Miracle-dz/UniFAR-FTUs huggingface dataset:
T cells expressing the γδ T cell receptor are not required for egg granuloma formation in schistosomiasis

Immunopathology in schistosomiasis consists of a granulomatous response around parasite eggs. It has been established that granuloma formation is mediated by CD4+ T helper cells. However, the role of T cells bearing the γδ T cell receptor (TCR) has not been determined. In this study we utilized mutant mice that lack either αβ or γδ T cells as a result of gene targeting to investigate the relative roles of αβ and γδ T cells in the induction of immunopathology related to schistosomiasis. Mutant and control mice were infected with Schistosoma mansoni and granuloma formation as well as lymph node cell proliferative responses to egg antigens were analyzed after 8 weeks. TCR δ mutant mice (lacking γδ T cells) displayed vigorous formation of egg granulomas that were not significantly different from those observed in normal controls, both in terms of granuloma size and cellular composition. In contrast, TCR α and TCR β mutant mice (lacking αβ T cells) were unable to form granulomas. Moreover, mesenteric lymph node cells from TCR δ mutant and control mice responded strongly to egg antigens in vitro, while TCR α and β mutant mice did not. Our studies show that in schistosomiasis granuloma formation and proliferative responses to egg antigens are strictly dependent on αβ T cells. They also suggest that γδ T cells by themselves can neither mediate a granulomatous inflammation, nor significantly modify one mediated by αβ T cells.
Quantifying the functional responses of vegetation to drought and oxygen stress in temperate ecosystems

Summary 1. Our understanding of the generality of plant functional responses to water availability is limited; current field studies use either very rough approximations of water and oxygen availability or only focus on water-stressed ecosystems. Studies that relate species’ responses to a surplus of water are limited to controlled experiments. 2. The aim of this study was to investigate how traits are selected along a gradient of soil moisture, ranging from oxygen-stressed to drought-stressed. We tested 15 traits: eight leaf traits, two root traits, two seed traits and three allometry traits and related their community means to process-based measures of drought stress and oxygen stress for 171 plots in the Netherlands. Because the trait values had been taken from a large database, an independent field survey was carried out to validate the relationships thus derived. 3. We show that root porosity and seed floating capacity are mostly strongly related, although still moderately, to oxygen and drought stress (R 2 = 27% and 42%, respectively). Leaf traits responded weakly to either of the stressors. The field survey yielded similar relationships. Trait combinations were much more closely related to oxygen or drought stress than individual traits, suggesting that there are multiple trait solutions at a given level of water and oxygen stress. 4. The relatively weak relationships found between traits and water-related stressors contrast with the strong control of other environmental drivers (disturbance, nutrients) on traits and suggest that these strong constraints imposed by other environmental drivers necessitate varied solutions to cope with water availability.
Dynamic configurations of meiotic hotspot determinants

During meiosis, appropriate DNA double-strand break (DSB) and crossover distributions are required for proper homologous chromosome segregation in most species. Linear element proteins (LinEs) of Schizosaccharomyces pombe are DSB hotspot determinants. Clusters of LinE-bound hotspots form within ∼200 kb chromosomal regions independent of DSB formation. Previous reports showed that LinEs form chromatin-bound, dot-like nuclear foci in nuclear spreads and in fixed cells. Here, we investigated the regulation of LinE configuration and distribution in live cells using super-resolution fluorescence microscopy. In live cells at optimal meiotic temperature (∼25°C), LinEs made long linear forms, not previously reported, in both zygotic and azygotic meiosis and shared other characteristics with the synaptonemal complex in other species. LinE structures appeared around the time of replication, underwent a dotty-to-linear-to-dotty configurational transition, and disassembled before the first meiotic division. DSB formation and repair did not detectably influence LinE structure formation, but failure of DSB formation delayed LinE structure disassembly. Several LinE missense mutations formed dotty but not linear LinE configurations. Our study reveals a second, important configuration of LinEs, which suggests that LinE complexes are involved in regulating meiotic events, such as DSB repair, in addition to their established role in DSB formation.
Development of PCR-based markers for a major locus conferring powdery mildew resistance in mungbean (Vigna radiata)

Powdery mildew (PM) can cause significant yield loss in mungbean and several loci conferring resistance to this disease have been identified. A restriction fragment length polymorphism (RFLP) marker (VrCS65) linked closely to one of these loci was used to screen a mungbean bacterial artificial chromosome (BAC) library and positive BAC clones identified were used to develop simple sequence repeat (SSR or microsatellite) and sequence tagged site (STS) markers. Four of the new PCR markers (including two SSRs and two STSs) co-segregated with the original RFLP marker VrCS65, and another SSR marker (VrCS SSR2) was located 0.5 cM away from it. These PCR-based and locus-specific markers could be useful in breeding cultivars with enhanced resistance to PM and in the further characterization of the locus including the isolation of gene(s) responsible for the resistance.
Generation of Heart Organoids Modeling Early Human Cardiac Development Under Defined Conditions

Cardiovascular-related disorders are a significant worldwide health problem. Cardiovascular disease (CVD) is the leading cause of death in developed countries, making up a third of the mortality rate in the US1. Congenital heart defects (CHD) affect ∼1% of all live births2, making it the most common birth defect in humans. Current technologies provide some insight into how these disorders originate but are limited in their ability to provide a complete overview of disease pathogenesis and progression due to their lack of physiological complexity. There is a pressing need to develop more faithful organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here, we report the most faithful in vitro organoid model of human cardiovascular development to date using human pluripotent stem cells (hPSCs). Our protocol is highly efficient, scalable, shows high reproducibility and is compatible with high-throughput approaches. Furthermore, our hPSC-based heart organoids (hHOs) showed very high similarity to human fetal hearts, both morphologically and in cell-type complexity. hHOs were differentiated using a two-step manipulation of Wnt signaling using chemical inhibitors and growth factors in completely defined media and culture conditions. Organoids were successfully derived from multiple independent hPSCs lines with very similar efficiency. hHOs started beating at ∼6 days, were mostly spherical and grew up to ∼1 mm in diameter by day 15 of differentiation. hHOs developed sophisticated, interconnected internal chambers and confocal analysis for cardiac markers revealed the presence of all major cardiac lineages, including cardiomyocytes (TNNT2+), epicardial cells (WT1+, TJP+), cardiac fibroblasts (THY1+, VIM+), endothelial cells (PECAM1+), and endocardial cells (NFATC1+). Morphologically, hHOs developed well-defined epicardial and adjacent myocardial regions and presented a distinct vascular plexus as well as endocardial-lined microchambers. RNA-seq time-course analysis of hHOs, monolayer differentiated iPSCs and fetal human hearts revealed that hHOs recapitulate human fetal heart tissue development better than previously described differentiation protocols3,4. hHOs allow higher-order interaction of distinct heart tissues for the first time and display biologically relevant physical and topographical 3D cues that closely resemble the human fetal heart. Our model constitutes a powerful novel tool for discovery and translational studies in human cardiac development and disease.
AN ADMIXTURE SIGNAL IN ARMENIANS AROUND THE END OF THE BRONZE AGE REVEALS WIDESPREAD POPULATION MOVEMENT ACROSS THE MIDDLE EAST

The Armenians, a population inhabiting the region in West Asia known as the Armenian Highland, has been argued to show a remarkable degree of population continuity since the Early Neolithic. Here we test the degree of continuity of this population as well as its plausible origin, by collating modern and ancient genomic data, and adding a number of novel contemporary genomes. We show that Armenians have indeed remained unadmixed through the Neolithic and at least until the first part of the Bronze Age, and fail to find any support for historical suggestions by Herodotus of an input from the Balkans. However, we do detect a genetic input of Sardinian-like ancestry during or just after the Middle-Late Bronze Age. A similar input at approximately the same time was detected in East Africa, suggesting large-scale movement both North and South of the Middle East. Whether such large-scale population movement was a result of climatic or cultural changes is unclear, as well as the true source of gene flow remains an open question that needs to be addressed in future ancient DNA studies.
Data integration uncovers the metabolic bases of phenotypic variation in yeast

The relationship between different levels of integration is a key feature for understanding the genotype-phenotype map. Here, we describe a novel method of integrated data analysis that incorporates protein abundance data into constraint-based modeling to elucidate the biological mechanisms underlying phenotypic variation. Specifically, we studied yeast genetic diversity at three levels of phenotypic complexity in a population of yeast obtained by pairwise crosses of eleven strains belonging to two species, Saccha-romyces cerevisiae and S. uvarum. The data included protein abundances, integrated traits (life-history/fermentation) and computational estimates of metabolic fluxes. Results highlighted that the negative correlation between production traits such as population carrying capacity (K) and traits associated with growth and fermentation rates (Jmax) is explained by a differential usage of energy production pathways: a high K was associated with high TCA fluxes, while a high Jmax was associated with high glycolytic fluxes. Enrichment analysis of protein sets confirmed our results. This powerful approach allowed us to identify the molecular and metabolic bases of integrated trait variation, and therefore has a broad applicability domain.
The neural dynamics underlying prioritisation of task-relevant information

The human brain prioritises relevant sensory information to perform different tasks. Enhancement of task-relevant information requires flexible allocation of attentional resources, but it is still a mystery how this is operationalised in the brain. We investigated how attentional mechanisms operate in situations where multiple stimuli are presented in the same location and at the same time. In two experiments, participants performed a challenging two-back task on different types of visual stimuli that were presented simultaneously and superimposed over each other. Using electroencephalography and multivariate decoding, we analysed the effect of attention on the neural coding of each individual stimulus. Whole brain neural responses contained considerable information about both the attended and unattended stimuli, even though they were presented simultaneously and represented in overlapping receptive fields. As expected, attention enhanced stimulus-related information contained in the neural responses, but this enhancement was evident earlier for stimuli that were presented at smaller sizes. Our results show that early neural responses to stimuli in fast-changing displays contain remarkable detail about the sensory environment but are also modulated by attention in a manner dependent on perceptual characteristics of the relevant stimuli. Stimuli, code, and data for this study can be found at https://osf.io/7zhwp/.
The Evolution of Insect Metallothioneins

Metallothioneins (MTs) are a family of cysteine-rich metal-binding proteins that are important in the chelating and detoxification of toxic heavy metals. Until now, the short length and the low sequence complexity of MTs has hindered the possibility of any phylogenetic reconstruction, hampering the study of their evolution. To answer this longstanding question, we developed an iterative BLAST search pipeline that allowed us to build a unique dataset of more than 300 MT sequences in insects. By combining phylogenetics and synteny analysis, we reconstructed the evolutionary history of MTs in insects. We show that the MT content in insects has been shaped by lineage-specific tandem duplications from a single ancestral MT. Strikingly, we also uncovered a sixth MT, MtnF, in the model organism Drosophila melanogaster. MtnF evolves faster than other MTs and is characterized by a non-canonical length and higher cysteine content. Our methodological framework not only paves the way for future studies on heavy metal detoxification but also can allow us to identify other previously unidentified genes and other low complexity genomic features.
Population Bottlenecks and Intra-host Evolution During Human-to-Human Transmission of SARS-CoV-2

The emergence of the novel human coronavirus, SARS-CoV-2, causes a global COVID-19 (coronavirus disease 2019) pandemic. Here, we have characterized and compared viral populations of SARS-CoV-2 among COVID-19 patients within and across households. Our work showed an active viral replication activity in the human respiratory tract and the co-existence of genetically distinct viruses within the same host. The inter-host comparison among viral populations further revealed a narrow transmission bottleneck between patients from the same households, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Author summary In this study, we compared SARS-CoV-2 populations of 13 Chinese COVID-19 patients. Those viral populations contained a considerable proportion of viral sub-genomic messenger RNAs (sgmRNA), reflecting an active viral replication activity in the respiratory tract tissues. The comparison of 66 identified intra-host variants further showed a low viral genetic distance between intra-household patients and a narrow transmission bottleneck size. Despite the co-existence of genetically distinct viruses within the same host, most intra-host minor variants were not shared between transmission pairs, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Furthermore, the narrow bottleneck and active viral activity in the respiratory tract show that the passage of a small number of virions can cause infection. Our data have therefore delivered a key genomic resource for the SARS-CoV-2 transmission research and enhanced our understanding of the evolutionary dynamics of SARS-CoV-2.
Nfkbid is required for immunity and antibody responses to Toxoplasma gondii

Protective immunity to parasitic infections has been difficult to elicit by vaccines. Among parasites that evade vaccine-induced immunity is Toxoplasma gondii, which causes lethal secondary infections in chronically infected mice. Here we report that unlike susceptible C57BL/6J mice, A/J mice were highly resistant to secondary infection. To identify correlates of immunity, we utilized forward genetics to identify Nfkbid, a nuclear regulator of NF-κB that is required for B cell activation and B-1 cell development. Nfkbid-null mice (bumble) did not generate parasite-specific IgM and lacked robust parasite-specific IgG, which correlated with defects in B-2 cell maturation and class-switch recombination. Though high-affinity antibodies were B-2 derived, transfer of B-1 cells partially rescued the immunity defects observed in bumble mice and were required for 100% vaccine efficacy in bone marrow chimeric mice. Immunity in resistant mice correlated with robust isotype class-switching in both B cell lineages, which can be fine-tuned by Nfkbid gene expression. We propose a model whereby humoral immunity to T. gondii is regulated by Nfkbid and requires B-1 and B-2 cells for full protection. AUTHOR SUMMARY Eukaryotic parasitic diseases account for approximately one fifth of all childhood deaths, yet no highly protective vaccine exists for any human parasite. More research must be done to discover how to elicit protective vaccine-induced immunity to parasitic pathogens. We used an unbiased genetic screen to find key genes responsible for immunity to the eukaryotic parasite Toxoplasma gondii. Our screen found Nfkbid, a transcription factor regulator, which controls B cell activation and innate-like B-1 cell development. Mice without Nfkbid were not protected against T. gondii and were deficient at making antibodies against the parasite. Our survival studies of vaccinated mice with and without B-1 compartments found that B-1 cells improved survival, suggesting that B-1 cells act in conjunction with B-2 cells to provide vaccine-induced immunity. Nfkbid and other loci identified in our unbiased screen represent potential targets for vaccines to elicit protective immune responses against parasitic pathogens.
Aging leads to stochastic loss of silencing at transposons in mammary luminal epithelial cells

Background: The aging process is characterized by an accumulation of cellular damage, including alterations to the epigenome. While it is clear, there is a general lack of DNA methylation fidelity with aging, the mechanisms behind epigenomic alterations - and the functional consequences of these changes - have remained unclear. One of the primary roles of DNA methylation in mammalian genomes is in the repression of retrotransposons. Many of these repetitive elements contain regulatory sequences, and loss of repression can lead to aberrant transcriptional regulation. Aging-associated DNA methylation loss at transposable elements (TEs), therefore, has the potential to rewire gene expression networks to be favorable for pathologies, including age-related diseases such as cancer. However, the extent of loss of epigenetic silencing at transposable elements during aging and the functional consequences of this have remained unclear. Results: We profiled DNA methylation across the genome for human mammary luminal epithelial cells (LEPs), a key cell type associated with age-related luminal breast cancer at different ages. Our analysis reveals distinct DNA methylation patterns in old LEPs. Luminal lineage-specific regulatory elements gain methylation, while myoepithelial lineage-specific regulatory elements lose methylation. These methylation changes are partly driven by altered activity of lineage-specific transcription factors. Analysis of DNA methylation differences at transposable elements between young and old LEPs reveal that TEs can lose DNA methylation. Evolutionarily young transposons lose DNA methylation in a stochastic manner, presumably due to loss of fidelity of maintenance methylation. Moreover, aging dependent methylation loss at TEs correlates with elevated breast cancer risk. Conclusions: The results indicate that aging leads to widespread alterations in the DNA methylation landscape of the genome, especially at young TEs. These alterations have the potential to rewire gene networks that may be important for age-associated breast cancers.
Adult survival is reduced when endogenous period deviates from 24h in a non-human primate (Microcebus murinus), depending on sex and season

Circadian rhythms are ubiquitous attributes across living organisms and allow the coordination of internal biological functions with optimal phases of the environment, suggesting a significant adaptive advantage. The endogenous period called tau lies close to 24h and is thought to be implicated in individuals’ fitness: according to the circadian resonance theory, fitness is reduced when tau gets far to 24h. In this study, we measured the endogenous period of 142 mouse lemurs (Microcebus. murinus), and analyzed how it affects their survival. We found different effects according to sex and season. No impact of tau on mortality was found in females. However, in males, the deviation of tau from 24h substantially increased mortality, particularly during the inactive season (winter). These results, comparable to other observations in mice or drosophila, show that captive gray mouse lemurs enjoy better fitness when their circadian period closely matches the environmental periodicity. In addition to their deep implications in health and aging research, these results raise further ecological and evolutionary issues regarding the relationships between fitness and circadian clock.
Interactive dynamics of matrix adhesion and reaction-diffusion predict diverse multiscale strategies of cancer cell invasion

The metastasis of malignant epithelial tumors begins with the egress of transformed cells from the confines of their basement membrane to their surrounding collagenous stroma. Invasion can be morphologically diverse, ranging from dispersed mesenchymal cells to multicellular collectives. When breast cancer cells are cultured within basement membrane-like matrix (BM), or Type 1 collagen, or a combination of both, they exhibit collective-, dispersed mesenchymal-, and hybrid collective-dispersed (multiscale) invasion, respectively. In this paper, we asked how distinct these invasive modes are with respect to the cellular and microenvironmental cues that drive them. A rigorous computational exploration of invasion was performed within an experimentally motivated Cellular Potts-based modeling environment. The model comprises of adhesive interactions between cancer cells, BM- and collagen-like extracellular matrix (ECM), and reaction-diffusion-based remodeling of ECM. The model outputs were parameters cognate to dispersed- and collective- invasion. Input sweeps gave rise to a spatial output distribution that consisted of dispersed-, collective- and multiscale- invasion. K-means clustering of the output distribution followed by silhouette analysis revealed three optimal clusters: one signifying indolent invasion and two representing multiscale invasions, which we call collective-multiscale (CMI), and dispersed multiscale invasion (DMI), respectively. Constructing input-output mapped phenotypic spaces suggested that adhesion to BM- and collagen- matrix specify CMI and DMI respectively. Parameter perturbations confirmed these associations and revealed how the cellular phenotype may transition between the three states. Our systems-level analysis provides quantitative insights into how the diversity in matrix microenvironments may steer invasion into distinct phenotypic modes during metastasis.