spike protein genes to predict where these genomic regions are under directional or purifying selection between divergent viral lineages at various scales of relatedness. With this analysis, we determine a region inside the receptor-binding domain with putative sites under positive selection interspersed among highly conserved sites, which are implicated in structural stability of the viral spike protein and its union with human receptor hACE2. Next, to gain further insights into factors associated with coronaviruses recognition of the human host receptor, we performed modeling studies of five different coronaviruses and their potential binding to hACE2. Modeling results indicate that interfering with the salt bridges at hot spot 353 could be an effective strategy for inhibiting binding, and hence for the prevention of coronavirus infections. We also propose that a glycine residue at the receptor binding domain of the spike glycoprotein can have a critical role in permitting bat variants of the coronaviruses to infect human cells.
Lack of correlation between number of neurons and behavioral performance in Swiss mice

Neuronal number varies by several orders of magnitude across species, and has been proposed to predict cognitive capability across species. Remarkably, numbers of neurons vary across individual mice by a factor of 2 or more. We directly addressed the question of whether there is a relationship between performance in behavioral tests and the number of neurons in functionally relevant structures in the mouse brain. Naïve Swiss mice went through a battery of behavioral tasks designed to measure cognitive, motor and olfactory skills. We estimated the number of neurons in different brain regions (cerebral cortex, hippocampus, olfactory bulb, cerebellum and remaining areas) and crossed the two datasets to test the a priori hypothesis of correlation between cognitive abilities and numbers of neurons. As previous evidence indicates that environmental enrichment may increase neurogenesis and improve neuronal survival, we added a control group that did not undergo cognitive testing to rule out the possibility that our test battery could alter the neuronal number. We found that behavioral testing did not change numbers of neurons in the cerebral cortex and in the hippocampus. Surprisingly, performance in the behavioral tasks did not correlate strongly with number of neurons in any of the brain regions studied. Our results show that whereas neuronal number is a good predictor of cognitive skills across species, it is not a predictor of cognitive, sensory or motor ability across individuals within a species, which suggests that other factors are more relevant for explaining cognitive differences between individuals of the same species.
Neuronal octopamine signaling regulates mating-induced germline stem cell proliferation in female Drosophila melanogaster

Stem cells fuel the development and maintenance of tissues. Many studies have addressed how local signals from neighboring niche cells regulate stem cell identity and their proliferative potential. However, the regulation of stem cells by tissue-extrinsic signals in response to external cues remains poorly understood. Here we report that efferent octopaminergic neurons projecting to the ovary are essential for germline stem cell (GSC) proliferation in response to mating in female Drosophila. The neuronal activity of the octopaminergic neurons is required for mating-induced GSC proliferation as they relay the mating signal from Sex peptide receptor-positive cholinergic neurons. Octopamine and its receptor Oamb are also required for mating-induced GSC proliferation via intracellular Ca2+ signaling. Moreover, we identified Matrix metalloproteinase-2 as a downstream component of the octopamine-Ca2+ signaling to induce GSC proliferation. Our study provides a mechanism describing how neuronal system couples stem cell behavior to external cues through stem cell niche signaling.
Novel ‘housekeeping’ genes and an unusually heterogeneous distribution of transporter expression profiles in human tissues and cell lines, assessed using the Gini coefficient

We analyse two comprehensive transcriptome datasets from human tissues and human-derived cell lines in terms of the expression profiles of the SLC and ABC families of membrane transporters. The Gini index (coefficient) characterises inequalities of distributions, and is used in a novel way to describe the distribution of the expression of each transporter among the different tissues and cell lines. In many cases, transporters exhibit extremely high Gini coefficients, even when their supposed substrates might be expected to be available to all tissues, indicating a much higher degree of specialisation than is usually assumed. This is consistent with divergent evolution from a more restricted set of ancestors. Similar trends hold true for the expression profiles of transporters in different cell lines, suggesting that cell lines exhibit largely similar transport behaviour to that of tissues. By contrast, the Gini coefficients for ABC transporters tend to be larger in cell lines than in tissues, implying that some kind of a selection process has taken place. In particular, with some exceptions such as olfactory receptors and genes involved in keratin production, transporter genes are significantly more heterogeneously expressed than are most non-transporter genes. The Gini index also allows us to determine those transcripts with the most stable expression; these often differ significantly from the ‘housekeeping’ genes commonly used for normalisation in transcriptomics and qPCR studies. The lowest four in tissues are FAM32A, ABCB7, MRPL21 and PCBP1, while the lowest three in cell lines are SF3B2, NXF1 and RBM45. PCBP1 is both reasonably highly expressed and has a low Gini coefficient in both tissues and cell lines, and is an excellent novel housekeeping gene. Overall, our analyses provide novel opportunities for the normalisation of genome-wide expression profiling data.