New phylogenetic Markov models for inapplicable morphological characters This paper describes new Markov models for phylogenetic inference with inapplicable (anatomically dependent) morphological characters. It shows that the new solutions fall into two categories depending on the type of character hierarchy and require use of different Markov models. A combination of the new models and previous solutions is capable to model all general types of dependencies that may exists between morphological traits. The performance of the new models is assessed using theory and simulations. Bayesian phylogenetic inference with the new models and their construction for a hierarchy of custom complexity is demonstrated using RevBayes and the R package rphenoscate respectively.
The genetic basis of interspecies cooperation and conflict in naturally-occurring isolates of a model plant symbiont Given the need to predict the outcomes of evolution in host-associated microbiomes, whether microbial and host fitnesses tend to trade off, generating conflict, remains a pressing question. Examining the relationships between host and microbe fitness proxies at both the phenotypic and genomic levels can illuminate the mechanisms underlying interspecies cooperation and conflict. We conducted genome-wide association studies (GWAS) to examined naturally-occurring genetic variation in 191 strains of the model microbial symbiont, Ensifer meliloti, paired with each of two host Medicago truncatula genotypes in single- or multi-strain experiments. Using this data, we determine how multiple proxies of microbial and host fitness were related to one another and test key predictions about mutualism evolution at the genomic scale, while also addressing the challenge of measuring microbial fitness. We found little evidence for interspecies fitness conflict; loci tended to have concordant effects on both microbe and host fitnesses, even in environments with multiple co-occurring microbes. Our results emphasize the importance of quantifying microbial relative fitness for understanding microbiome evolution and thus harnessing microbiomes to improve host fitness. Additionally, we find that mutualistic coevolution between hosts and microbes potentially acts to maintain, rather than erode, genetic diversity, thus, explaining why variation in mutualism traits persists in nature.
The Digital 3D-Atlas MAKER (DAMAKER): a dynamic and expandable digital 3D-tool for monitoring the temporal changes in tissue growth during hindbrain morphogenesis Reconstruction of prototypic three-dimensional (3D) atlases at the scale of whole tissues or organs requires specific methods to be developed. We have established a digital 3D-atlas maker (DAMAKER) and built a digital 3D-temporal atlas to monitor the changes in the growth of the tissue and neuronal differentiation domain in the zebrafish hindbrain. DAMAKER integrates spatial and temporal data from cell populations, neuronal differentiation and brain morphogenesis, through in vivo imaging techniques paired with image analyses and segmentation tools. First, we generated a 3D-reference from several imaged hindbrains and segmented them using a trainable tool; these were aligned using rigid registration, revealing distribution of neuronal differentiation growth patterns along the axes. Second, we quantified the dynamic growth of the neuronal differentiation domain vs. the progenitor domain, and by in vivo neuronal birthdating experiments we generated a digital 3D-temporal map of the neuronal growth in the whole hindbrain, revealing the spatiotemporal dynamics of neuronal differentiation upon morphogenesis. Last, we applied it to glutamatergic and GABAergic neurons, as proof-of-concept that the digital 3D-temporal map could be used as a proxy to infer neuronal birthdate. As this protocol uses open-access tools and algorithms, it can be shared for standardized, accessible, tissue-wide cell population atlas construction. Sharpened and mechanically durable carbon fiber electrode arrays for neural interfacing Bioelectric medicine treatments target disorders of the nervous system unresponsive to pharmacological methods. While current stimulation paradigms effectively treat many disorders, the underlying mechanisms are relatively unknown, and current neuroscience recording electrodes are often limited in their specificity to gross averages across many neurons or axons. Here, we develop a novel, durable carbon fiber electrode array adaptable to many neural structures for precise neural recording. Carbon fibers were sharpened using a reproducible blowtorch method that uses the reflection of fibers against the surface of a water bath. The arrays were developed by partially embedding carbon fibers in medical-grade silicone to improve durability. We recorded acute spontaneous electrophysiology from the rat cervical vagus nerve (CVN), feline dorsal root ganglia (DRG), and rat brain. Blowtorching resulted in fibers of 72.3 {+/-} 33.5 degree tip angle with 146.8 {+/-} 17.7 m exposed carbon. Silicone-embedded carbon fiber arrays were durable with 87.5% of fibers remaining after 50,000 passes. Observable neural clusters were recorded using sharpened carbon fiber electrodes from rat CVN (41.8 Vpp), feline DRG (101.1 Vpp), and rat brain (80.7 Vpp). Recordings from the feline DRG included physiologically-relevant signals from increased bladder pressure and cutaneous brushing. These results suggest that this carbon fiber array is a uniquely durable and adaptable neural recording device. In the future, this device may be useful as a bioelectric medicine tool for diagnosis and closed-loop neural control of therapeutic treatments and monitoring systems. Medium-throughput zebrafish optogenetic platform identifies deficits in subsequent neural activity following brief early exposure to cannabidiol and Δ-9-tetrahydrocannabinol In the light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. Here, zebrafish embryos were exposed to cannabidiol (CBD) and {Delta}-9-tetrahydrocannabinol l (THC) until the end of gastrulation (1-10 hours post-fertilization) and analyzed later in development (4-5 days post-fertilization). In order to measure neural activity, we implemented CaMPARI (Calcium-Modulated Photoactivatable Ratiometric Integrator) and optimized the protocol for a 96-well format complemented by locomotor analysis. Our results revealed that neural activity was decreased by CBD more than THC. At higher doses, both cannabinoids could dramatically reduce neural activity and locomotor activity. Interestingly, the decrease was more pronounced when CBD and THC were combined. At the receptor level, CBD-mediated reduction of locomotor activity was partially prevented using cannabinoid type 1 and 2 receptor inhibitors. Overall, we report that CBD toxicity occurs via two cannabinoid receptors and is synergistically enhanced by THC exposure to negatively impact neural activity late in larval development. Future studies are warranted to reveal other cannabinoids and receptors involved in this pathway to understand the subsequent health implications of cannabis consumption on fetal development. Reciprocal Priming between RTKs at Recycling Endosomes Orchestrates Cellular Signaling Outputs Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling-dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF-mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers. Etmopterus lantern sharks use coelenterazine as the substrate for their luciferin-luciferase bioluminescence system The lantern shark genus Etmopterus is a group of deep-sea bioluminescent fishes. They emit blue light mainly from the ventral body surface, and the primary biological function is considered to be for camouflage by counterillumination. In this study, we detected both coelenterazine and coelenterazine-specific luciferase activity in the ventral photophore tissues. The results suggested that bioluminescence in lantern sharks is produced using coelenterazine as the substrate for the luciferin-luciferase reaction. Differential regulation of degradation and immune pathways underlies adaptation of the ectosymbiotic nematode Laxus oneistus to oxic-anoxic interfaces Eukaryotes may experience oxygen deprivation under both physiological and pathological conditions. Because oxygen shortage leads to a reduction in cellular energy production, all eukaryotes studied so far conserve energy by suppressing their metabolism. However, the molecular physiology of animals that naturally and repeatedly experience anoxia is underexplored. One such animal is the marine nematode Laxus oneistus. It thrives, invariably coated by its sulfur-oxidizing symbiont Candidatus Thiosymbion oneisti, in anoxic sulfidic or hypoxic sand. Here, transcriptomics and proteomics showed that, whether in anoxia or not, L. oneistus mostly expressed genes involved in ubiquitination, energy generation, oxidative stress response, immune response, development, and translation. Importantly, ubiquitination genes were also upregulated when the nematode was subjected to anoxic sulfidic conditions, together with genes involved in autophagy, detoxification and ribosome biogenesis. We hypothesize that these degradation pathways were induced to recycle damaged cellular components (mitochondria) and misfolded proteins into nutrients. Remarkably, when L. oneistus was subjected to anoxic sulfidic conditions, lectin and mucin genes were also upregulated, potentially to promote the attachment of its thiotrophic symbiont. Furthermore, the nematode appeared to survive oxygen deprivation by using an alternative electron carrier (rhodoquinone) and acceptor (fumarate), to rewire the electron transfer chain. On the other hand, under hypoxia, genes involved in costly processes (e.g., amino acid biosynthesis, development, feeding, mating) were upregulated, together with the worms Toll- like innate immunity pathway and several immune effectors (e.g., Bacterial Permeability Increasing proteins, fungicides).

In conclusion, we hypothesize that, in anoxic sulfidic sand, L. oneistus upregulates degradation processes, rewires oxidative phosphorylation and by reinforces its coat of bacterial sulfur-oxidizers. In upper sand layers, instead, it appears to produce broad-range antimicrobials and to exploit oxygen for biosynthesis and development. Spontaneous differentiation leads to emergence of hybrid cell states relate to poor prognosis in oral cancer PurposeCellular dynamics between phenotypically heterogeneous subpopulations of cancer cells within individual tumor is shown to be responsible for drug tolerance and overall poor prognosis; however, evidences were largely missing in oral cancer. Therefore, this study was undertaken to describe the dynamic phenotypic states among oral cancer cells, its influence on transcriptomic heterogeneity as well as its clinical significance.

Experimental DesignWe multiplexed phenotypic markers of putative oral-stem-like cancer cells (SLCCs) and characterized diversity among CD44-positive oral cancer cell subpopulations with respect to distinct expression of CD24 and aldehyde dehydrogenase (ALDH)-activity in multiple cell lines. Population trajectories were characterized by Markov model and cell states were defined based on the population specific RNA sequencing (RNAseq). ssGSEA based gene expression signatures were explore for prognostic significance.

ResultsOral cancer cells followed two distinct patterns of spontaneous repopulation dynamics with stochastic inter-conversions on  ALDH-axis, however a strict non-interconvertible transition on  CD24-axis. Interestingly, plastic  ALDH-axis was harnessed to enrich ALDHHigh subpopulations in response to Cisplatin treatment, to adapt a drug tolerant state. Phenotype-specific RNAseq results suggested the organization of subpopulations into hierarchical structure with possible maintenance of intermediate states of stemness within the differentiating oral cancer cells. Further, survival analysis with each subpopulation-specific gene signature strongly suggested that the cell-state dynamics may act as possible mechanism to drive ITH, resulting in poor prognosis in patient.

ConclusionsOur results emphasized the prognostic power of the population dynamics in oral cancer. Importantly, we have described the phenotypic-composition of heterogeneous subpopulations critical for global tumor behaviour in oral cancer; which is a prerequisite knowledge important for precision treatment, however largely lacking for most solid tumors.

Graphical AbstractWe have characterized diversity among CD44-positive oral cancer cells lines with respect to distinct expression of CD24 and ALDH-activity. Subpopulations showed stochastic inter-conversions on ALDH-axis but a strict non-interconvertible transition of CD24Low to CD24High phenotype, even in response to chemotherapy-induced stress. RNAseq study suggested the organization of subpopulations into hierarchical structure with possible maintenance of intermediate alternate states of stemness within the differentiating oral cancer cells. The described population dynamics demonstrtaed influence tumor behaviour possibly by increasing intratumoral heterogeneity in aggressive oral tumors.



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org.highwire.dtl.DTLVardef@1dc6a7org.highwire.dtl.DTLVardef@dd0948org.highwire.dtl.DTLVardef@18c9603org.highwire.dtl.DTLVardef@cca8fb_HPS_FORMAT_FIGEXP  M_FIG C_FIG Translational relevanceIntratumoral heterogeneity (ITH) has been the clinically important factor, impacting aggressive cancer behaviour, drug tolerance and overall poor prognosis. Recent high-throughput studies have provided better cellular and molecular resolution of ITH; however, the prerequisite knowledge which defines the composition of subpopulations critical for global tumor behaviour is majorly lacking for most of the solid tumors. By combining phenotypic markers, we have defined four subpopulations of oral cancer cells. These subpopulations showed stochastic inter-conversions as well as a strict non-interconvertible transition among them to acheive heterogeneity. Importantly, transcriptional states of each subpopulations indicated a clinically relevant signatures for patient prognosis. Also, we observed interconversions of these subpopulations in response to Cisplatin to accumulate drug-tolerant cell state, as rapid and reversible strategy to respond to chemotherapy induced stress. Thus, the characteristics of described phenotypic subgroups may be translated to the clinic for estimating the extent of intratumoral heterogeneity in oral cancer patients. Ecophysiological differentiation between life stages in filmy ferns (Hymenophyllaceae) Desiccation tolerance was a key trait that allowed plants to colonize land. However, little is known about the transition from desiccation tolerant non-vascular plants to desiccation sensitive vascular ones. Filmy ferns (Hymenophyllaceae) represent a useful system to investigate how water-stress strategies differ between non-vascular and vascular stages within a single organism because they have vascularized sporophytes and nonvascular gametophytes that are each capable of varying degrees of desiccation tolerance. To explore this, we surveyed sporophytes and gametophytes of 19 species (22 taxa including varieties) of filmy ferns on Moorea (French Polynesia) and used chlorophyll fluorescence to measure desiccation tolerance and light responses. We conducted phylogenetically informed analyses to identify differences in physiology between life stages and growth habits. Gametophytes had similar or less desiccation tolerance (ability to recover from 2 d desiccation at -86 MPa) and lower photosynthetic optima (maximum electron transport rate of photosystem II and light level at 95% of that rate) than sporophytes. Epiphytes were more tolerant of desiccation than terrestrial species in both life stages. Despite their lack of greater physiological tolerances, gametophytes of several species occurred over a wider elevational range than conspecific sporophytes. Our results demonstrate that filmy fern gametophytes and sporophytes differ in their physiology and niche requirements, and point to the importance of microhabitat in shaping the evolution of water-use strategies in vascular plants. Reconstitution of minimal motility system based on Spiroplasma swimming by expressing two bacterial actins in synthetic minimal bacterium Motility is one of the most important features of life, but its evolutionary origin remains unknown. In this study, we focused on Spiroplasma, commensal, or parasitic bacteria. They swim by switching the helicity of a ribbon-like cytoskeleton that comprises six proteins, each of which evolved from a nucleosidase and bacterial actin called MreB. We expressed these proteins in a synthetic, non-motile minimal bacterium, JCVI-syn3.0B, whose reduced genome was computer-designed and chemically synthesized. The synthetic bacterium exhibited swimming motility with features characteristic of Spiroplasma swimming. Moreover, some combinations of the two proteins produced a helical cell shape and swimming, suggesting that the swimming originated from the differentiation and coupling of bacterial actins, and we also obtained a minimal system for motility of the synthetic bacterium.

One-Sentence SummaryThe minimal system comprised two bacterial actins that provided cell helicity and swimming to the synthetic minimal bacterium. Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition The teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching  acanthodian-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckels cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth of Acanthodopsis are borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly. Cryo-EM Structures of the N501Y SARS-CoV-2 Spike Protein in Complex with ACE2 and Two Potent Neutralizing Antibodies The recently reported "UK variant" of SARS-CoV-2 is thought to be more infectious than previously circulating strains as a result of several changes, including the N501Y mutation. We present a 2.9-[A] resolution cryo-EM structure of the complex between the ACE2 receptor and N501Y spike protein ectodomains that shows Y501 inserted into a cavity at the binding interface near Y41 of ACE2. The additional interactions result in increased affinity of ACE2 for the N501Y mutant, accounting for its increased infectivity. However, this mutation does not result in large structural changes, enabling important neutralization epitopes to be retained in the spike receptor binding domain. We confirmed this through biophysical assays and by determining cryo-EM structures of spike protein ectodomains bound to two representative potent neutralizing antibody fragments.

Short summaryThe N501Y mutation found in the coronavirus UK variant increases infectivity but some neutralizing antibodies can still bind. Dynamic modulation of enhancer responsiveness by core promoter elements in living Drosophila embryo Regulatory interactions between enhancers and core promoters are fundamental for the temporal and spatial specificity of gene expression in development. The central role of core promoters is to initiate productive transcription in response to enhancers activation cues. However, it has not been systematically assessed how individual core promoter elements affect the induction of transcriptional bursting by enhancers. Here, we provide evidence that each core promoter element dynamically alters "enhancer responsiveness" by changing functional parameters of transcriptional bursting in developing Drosophila embryos. Quantitative live imaging analysis revealed that the timing and the continuity of burst induction are common regulatory steps on which core promoter elements impact. We also show that core promoters use the upstream TATA box as an amplifier of transcriptional bursting upon interaction with enhancers. Genome editing analysis of the pair-rule gene fushi tarazu further revealed that the endogenous TATA box and the downstream core promoter element are both essential for the correct expression and the function of key developmental genes in early embryos. We suggest that core promoter elements serve as a key regulatory module in converting enhancer activity into transcription dynamics during animal development. Genetic variation associated with plastic and homeostatic growth responses to drought in Arabidopsis O_LINatural genetic variation influences plant responses to environmental stressors. However, the extent to which such variation underlies plastic versus homeostatic response phenotypes has been little studied.
C_LIO_LIWe quantified the extent of drought-induced changes in leaf area in a set of Iberian Arabidopsis accessions and then performed association studies correlating variation in this phenotype with genomic and transcriptomic variation.
C_LIO_LIDrought-induced plastic reductions in relative leaf area typified accessions originating from productive environments. In contrast, homeostasis in relative leaf area typified accessions originating from unproductive environments. Genome-Wide Association Studies (GWAS), Transcriptome Wide Association Studies (TWAS), and expression GWAS (eGWAS) highlighted the importance of auxin-related processes and, in particular, the potential role of the SMALL AUXIN UP RNA 26 (SAUR26) gene in conferring leaf area plasticity. Homeostatic responses in relative leaf area were associated with a diverse gene set and positively associated with a higher intrinsic water use efficiency (WUEi) as confirmed in a TWAS metanalysis of previously published {delta}13C measurements.
C_LIO_LIWe have identified not only candidate "plasticity genes" but also candidate "homeostasis genes" controlling leaf area. Our results demonstrate the value of a combined GWAS, TWAS, and eGWAS approach to identify mechanisms underlying phenotypic responses to stress.
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One-sentence summaryInformation on phenotype, genotype, and transcript abundance is integrated to identify both plasticity and homeostasis genes and processes associated with local adaptation to drought stress in Arabidopsis accessions of the Iberian Peninsula. Population differences in the length and early-life dynamics of telomeres among European pied flycatchers Telomere length and shortening rate are increasingly used as biomarkers for long-term costs in ecological and evolutionary studies because of their relationships with survival and fitness. Both early-life conditions and growth, and later-life stressors can create variation in telomere shortening rate. Studies on between- population telomere length and dynamics are scarce, despite the expectation that populations exposed to varying environmental constraints would present divergent telomere length patterns. The pied flycatcher (Ficedula hypoleuca) is a passerine bird breeding across Eurasia (from Spain to western Siberia) and migrating through the Iberian Peninsula to spend the non-breeding period in sub-Saharan Africa. Thus, different populations show marked differences in migration distance. We studied the large-scale variation of telomere length and early-life dynamics in the pied flycatcher by comparing six European populations across a north- south gradient (Finland, Estonia, England, and Spain) predicting negative effect of migration distance on adult telomere length, and of nestling growth on nestling telomere dynamics. There were clear population differences in telomere length, with English birds from mid-latitudes having the longest telomeres. Telomere length did not thus show consistent latitudinal variation and was not linearly linked to differences in migration distance. Early-life telomere shortening rate tended to vary between populations. Fast growth was associated with shorter telomeres in the early life, but faster nestling growth affected telomeres more negatively in northern than southern populations. While the sources of between-population differences in telomere-related biology remain to be more intensively studied, our study illustrates the need to expand telomere studies at the between-population level. Glucose inhibits haemostasis and accelerates diet-induced hyperlipidaemia in zebrafish larvae Hyperglycaemia damages the microvasculature in part through the reduced recruitment of immune cells and interference with platelet signalling, leading to poor wound healing and accelerated lipid deposition in mammals. We investigated the utility of zebrafish larvae to model the effect of glucose on neutrophil and macrophage recruitment to a tail wound, wound-induced haemostasis, and chicken egg yolk feed challenge-induced hyperlipidaemia by supplementing larvae with exogenous glucose by immersion or injection. Neither method of glucose supplementation affected the recruitment of neutrophils and macrophages following tail transection. Glucose injection reduced thrombocyte retention and fibrin plug formation while only thrombocyte retention was reduced by glucose immersion following tail transection. We observed accelerated lipid accumulation in glucose-injected larvae challenged with high fat chicken egg yolk feeding. Our study identifies conserved and divergent effects of high glucose on inflammation, haemostasis, and hyperlipidaemia in zebrafish larvae compared to mammals. Conformist social learning leads to self-organised prevention against adverse bias in risky decision making Given the ubiquity of potentially adverse behavioural bias owing to myopic trial-and-error learning, it seems paradoxical that improvements in decision-making performance through conformist social learning, a process widely considered to be bias amplification, still prevail in animal collective behaviour. Here we show, through model analyses and large-scale interactive behavioural experiments with 585 human subjects, that conformist influence can indeed promote favourable risk taking in repeated experience-based decision making, even though many individuals are systematically biased towards adverse risk aversion. Although strong positive feedback conferred by copying the majoritys behaviour could result in unfavourable informational cascades, our differential equation model of collective behavioural dynamics identified a key role for increasing exploration by negative feedback arising when a weak minority influence undermines the inherent behavioural bias. This  collective behavioural rescue, emerging through coordination of positive and negative feedback, highlights a benefit of collective learning in a broader range of environmental conditions than previously assumed and resolves the ostensible paradox of adaptive collective behavioural flexibility under conformist influences. Naming Human Diseases: Ethical Principles of Curating Exclusive Substitute for Inopportune Nosology BackgroundIn the medical sphere, understanding naming conventions strengthen the integrity of naming human diseases remains nominal rather than substantial yet. Since the current nosology-based standard for human diseases could not offer a one-size-fits-all corrective mechanism, many idiomatic but flawed names frequently appear in scientific literature and news outlets at the cost of sociocultural impacts.

ObjectiveWe attempt to examine the ethical oversights of current naming practices and propose heuristic rationales and approaches to determine a pithy name instead of an inopportune nosology.

MethodsFirst, we examined the compiled global online news volumes and emotional tones on some inopportune nosology like German measles, Middle Eastern Respiratory Syndrome, Spanish flu, Hong Kong flu, and Huntingtons disease in the wake of COVID-19. Second, we prototypically scrutinize the lexical dynamics and pathological differentials of German measles and common synonyms by leveraging the capacity of the Google Books Ngram Corpus. Third, we demonstrated the empirical approaches to curate an exclusive substitute for an anachronistic nosology German measles based on deep learning models and post-hoc explanations.

ResultsThe infodemiological study shows that the public informed the offensive names with extremely negative tones in textual and visual narratives. The findings of the historiographical study indicate that many synonyms of German measles did not survive, while German measles became an anachronistic usage, and rubella has taken the dominant place since 1994. The PubMedBERT model could identify rubella as a potential substitution for German measles with the highest semantic similarity. The results of the semantic drift experiments further indicate that rubella tends to survive during the ebb and flow of semantic drift.

ConclusionsOur findings indicate that the nosological evolution of anachronistic names could result in sociocultural impacts without a corrective mechanism. To mitigate such impacts, we introduce some ethical principles for formulating an improved naming scheme. Based on deep learning models and post-hoc explanations, our illustrated experiments could provide hallmark references to the remedial mechanism of naming practices and pertinent credit allocations. Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity Developmental trajectories of gene expression may reverse in their direction during ageing, a phenomenon previously linked to cellular identity loss. Our analysis of cerebral cortex, lung, liver and muscle transcriptomes of 16 mice, covering development and ageing intervals, revealed widespread but tissue-specific ageing-associated expression reversals. Cumulatively, these reversals create a unique phenomenon: mammalian tissue transcriptomes diverge from each other during postnatal development, but during ageing, they tend to converge towards similar expression levels, a process we term Divergence followed by Convergence, or DiCo. We found that DiCo was most prevalent among tissue-specific genes and associated with loss of tissue identity, which is confirmed using data from independent mouse and human datasets. Further, using publicly available single-cell transcriptome data, we showed that DiCo could be driven both by alterations in tissue cell type composition and also by cell-autonomous expression changes within particular cell types. Invasive grass dominance over native forbs is linked to shifts in the bacterial rhizosphere microbiome Rhizosphere microbiomes have received growing attention in recent years for their role in plant health, stress tolerance, soil nutrition, and invasion. Still, relatively little is known about how these microbial communities are altered under plant competition, and even less about whether these shifts are tied to competitive outcomes between native and invasive plants. We investigated the structure and diversity of rhizosphere bacterial and fungal microbiomes of native annual forbs and invasive annual grasses individually and in competition using high-throughput amplicon sequencing of the bacterial 16S rRNA gene and the fungal ITS region. We assessed how differentially abundant microbial families correlate to plant biomass under competition We find that bacterial diversity and structure differ between native forbs and invasive grasses, but fungal diversity and structure do not. Further, bacterial community structures under competition are distinct from individual bacterial community structures. We also identified five bacterial families that varied in normalized abundance between treatments and that were correlated with plant biomass under competition. We speculate that invasive grass dominance over these natives may be partially due to effects on the rhizosphere community, with changes in specific bacterial families potentially benefiting invaders at the expense of natives. Ultrafast, alignment-free detection of repeat expansions in next-generation DNA and RNA sequencing data Short tandem repeat expansions are an established cause of diseases such as Huntingtons disease. Bioinformatic methods for detecting repeat expansions in short-read sequencing have revealed new repeat expansions in humans. Current bioinformatic methods to detect repeat expansions require alignment information to identify repetitive motif enrichment at genomic locations. We present superSTR, an ultrafast method that does not require alignment. We demonstrate superSTRs ability to efficiently process both whole-genome and whole-exome sequencing data. Using superSTR we perform the first analysis of the UK Biobank to efficiently screen the exomes of 49,953 biobank participants for repeat expansions. We identify known mutations, as well as diseases not previously associated with REs. We further demonstrate the first bioinformatic screening of RNA sequencing data to detect repeat expansions in patients with spinocerebellar ataxia and Fuchs endothelial corneal dystrophy, and mouse models of myotonic dystrophy. superSTR is a highly computationally-efficient repeat expansion tool screening and detection tool for genomewide novel repeat expansion analysis, significantly outperforming existing methods. superSTR is available from https://github.com/bahlolab/superSTR. A generic hidden Markov model for multi-parent populations A common step in the analysis of multi-parent populations is genotype reconstruction: identifying the founder origin of haplotypes from dense marker data. This process often makes use of a probability model for the pattern of founder alleles along chromosomes, including the relative frequency of founder alleles and the probability of exchanges among them, which depend on a model for meiotic recombination and on the mating design for the population. While the precise experimental design used to generate the population may be used to derive a precise characterization of the model for exchanges among founder alleles, this can be tedious, particularly given the great variety of experimental designs that have been proposed. We describe an approximate model that can be applied for a variety of multi-parent populations. We have implemented the approach in the R/qtl2 software, and we illustrate its use in applications to publicly-available data on Diversity Outbred and Collaborative Cross mice Predictive coding across the left fronto-temporal hierarchy during language comprehension We used MEG and ERPs to track the time-course and localization of evoked activity produced by expected, unexpected plausible and implausible words during incremental language comprehension. We interpret the full pattern of evoked responses and functional connectivity within a hierarchical predictive coding framework in which evoked activity reflects residual information (error) that is passed up and down the cortical hierarchy. Between 300-500ms, the three conditions produced progressively larger responses within left temporal cortex (lexico-semantic prediction error), while implausible inputs produced a selectively enhanced response within left inferior frontal cortex (event-level prediction error). Between 600-1000ms, unexpected plausible words activated left inferior frontal and middle temporal cortices (feedback activity that induced top-down shifts of event-level and lexico-semantic representations), while highly implausible inputs activated posterior fusiform and medial temporal cortices, supporting orthographic reanalysis and new learning. Therefore, predictive coding may provide a unifying theory that links language comprehension to other domains of cognition. Autoantibodies against Progranulin and IL-1 receptor antagonist due to immunogenic posttranslational isoforms contribute to hyperinflammation in critically ill COVID-19 STRUCTURED ABSTRACTHyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, associated with autoantibodies in a proportion of patients, lead to severe courses of disease. In addition, hyperactive responses of the humoral immune system have been described.

In the current study we investigated a possible role of neutralizing autoantibodies against antiinflammatory mediators. Plasma from adult patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-1-Ra, IL-10, IL-18BP, IL-22BP, IL-36-Ra, CD40, IFN-2, IFN-{gamma}, IFN-{omega} and serpinB1. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations.

In a discovery cohort with severe to critical COVID-19 high titers of PGRN-autoantibodies were detected in 11 of 30 (36.7%), and of IL-1-Ra-autoantibodies in 14 of 30 (46.7%) patients. In a validation cohort of 64 patients with critical COVID-19 high-titer PGRN-Abs were detected in 25 (39%) and IL-1-Ra-Abs in 32 of 64 patients (50%). PGRN-Abs and IL-1-Ra-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-Ra-Abs were detected in low frequency (i.e. in < 5% of patients) and at low titers. Neither PGRN-nor IL-1-Ra-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2 or 188 unvaccinated healthy controls. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins nor against IL-1-Ra. Plasma levels of both free PGRN and free IL-1-Ra were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID-19 controls. In vitro PGRN-Abs from patients functionally reduced PGRN-dependent inhibition of TNF- signaling, and IL-1-Ra-Abs from patients reduced IL-1-Ra- or anakinra-dependent inhibition of IL-1{beta} signaling. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a hyperphosphorylated IL-1-Ra isoform was only found in patients with high-titer IL-1-Ra-Abs. Thr111 was identified as the hyperphophorylated amino acid of IL-1-Ra. In longitudinally collected samples hyperphosphorylated isoforms of both PGRN and IL-1-Ra emerged transiently, and preceded the appearance of autoantibodies. In hospitalized patients, the presence of IL-1-Ra-Abs or IL-1-Ra-Abs in combination with PGRN-Abs was associated with a higher morbidity and mortality.

To conclude, neutralizing autoantibodies to IL-1-Ra and PGRN occur in a significant portion of patients with critical COVID-19, with a concomitant decrease in circulating free PGRN and IL-1-Ra, indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical hyperphosphorylated isoforms of both antigens, whose appearances precede autoantibody induction. Our data suggest that these immunogenic secondary modifications are induced by the SARS-CoV-2-infection itself or the inflammatory environment evoked by the infection and predispose for a critical course of COVID-19. Probing Patterning in Microbial Consortia with picCASO: a Cellular Automaton for Spatial Organisation Microbial consortia exhibit spatial patterning across diverse environments. Since probing the self-organization of natural microbial communities is limited by their inherent complexity, synthetic models have emerged as attractive alternatives. In this study, we develop novel frameworks of bacterial communication and explore the emergent spatiotemporal organization of microbes. Specifically, we build quorum sensing-mediated models of microbial growth that are utilized to characterize the dynamics of communities from arbitrary initial configurations and establish the effectiveness of our communication strategies in coupling the growth rates of microbes. Our simulations indicate that the behavior of quorum sensing-coupled consortia can be most effectively modulated by the rates of secretion of AHLs. Such a mechanism of control enables the construction of desired relative populations of constituent species in spatially organized populations. Our models accurately recapitulate previous experiments that have investigated pattern formation in synthetic multi-cellular systems. Additionally, our software tool enables the easy implementation and analysis of our frameworks for a variety of initial configurations and simplifies the development of sophisticated gene circuits facilitating distributed computing. Overall, we demonstrate the potential of spatial organization as a tunable parameter in synthetic biology by introducing a communication paradigm based on the location and strength of coupling of microbial strains.

Author SummaryInteracting microorganisms that coexist in a given environment tend to have well-defined spatial arrangements. While the emergence of such organization is seen across different microbiomes in nature, it is hitherto not well understood. Decoding the inherent spatial patterning of microbes is constrained by the complexity of their natural habitats. Here, we take advantage of synthetic models of microbial communities to study the dynamics of emergent spatial organization. Our framework of bacterial communication utilizes modular synthetic devices to couple growth rates. In addition to uncovering potential principles of spatial organization, this work enables the construction of complex genetic circuits distributed across communicating strains. Additionally, we have developed a software tool, picCASO, that streamlines the investigation of microbial systems communicating through such frameworks.