Negative Selection Algorithm

Current models suggest that (i) filamentous bacteria are protected against predation by nanoflagellates, (ii) prey size is positively correlated with prey-predator contact probability, and (iii) contact probability is mainly responsible for size-selective predation by interception-feeding flagellates. We used five strains of filamentous bacteria and one bacterivorous nanoflagellate, Ochromonas sp. strain DS, to test these assumptions. The five strains, including one spirochete and four Betaproteobacteria strains, were isolated by the filtration-acclimatization method. All five strains possess flexible cells, but they differ in average cell length, which ranged from 4.5 to 13.7 μm. High-resolution video microscopy was used to measure contact, capture, and ingestion rates, as well as selectivity of the flagellate feeding. Growth and feeding experiments with satiating and nonsatiating food conditions, as well as experiments including alternative well-edible prey, were performed. In con...

Thymic maturation of T cells depends on the intracellular interpretation of αβTCR signals by processes that are poorly understood. In this study, we report that α-catenin/Tcf signaling was activated in double-positive thymocytes in response to TCR engagement and impacted thymocyte selection. TCR engagement combined with activation of β-catenin signaled thymocyte deletion, whereas Tcf-1 deficiency rescued from negative selection. Survival/apoptotis mediators including Bim, Bcl-2, and Bcl-x L were alternatively influenced by stabilization of β-catenin or ablation of Tcf-1, and Bim-mediated β-catenin induced thymocyte deletion. TCR activation in double-positive cells with stabilized β-catenin triggered signaling associated with negative selection, including sustained overactivation of Lat and Jnk and a transient activation of Erk. These observations are consistent with β-catenin/Tcf signaling acting as a switch that determines the outcome of thymic selection downstream the αβTCR cascade. Productive rearrangement of the TCRα gene at the CD4 + CD8 + double-positive (DP) 6 stage of thymocyte development leads to the surface assembly of a mature αβTCR. This initiates a cascade of processes, ultimately leading to development of the various T cell lineages and shaping of the T cell repertoire. The outcome of thymocyte selection depends on the quality of αβTCR interactions with self-peptide-MHC complexes. Most DP thymocytes fail to

Clonal deletion in the thymus by apoptosis is involved in purging the immune system of self-reactive T lymphocytes (negative selection). Cysteine proteases (caspases) belonging to the CPP32 family are activated during this process. We have produced transgenic mice expressing baculovirus p35, a broad-range caspase inhibitor. Thymocytes from p35 transgenic mice were resistant in vitro to several apoptosis-inducing agents; this resistance correlated with the inhibition of CPP32like activity. Negative selection in vivo of thymocytes triggered by two exogenous antigens, staphylococcal enterotoxin B superantigen and an antigenic peptide in the F5 T-cell receptor transgenic model, was specifically inhibited in p35 transgenic mice. Our results provide direct evidence for caspase involvement in negative selection during thymocyte development.

An immune inspired model that can detect anomalies, even when trained only with normal samples, and can learn from encounters with new anomalies is presented. The model combines a negative selection algorithm and a self-organizing map (SOM) in an immune inspired architecture. The proposed system is able to produce a visual representation of the self/non-self feature space, thanks to the topological 2dimensional map produced by the SOM. Some experiments were performed on classification data; the results are presented and discussed.

Background: Mobile elements comprise a large fraction of metazoan genomes. Accumulation of mobile elements is bound to produce multiple putative double-stranded RNA (dsRNA) structures within the transcriptome. These endogenous dsRNA structures resemble viral RNA and may trigger false activation of the innate immune response, leading to severe damage to the host cell. Adenosine to inosine (A-to-I) RNA editing is a common posttranscriptional modification, abundant within repetitive elements of all metazoans. It was recently shown that a key function of A-to-I RNA editing by ADAR1 is to suppress the immunogenic response by endogenous dsRNAs. Results: Here, we analyze the transcriptomes of dozens of species across the Metazoa and identify a strong genomic selection against endogenous dsRNAs, resulting in their purification from the canonical transcriptome. This purifying selection is especially strong for long and nearly perfect dsRNAs. These are almost absent from mRNAs, but not pre-mRNAs, supporting the notion of selection due to cytoplasmic processes. The few long and nearly perfect structures found in human transcripts are weakly expressed and often heavily edited. Conclusion: Purifying selection of long dsRNA is an important defense mechanism against false activation of innate immunity. This newly identified principle governs the integration of mobile elements into the genome, a major driving force of genome evolution. Furthermore, we find that most ADAR1 activity is not required to prevent an immune response to endogenous dsRNAs. The critical targets of ADAR1 editing are, likely, to be found mostly in non-canonical transcripts.

Most network-on-chip (NoC) architectures are based on a mesh-based interconnection structure. In this paper, we present a new NoC architecture, which relies on source synchronous data transfer over a ring. The source synchronous ring data is clocked by a resonant clock, which operates significantly faster than individual processors that are served by the ring. This allows us to significantly improve the cross section bandwidth and the latency of the NoC. We have validated the design using a 22nm predictive process. Compared to the state-of-the-art mesh based NoC, our scheme achieves a 4.5× better bandwidth, 7.4× better contention free latency with 11% lower area and 35% lower power.

Aquatic mammals (marine and freshwater species) share significant and similar adaptations, enabling them to tolerate hypoxia during regular breath-hold diving. Despite the established importance of HIF1A, a master regulator in the molecular mechanism of hypoxia response, and other associated genes, their role in the evolutionary adaptation of aquatic mammals is not fully understood. In this study, we investigated this topic by employing a candidate gene approach to analyze 11 critical genes involved in the HIF1A signaling pathway in aquatic mammals. Our gene analyses included evaluating positive and negative selection, relaxation or constriction of selection, and molecular convergence compared to other terrestrial mammals, including subterranean mammals. Evidence of selection suggested a significant role of negative selection, as well as relaxation of the selective regime in cetaceans for most of these genes. We found that the glutamine 68 variant in the HIF3α protein is unique to c...

Plant domestication involved a process of selection through human agency of a series of traits collectively termed the domestication syndrome. Current debate concerns the pace at which domesticated plants emerged from cultivated wild populations and how many genes were involved. Here we present simulations that test how many genes could have been involved by considering the cost of selection. We demonstrate the selection load that can be endured by populations increases with decreasing selection coefficients and greater numbers of loci down to values of about s = 0.005, causing a driving force that increases the number of loci under selection. As the number of loci under selection increases, an effect of co-selection increases resulting in individual unlinked loci being fixed more rapidly in out-crossing populations, representing a second driving force to increase the number of loci under selection. In inbreeding systems co-selection results in interference and reduced rates of fixation but does not reduce the size of the selection load that can be endured. These driving forces result in an optimum pace of genome evolution in which 50-100 loci are the most that could be under selection in a cultivation regime. Furthermore, the simulations do not preclude the existence of selective sweeps but demonstrate that they come at a cost of the selection load that can be endured and consequently a reduction of the capacity of plants to adapt to new environments, which may contribute to the explanation of why selective sweeps have been so rarely detected in genome studies.

Plant domestication involved a process of selection through human agency of a series of traits collectively termed the domestication syndrome. Current debate concerns the pace at which domesticated plants emerged from cultivated wild populations and how many genes were involved. Here we present simulations that test how many genes could have been involved by considering the cost of selection. We demonstrate the selection load that can be endured by populations increases with decreasing selection coefficients and greater numbers of loci down to values of about s = 0.005, causing a driving force that increases the number of loci under selection. As the number of loci under selection increases, an effect of co-selection increases resulting in individual unlinked loci being fixed more rapidly in out-crossing populations, representing a second driving force to increase the number of loci under selection. In inbreeding systems co-selection results in interference and reduced rates of fixation but does not reduce the size of the selection load that can be endured. These driving forces result in an optimum pace of genome evolution in which 50-100 loci are the most that could be under selection in a cultivation regime. Furthermore, the simulations do not preclude the existence of selective sweeps but demonstrate that they come at a cost of the selection load that can be endured and consequently a reduction of the capacity of plants to adapt to new environments, which may contribute to the explanation of why selective sweeps have been so rarely detected in genome studies.

We have tested whether the thymidine kinase gene of herpes simplex virus 1 (HSV-1 tk) could function as a negative selectable marker in Leishmania major. Several drug resistance markers have been used for positive selection of transfected DNA in trypanosomatids, including neomycin phosphotransferase (NEO; refs. 1-4) and hygromycin phosphotransferase (HYG; refs. 5,. Negative selectable markers, that is genes whose expression is lethal to cells, have also proven useful for a variety of purposes in prokaryotic and eukaryotic systems. For example, negative selections have been used to enrich for homologous versus random recombinants in cultured mammalian cells , to ablate specific cell lineages in transgenic mice after fusion of the negative marker to a cell type-specific enhancer/promoter

Exogenous introduction of particle-associated proteins of human cytomegalovirus (HCMV) into the major histocompatibility complex (MHC) class I presentation pathway by subviral dense bodies (DB) is an effective way to sensitize cells against CD8 T-cell (CTL) recognition and killing. Consequently, these particles have been proposed as a platform for vaccine development. We have developed a strategy to refine the antigenic composition of DB. For proof of principle, an HCMV recombinant (RV-VM3) was generated that encoded the immunodominant CTL determinant IE1 TMY from the IE1 protein in fusion with the major constituent of DB, the tegument protein pp65. To generate RV-VM3, a bacterial artificial chromosome containing the HCMV genome was modified by applying positive/negative selection based on the expression of the bacterial galactokinase in conjunction with l Red-mediated homologous recombination. This method allowed the efficient and seamless insertion of the DNA sequence encoding IE1 TMY in frame into the pp65 open reading frame (UL83) of the viral genome. RV-VM3 expressed its fusion protein to high levels. The fusion protein was packaged into DB and into virions. Its delivery into fibroblasts by these viral particles led to the loading of the MHC class I presentation pathway with IE1 TMY and to efficient killing by specific CTLs. This demonstrated that a heterologous peptide, not naturally present in HCMV particles, can be processed from a recombinant, DB-derived protein to be subsequently presented by MHC class I. The results presented here provide a rationale for the optimization of a vaccine based on recombinant DB. Supplementary methods describing HCMV BAC recombineering using galK positive/negative selection are available with the online version of this paper.

This paper presents a load-balancing routing (LBR) algorithm for multi-channel wireless mesh networks (WMNs). The objective of this algorithm is to reduce interference and balance network load among links. The LBR algorithm is composed of link allocation algorithm and load-balancing route-selection algorithm. First, the network model is presented. Based on this model, a link allocation algorithm is proposed to allocate all links to channels which aims to minimise interference degree of networks. After links are allocated to channels, a route-selection algorithm is proposed to select a path from source to destination to balance network load. Simulation results demonstrate that the proposed algorithm balances network load and improves the network throughput significantly.

We report on two brothers and one maternal cousin with severe mental retardation, microcephaly, short stature, cryp- torchidism, and spastic diplegia. The patients were born to normal and non- consanguineous parents. All other mem- bers of the family, almost exclusively females, were clinically normal, suggest- ing X linked inheritance. By multipoint linkage analysis with markers spanning the whole X chromosome, we have tenta- tively assigned the underlying genetic defect to Xpll.4-q21, achieving a maxi- mum lod score of 1.3. This localisation overlaps MRXS3, a syndromic form of mental retardation resembling that found in the family described here, although with a milder presentation. We discuss the possibility that both phenotypes might be allelic variants of the same gene localised in the pericentromeric region of the X chromosome. Analysis of the X inactivation pattern in one potential and three obligate carrier females showed non-random inactivation of the allele linked to the disease. This finding may be interpreted as: (1) a nega- tive selection effect on cells bearing the mutation on the active X chromosome; (2) both the disease causing gene and the X inactivation centre are simultaneously affected by the same alteration, a deletion for instance; or (3) the skewed inactivation is the consequence of an independent event randomly associated with the dis- ease. In any case, the observation of consistent X inactivation supports X link- age of the disease.

Selection of T cells does not end with events in the thymus, but continues in extrathymic tissues and for the life of the organism. In this review, we examine how self-reactive T cells are rendered harmless and the processes that select for T cells that are most efficient at combating pathogens. The implications of peripheral T-cell selection for the immune response as animals age are discussed as is the critical role of dendritic cells in directing T-cell differentiation.

Proteins encoded by highly expressed genes evolve more slowly. This correlation is thought to arise owing to purifying selection against toxicity of misfolded proteins (that should be more crucial for highly expressed genes). It is now widely accepted that this individual (by-gene) effect is a dominant cause in protein evolution. Here, I show that in mammals, the evolutionary rate of a protein is much more strongly related to the evolutionary rate of coexpressed proteins (and proteins of the same biological pathway) than to the expression level of its encoding gene. The complexity of gene regulation (estimated by the numbers of transcription factor targets and regulatory microRNA targets in the encoding gene) is another important cause, which is much stronger than gene expression level. Proteins encoded by complexly regulated genes evolve more slowly. The intronic length and the ratio of intronic to coding sequence lengths also correlate negatively with protein evolutionary rate (which contradicts the expectation from the negative link between expression level and evolutionary rate). One more important factor, which is much stronger than gene expression level, is evolutionary age. More recent proteins evolve faster, and expression level of an encoding gene becomes quite a minor cause in the evolution of mammal proteins of metazoan origin. These data suggest that, in contrast to a widespread opinion, systemic factors dominate mammal protein evolution.

Proteins encoded by highly expressed genes evolve more slowly. This correlation is thought to arise owing to purifying selection against toxicity of misfolded proteins (that should be more crucial for highly expressed genes). It is now widely accepted that this individual (by-gene) effect is a dominant cause in protein evolution. Here, I show that in mammals, the evolutionary rate of a protein is much more strongly related to the evolutionary rate of coexpressed proteins (and proteins of the same biological pathway) than to the expression level of its encoding gene. The complexity of gene regulation (estimated by the numbers of transcription factor targets and regulatory microRNA targets in the encoding gene) is another important cause, which is much stronger than gene expression level. Proteins encoded by complexly regulated genes evolve more slowly. The intronic length and the ratio of intronic to coding sequence lengths also correlate negatively with protein evolutionary rate (wh...

Background: False occurrences of functional motifs in protein sequences can be considered as random events due solely to the sequence composition of a proteome. Here we use a numerical approach to investigate the random appearance of functional motifs with the aim of addressing biological questions such as: How are organisms protected from undesirable occurrences of motifs otherwise selected for their functionality? Has the random appearance of functional motifs in protein sequences been affected during evolution? Results: Here we analyse the occurrence of functional motifs in random sequences and compare it to that observed in biological proteomes; the behaviour of random motifs is also studied. Most motifs exhibit a number of false positives significantly similar to the number of times they appear in randomized proteomes (=expected number of false positives). Interestingly, about 3% of the analysed motifs show a different kind of behaviour and appear in biological proteomes less than they do in random sequences. In some of these cases, a mechanism of evolutionary negative selection is apparent; this helps to prevent unwanted functionalities which could interfere with cellular mechanisms. Our thorough statistical and biological analysis showed that there are several mechanisms and evolutionary constraints both of which affect the appearance of functional motifs in protein sequences.

Protection against the universe of pathogens requires a functional, diverse T cell repertoire. However, the price that is paid for an evolved, effective immune system includes the potential danger of generating autoaggressive T cells. Autoimmune diseases result from inherent breach of tolerance to self-antigens leading to disruption of the regulatory to autoaggressive T cell homeostatic balance. The immune system has evolved mechanisms to control those processes. For T cells, positive and negative selection in the thymus assures that only fully functional, non-selfreactive T cells will populate the periphery. Failure of this central tolerance would result in autoaggressive T cells escaping into the periphery. However, other means of escaping negative selection can occur in the periphery, i.e., TCR revision, or the altering of TCR expression after thymic egress. Here the potential benefits, i.e., expansion and re-shaping of the T cell repertoire as potentiated by TCR editing and revision are considered. Furthermore, the potential to develop autoaggressive TCR and thus enhance autoimmunity is considered.

The immune system has evolved sophisticate mechanisms controlling the development of responses to dangerous antigens while avoiding unnecessary attacks to innocuous, commensal or self antigens. The risk of autoimmunity is continuously checked and balanced against the risk of succumbing to exogenous infectious agents. It is therefore of paramount importance to understand the molecular events linking the breakdown of tolerance and the development of immunodeficiency. Apoptotic mechanisms are used to regulate the development of thymocytes, the shaping of T cell repertoire, its selection and the coordinate events leading to immune responses in the periphery. Moreover, they are at the heart of the homeostatic controls restoring T cell numbers and establishing T cell memory. T lymphocytes shift continuously from survival to death signals to ensure immune responsiveness without incurring in autoimmune damage. In this review we shall consider some key facts on the relationship of lymphopenia to autoreactivity, the mechanisms controlling positive and negative selection in the thymus, the role of apoptosis in selected primary immunodeficiency states and in systemic and organ-specific autoimmunity, with examples from human diseases and their animal models.

One of the most difficult tasks in the whole KDD process is to choose the right data mining technique, as the commercial software tools provide more and more possibilities together and the decision requires more and more expertise on the methodological point of view. Indeed, there are a lot of data mining techniques available for an environmental scientist wishing to discover some model from her/his data. This diversity can cause some troubles to the scientist who often have not a clear idea of what are the available methods, and moreover, use to have doubts about the most suitable method to be applied to solve a concrete domain problem. Within the data mining literature there is not a common terminology. A classification of the data mining methods would greatly simplify the understanding of the whole space of available methods. Furthermore, most data mining products either do not provide intelligent assistance for addressing the data mining process or tend do so in the form of rudimentary "wizard-like" interfaces that make hard assumptions about the user's background knowledge. In this work, a classification of most common data mining methods is presented in a conceptual map which makes easier the selection process. Also an intelligent data mining assistant is presented. It is oriented to provide model/algorithm selection support, suggesting the user the most suitable data mining techniques for a given problem.

Cryopreservation of PBSC for allo-SCT offers potential advantages; however, its impact on engraftment and outcomes remains unclear. A total of 76 allo-SCT performed using cryopreserved PBSC from HLA identical related (n=57) and unrelated donors (n=19) were compared with 123 fresh PBSC allo-SCT. Median neutrophil engraftment was on day 12 for both cryopreserved and fresh PBSC; in multivariate analysis, there was a slight but significant delay in neutrophil engraftment after the median date (hazard ratio (HR)=1.44, P=0.003). Platelet engraftment was significantly delayed in cryopreserved PBSC recipients (median time 19 vs 14 days). In multivariate analysis cryopreservation (HR=1.85, P<0.001), earlier date of transplant and lower CD34+ cell dose were associated with delayed platelet engraftment. Two-year OS and relapse and 1-year TRM rates did not differ significantly. Acute GVHD incidence was comparable, and extensive chronic GVHD at 1 year was higher in cryopreserved PBSC recipien...

Evidence for natural selection, positive or negative, on gene encoding antigens may indicate variation or functional constraints that are immunologically relevant. Most malaria surface antigens with high genetic diversity have been reported to be under positive-diversifying selection. However, antigens with limited genetic variation are usually ignored in terms of the role that natural selection may have in generating such patterns. We investigated orthologous genes encoding two merozoite proteins, MSP8 and MSP10, among several mammalian Plasmodium spp. These antigens, together with MSP1, are among the few MSPs that have two epidermal growth factor-like domains (EGF) at the C-terminal. Those EGF are relatively conserved (low levels of genetic polymorphism) and have been proposed to act as ligands during the invasion of RBCs. We use several evolutionary genetic methods to detect patterns consistent with natural selection acting on MSP8 and MSP10 orthologs in the human parasites Plasm...

Naked mole-rats (NMRs) are best known for their extreme longevity and cancer resistance, suggesting that their immune system might have evolved to facilitate these phenotypes. Natural killer (NK) and T cells have evolved to detect and destroy cells infected with pathogens and to provide an early response to malignancies. While it is known that NMRs lack NK cells, likely lost during evolution, little is known about their T-cell subsets in terms of the evolution of the genes that regulate their function, their clonotypic diversity, and the thymus where they mature. Here we find, using single-cell transcriptomics, that NMRs have a large circulating population of γδT cells, which in mice and humans mostly reside in peripheral tissues and induce anti-cancer cytotoxicity. Using single-cell-T-cell-receptor sequencing, we find that a cytotoxic γδT-cell subset of NMRs harbors a dominant clonotype, and that their conventional CD8 αβT cells exhibit modest clonotypic diversity. Consistently, pe...

The Omicron variant of SARS-CoV-2, which is a cause of concern, has various mutations in its spike protein. This protein is responsible for both viral infection and immunity. We have analyzed a particular sub-lineage of Omicron, designated XBB, which has undergone structural and functional changes in its spike protein as a response to the African selection pressures. Using molecular modeling, we compared the S protein structures of Omicron and XBB and discovered that XBB has a reduced receptor-binding domain (RBD) because of the loss of some β-sheets. This change may result in an increased affinity of XBB towards the human angiotensin-converting enzyme 2 (hACE2) receptor. We also conducted selection and recombination analysis of the S protein sequences of Omicron and XBB using Fast Unconstrained Bayesian Approximation (FUBAR) and Recombination Detection Program 4 (RDP 4). Our analysis detected signals of positive selection and recombination in the N-terminal domain (NTD) of the S1 s...

Multi-domain proteins form the majority of proteins in eukaryotes. During their formation by tandem duplication or gene fusion, new interactions between domains may arise as a result of the structurally-forced proximity of domains. The proper function of the formed proteins likely required the molecular adjustment of these stress zones by specific amino acid replacements, which should be detectable by the molecular signature of selection that governed their changes. We used multi-domain globins from three different invertebrate lineages to investigate the selective forces that acted throughout the evolution of these molecules. In the youngest of these molecules [Branchipolynoe scaleworm; original duplication ca. 60 million years (Ma)], we were able to detect some amino acids under positive selection corresponding to the initial duplication event. In older lineages (didomain globin from bivalve mollusks and nematodes), there was no evidence of amino acid positions under positive sele...

Knowledge sharing between various components of a system is a prerequisite for a successful knowledge management system. A knowledge sharing model includes providing knowledge workers with the knowledge, experiences and insights which they need to perform their tasks. We propose a multi-agent system that assists in the process of knowledge sharing between concerned knowledge worker groups. Each agent is a knowledge broker and organizer for a specialized knowledge worker group involved in the operations of a sub-system. In addition to timely access to knowledge, it should help in understanding the motivation which underlies decisions made by other groups and/or the information/knowledge bases for such decisions. Each agent is expected to learn about the activities, contexts of decisions, knowledge employed and experiences of other knowledge workers groups whose activities are considered to be relevant to the group it represents. We shall employ Partial Information State (PIS) to represent the knowledge of the agents. We shall employ a three-valued based nonmonotonic logic for reasoning about PISs. We present a multi-agent based model of argumentation and dialogue for knowledge sharing.

Identifying the best machine learning algorithm for a given problem continues to be an active area of research. In this paper we present a new method which exploits both meta-level information acquired in past experiments and active testing, an algorithm selection strategy. Active testing attempts to iteratively identify an algorithm whose performance will most likely exceed the performance of previously tried algorithms. The novel method described in this paper uses tests on smaller data sample to rank the most promising candidates, thus optimizing the schedule of experiments to be carried out. The experimental results show that this approach leads to considerably faster algorithm selection.

This paper presents new measures, based on the induced decision tree, to characterise datasets for meta-learning in order to select appropriate learning algorithms. The main idea is to capture the characteristics of dataset from the structural shape and size of decision tree induced from the dataset. Totally 15 measures are proposed to describe the structure of a decision tree. Their effectiveness is illustrated through extensive experiments, by comparing to the results obtained by the existing data characteristics techniques, including data characteristics tool (DCT) that is the most wide used technique in metalearning, and Landmarking that is the most recently developed method.

Objective: To examine the frequency and phenotype of Th17 cells in the peripheral blood of early RA (eRA) patients. Methods: CD4+ T cells were isolated from the peripheral blood of 33 eRA patients, 20 established RA patients and 53 healthy controls (HC), and from the synovial fluid of 20 established RA patients (RASF), by ficoll-hypaque gradient and magnetical negative selection. After polyclonal stimulation, the frequency of Th17 and Th1 cells was determined by flow cytometry and concentrations of IL-17, IFN-c, TNF-a and IL-10 were measured by ELISA in cell-free supernatants. Results: When all of our eRA patients were analyzed together, a significantly lower percentage of circulating Th17 cells and a lower CD4-derived IL-17 secretion were observed in comparison with HC. However, after stratifying by anti-CCP antibody status, circulating Th17 cells were decreased in anti-CCP(+) but not in anti-CCP(-)-eRA. All Th17 cells were CD45RO+CD45RAand CCR6+. Dual Th17/Th1 cells were also exclusively decreased in anti-CCP(+)-eRA. Circulating Th17 and Th17/Th1 cells were negatively correlated with anti-CCP titres. When anti-CCP(+)-eRA patients were retested one year after initiating treatment with oral methotrexate, their circulating Th17 frequency was no longer different from HC. Of note, the percentage of circulating Th1 cells and the secretion of CD4-derived IFN-c, TNF-a and IL-10 were not different between eRA patients and HC. In established RA patients, circulating Th17 and T17/Th1 cell frequencies were comparable to HC. In RASF, both Th17 and Th1 cells were increased when compared with blood of eRA patients, established RA patients and HC. Decreased circulating Th17 levels in eRA seem to be a marker of anti-CCP seropositivity, and return to levels observed in healthy controls after treatment with methotrexate.

Gene duplication may be an important mechanism for the evolution of new functions and for the adaptive modulation of gene expression via dosage effects. Here, we analyzed the fate of gene duplicates for two strains of a novel group of cyanobacteria (genus Acaryochloris) that produces the far-red light absorbing chlorophyll d as its main photosynthetic pigment. The genomes of both strains contain an unusually high number of gene duplicates for bacteria. As has been observed for eukaryotic genomes, we find that the demography of gene duplicates can be well modeled by a birth-death process. Most duplicated Acaryochloris genes are of comparatively recent origin, are strain-specific, and tend to be located on different genetic elements. Analyses of selection on duplicates of different divergence classes suggest that a minority of paralogs exhibit near neutral evolutionary dynamics immediately following duplication but that most duplicate pairs (including those which have been retained for long periods) are under strong purifying selection against amino acid change. The likelihood of duplicate retention varied among gene functional classes, and the pronounced differences between strains in the pool of retained recent duplicates likely reflects differences in the nutrient status and other characteristics of their respective environments. We conclude that most duplicates are quickly purged from Acaryochloris genomes and that those which are retained likely make important contributions to organism ecology by conferring fitness benefits via gene dosage effects. The mechanism of enhanced duplication may involve homologous recombination between genetic elements mediated by paralogous copies of recA.

Essential genes constitute the core of genes which cannot be mutated too much nor lost along the evolutionary history of a species. Natural selection is expected to be stricter on essential genes and on conserved (highly shared) genes, than on genes that are either nonessential or peculiar to a single or a few species. In order to further assess this expectation, we study here how essentiality of a gene is connected with its degree of conservation among several unrelated bacterial species, each one characterised by its own codon usage bias. Confirming previous results on E. coli, we show the existence of a universal exponential relation between gene essentiality and conservation in bacteria. Moreover, we show that, within each bacterial genome, there are at least two groups of functionally distinct genes, characterised by different levels of conservation and codon bias: i) a core of essential genes, mainly related to cellular information processing; ii) a set of less conserved nones...

This paper investigates the sorting of more productive workers into denser cities using administrative data for Spain that follow individuals continuously throughout their working lives. Migrants who move to denser cities are positively selected in terms of education, occupational skills, and individual productivity as proxied by pre-migration position in the local earnings distribution. However, not everyone is able to benefit equally from denser cities and this leads to a second round of sorting. Returnees are not only ex-ante less productive than permanent migrants, but are also those who, following the first move, have least boosted up their earnings in denser cities.

In independent mammalian lineages where females mate with multiple males (multi-male mating strategies), males have evolved larger testicles relative to those lineages where females mate with fewer males (single-male mating strategies). Here we study published bulk testis transcriptomes from humans, chimpanzees, gorillas and rhesus macaques, as well as mice and rats. Employing a formal model of adaptive evolution, we find that testis transcriptomes have also evolved convergently, reflecting each species’ mating strategy. Using deconvolution, we infer that testis transcriptome divergence patterns largely reflect convergent shifts in tissue cell type composition. However, we also identify modest amounts of convergent evolution at the cell-autonomous level by analyzing cell-type specific transcriptome data from spermatids and spermatocytes. We further show that in the single-male mating primates, human and gorilla, testis transcriptome profiles are paedomorphic relative to those of mul...

SummaryThe modern response to pandemics, critical for effective public health measures, is shaped by the availability and integration of diverse epidemiological outbreak data. Genomic surveillance has come to the forefront during the coronavirus disease 2019 (COVID-19) pandemic at both local and global scales to identify variants of concern. Tracking variants of concern (VOC) is integral to understanding the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in space and time. Combining phylogenetics with epidemiological data like case incidence, spatial spread, and transmission dynamics generates actionable information. Here we discuss the genome surveillance done in Pune, India, through sequencing 10,496 samples from infected individuals and integrating them with multiple heterogeneous outbreak data. The rise and fall of VOCs along with shifting transmission dynamics in the time interval of December 2020 to March 2022 was identified. Population-based estimat...