Adaptation Research Articles

Template switching during DNA replication is a prevalent source of adaptive gene amplification

Copy number variants (CNVs) are an important source of genetic variation underlying rapid adaptation and genome evolution. Whereas point mutation rates vary with genomic location and local DNA features, the role of genome architecture in the formation and evolutionary dynamics of CNVs is poorly understood. Previously, we found the GAP1 gene in Saccharomyces cerevisiae undergoes frequent amplification and selection in glutamine-limitation. The gene is flanked by two long terminal repeats (LTRs) and proximate to an origin of DNA replication (autonomously replicating sequence, ARS), which likely promote rapid GAP1 CNV formation. To test the role of these genomic elements on CNV-mediated adaptive evolution, we evolved engineered strains lacking either the adjacent LTRs, ARS, or all elements in glutamine-limited chemostats. Using a CNV reporter system and neural network simulation-based inference (nnSBI) we quantified the formation rate and fitness effect of CNVs for each strain. Removal of local DNA elements significantly impacts the fitness effect of GAP1 CNVs and the rate of adaptation. In 177 CNV lineages, across all four strains, between 26% and 80% of all GAP1 CNVs are mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) which results from template switching between the leading and lagging strand during DNA synthesis. In the absence of the local ARS, distal ones mediate CNV formation via ODIRA. In the absence of local LTRs, homologous recombination can mediate gene amplification following de novo retrotransposon events. Our study reveals that template switching during DNA replication is a prevalent source of adaptive CNVs.

Template switching during DNA replication is a prevalent source of adaptive gene amplification.

Copy number variants (CNVs) are an important source of genetic variation underlying rapid adaptation and genome evolution. Whereas point mutation rates vary with genomic location and local DNA features, the role of genome architecture in the formation and evolutionary dynamics of CNVs is poorly understood. Previously, we found the GAP1 gene in Saccharomyces cerevisiae undergoes frequent amplification and selection in glutamine-limitation. The gene is flanked by two long terminal repeats (LTRs) and proximate to an origin of DNA replication (autonomously replicating sequence, ARS), which likely promote rapid GAP1 CNV formation. To test the role of these genomic elements on CNV-mediated adaptive evolution, we evolved engineered strains lacking either the adjacent LTRs, ARS, or all elements in glutamine-limited chemostats. Using a CNV reporter system and neural network simulation-based inference (nnSBI) we quantified the formation rate and fitness effect of CNVs for each strain. Removal of local DNA elements significantly impacts the fitness effect of GAP1 CNVs and the rate of adaptation. In 177 CNV lineages, across all four strains, between 26% and 80% of all GAP1 CNVs are mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) which results from template switching between the leading and lagging strand during DNA synthesis. In the absence of the local ARS, distal ones mediate CNV formation via ODIRA. In the absence of local LTRs, homologous recombination can mediate gene amplification following de novo retrotransposon events. Our study reveals that template switching during DNA replication is a prevalent source of adaptive CNVs.

Adaptive Divergence and Functional Convergence: The Evolution of Pulmonary Gene Expression in Amphibians of the Qingzang Plateau.

The Qingzang Plateau, with its harsh environmental conditions-low oxygen, high ultraviolet radiation and significant temperature fluctuations-demands specialised adaptations for survival. While genetic adaptations have been extensively studied, gene expression's role in amphibian adaptation to high elevations remains understudied. This study analysed pulmonary gene expression in 119 amphibians across the plateau to explore how genetic and environmental factors shape expression evolution. Transcriptomic analyses revealed significant interspecies variation, driven by environmental factors like temperature, oxygen levels, UVB radiation and precipitation. Principal Component and Mantel analyses found no significant correlation between gene expression divergence and genetic distance. Instead, species-specific traits and environmental pressures were pivotal in shaping expression patterns. PERMANOVA analysis showed environmental factors had varying impacts on species. For instance, Bufo gargarizans exhibited a strong gene expression response to multiple environmental factors, while Scutiger boulengeri was less influenced, reflecting diverse adaptive strategies. Functional enrichment analysis highlighted convergence in key biological processes, such as energy metabolism, apoptosis and autophagy, despite species-specific gene expression differences. These processes are critical for surviving the plateau's extremes. The findings suggest that gene expression evolution in amphibians on the Qingzang Plateau is shaped by both genetic diversity and environmental pressures. Although gene expression profiles vary, they converge on essential functions, offering insights into adaptation mechanisms in extreme environments.

Evaluating the Centre‐Periphery Hypothesis Through Genomic Phylogeographical Comparisons of Two Sister Species of Liquidambar in East Asia's Tertiary Relict Forests

ABSTRACTAimUnderstanding the spatial distribution of genetic variation within species is a central tenet in evolutionary biology and conservation biology. This study explores how historical demographic processes and/or environmental factors interact to affect contemporary genetic variation and adaptive potential, with a specific focus on testing the ‘centre‐periphery’ hypothesis (CPH).LocationSubtropical China.Taxon Liquidambar. MethodsWe combined comparative phylogeography, landscape genomics and niche modelling to investigate the interplay between demographic history and past/current environmental factors in shaping genetic variation in Liquidambar formosana and L. acalycina, a sister pair of East Asia's Tertiary relict forests.ResultsIn both species, core populations occupied highly suitable habitats at highest densities. Consistent with the CPH, population genetic diversity decreased, and differentiation increased, from centre to margin in L. acalycina, but not in L. formosana, likely reflecting different demographic histories and different relative contributions of geography, past (LGM) and current climates to their present‐day genetic variation. In addition, L. formosana showed higher adaptive potential to future climate change than L. acalycina.Main ConclusionsThis study demonstrates that differences in contemporary genetic variation and adaptability among closely related species can be explained by contrasting demographic responses to multiple geographic/climatic factors. In turn, it should also expand our understanding of the CPH, while informing future conservation efforts for these two study species.

Gene Editing for Enhanced Swine Production: Current Advances and Prospects

Traditional pig breeding has improved production traits but faces limitations in genetic diversity, disease resistance, and environmental adaptation. Gene editing technologies, such as CRISPR/Cas9, base editing, and prime editing, enable precise genetic modifications, overcoming these limitations and expanding applications to biomedical research. Here, we reviewed the advancements in gene editing technologies in pigs and explored pathways toward optimized swine genetics for a resilient and adaptive livestock industry. This review synthesizes recent research on gene editing tools applied to pigs, focusing on CRISPR/Cas9 and its derivatives. It examines their impact on critical swine production traits and their role as human disease models. Significant advancements have been made in targeting genes for disease resistance, such as those conferring immunity to porcine reproductive and respiratory syndrome viruses. Additionally, gene-edited pigs are increasingly used as models for human diseases, demonstrating the technology’s broader applications. However, challenges such as off-target effects, ethical concerns, and varying regulatory frameworks remain. Gene editing holds substantial potential for sustainable and productive livestock production by enhancing key traits and supporting biomedical applications. Addressing technical and ethical challenges through integrated approaches will be essential to realize its full potential, ensuring a resilient, ethical, and productive livestock sector for future generations

Single-cell sequencing provides clues about the developmental genetic basis of evolutionary adaptations in syngnathid fishes

Seahorses, pipefishes, and seadragons are fishes from the family Syngnathidae that have evolved extraordinary traits including male pregnancy, elongated snouts, loss of teeth, and dermal bony armor. The developmental genetic and cellular changes that led to the evolution of these traits are largely unknown. Recent syngnathid genome assemblies revealed suggestive gene content differences and provided the opportunity for detailed genetic analyses. We created a single-cell RNA sequencing atlas of Gulf pipefish embryos to understand the developmental basis of four traits: derived head shape, toothlessness, dermal armor, and male pregnancy. We completed marker gene analyses, built genetic networks, and examined the spatial expression of select genes. We identified osteochondrogenic mesenchymal cells in the elongating face that express regulatory genes bmp4, sfrp1a, and prdm16. We found no evidence for tooth primordia cells, and we observed re-deployment of osteoblast genetic networks in developing dermal armor. Finally, we found that epidermal cells expressed nutrient processing and environmental sensing genes, potentially relevant for the brooding environment. The examined pipefish evolutionary innovations are composed of recognizable cell types, suggesting that derived features originate from changes within existing gene networks. Future work addressing syngnathid gene networks across multiple stages and species is essential for understanding how the novelties of these fish evolved.

Single-cell sequencing provides clues about the developmental genetic basis of evolutionary adaptations in syngnathid fishes.

Seahorses, pipefishes, and seadragons are fishes from the family Syngnathidae that have evolved extraordinary traits including male pregnancy, elongated snouts, loss of teeth, and dermal bony armor. The developmental genetic and cellular changes that led to the evolution of these traits are largely unknown. Recent syngnathid genome assemblies revealed suggestive gene content differences and provided the opportunity for detailed genetic analyses. We created a single-cell RNA sequencing atlas of Gulf pipefish embryos to understand the developmental basis of four traits: derived head shape, toothlessness, dermal armor, and male pregnancy. We completed marker gene analyses, built genetic networks, and examined the spatial expression of select genes. We identified osteochondrogenic mesenchymal cells in the elongating face that express regulatory genes bmp4, sfrp1a, and prdm16. We found no evidence for tooth primordia cells, and we observed re-deployment of osteoblast genetic networks in developing dermal armor. Finally, we found that epidermal cells expressed nutrient processing and environmental sensing genes, potentially relevant for the brooding environment. The examined pipefish evolutionary innovations are composed of recognizable cell types, suggesting that derived features originate from changes within existing gene networks. Future work addressing syngnathid gene networks across multiple stages and species is essential for understanding how the novelties of these fish evolved.

Oxidative adaptations in prokaryotes imply the oxygenic photosynthesis before the crown group Cyanobacteria

Abstract The metabolic transition from anaerobic to aerobic in prokaryotes reflects adaptations to oxidative stress. Methanogen, one of the earliest life forms on Earth, has evolved into three major groups within the Euryarchaeota, exhibiting different phylogenetic affiliations and metabolic characters. In comparison with other strictly anaerobic methanogenic groups, the Class II methanogens possess better capability to adapt to limited oxygen pressure. Cyanobacteria is considered the first and only prokaryote evolving oxygenic photosynthesis and responsible for the Great Oxidation Event on Earth. However, the connection between oxygenic Cyanobacteria and evolutionary adaptations to oxidative stress in prokaryotes remains elusive. Here, through the SMC (structural maintenance of chromosomes) protein-encoding gene, which was horizontally transferred from the ancient Class II methanogens to the last common ancestor of crown group Cyanobacteria, we demonstrate that the origin of extant Cyanobacteria was undoubtedly posterior to the occurrence of oxygen-tolerant Class II methanogens. In addition, we found that certain prokaryotic lineages had evolved the tolerance mechanisms against oxidative stress before the origin of extant Cyanobacteria. The contradiction that oxidative adaptations in Class II methanogens and other prokaryotes predating crown group oxygenic Cyanobacteria implies the existence of more ancient biological oxygenesis. We propose that these potential oxygenic organisms might represent the extinct phototrophs and first emerge during the Paleoarchean, contributing to the oxidative adaptations in the prokaryotic tree of life and facilitating the dispersal of reaction centers across the bacterial domain.

Disruption of Epistemic Trust in Borderline Personality Disorder: A Possible Adaptation to Avoid Making Costly Mistakes.

This paper applies error management theory (EMT) (Haselton and Buss 2000) to explore how disruptions in epistemic trust-trust in communicated information-can be understood as adaptive responses to early adversity in individuals with borderline personality disorder (BPD). I propose that epistemic mistrust (EM) and epistemic credulity (EC), characterized by inappropriate trust patterns, arise from the differential costs of trusting unreliable versus mistrusting reliable information. Although these biases may seem maladaptive, they function as evolutionary survival mechanisms in response to harsh environments. Signal detection analysis can provide empirical evidence for these trust biases by assessing how individuals with BPD make trust-related decisions. Clinically, understanding these biases as evolutionary adaptations helps reduce stigma and informs evolutionary-informed interventions to recalibrate trust responses and improve interpersonal relationships. This approach highlights the significance of integrating evolutionary perspectives in treating trust disturbances in BPD.

Genotype-by-Environment Effects of Cis-Variations in the Atgl Promoter Mediate the Divergent Pattern of Phenotypic Plasticity for Temperature Adaptation in Two Congeneric Oyster Species.

Phenotypic plasticity plays an essential role in adaptive evolution. However, the molecular mechanisms of how genotype-by-environment interaction (G × E) effects shape phenotypic plasticity in marine organisms remain poorly understood. The crucial temperature-responsive trait triacylglycerol (TAG) content and its major gene adipose triglyceride lipase (Atgl) expression have divergent plastic patterns in two congeneric oyster species (Crassostrea gigas and Crassostrea angulata) to adapt to relative-cold/northern and relative-warm/southern habitats, respectively. In this study, eight putative loci were identified in the Atgl promoter region (cis-variations) between wild C. gigas and C. angulata that exhibited differential environmental responsiveness (G × E). The G and G × E effects of each locus were further dissected by measuring the Atgl gene expression of different genotypes in response to temperature changes at the cellular and organismal levels. Two transcription factors, non-environmentally responsive non-POU domain-containing octamer-binding protein (Nono) and environmentally responsive heterogeneous nuclear ribonucleoprotein K (Hnrnpk), were screened for binding to g.-1804 (G locus) and g.-1919 (G + G × E locus), respectively. The specificity of Nono binding to the C. angulata allele mediated the G effects of g.-1804, and the lower environmental sensitivity of Hnrnpk in C. angulata mediated the G × E effects of g.-1919, jointly regulating the trade-offs between higher constitutive and lower plastic expression of Atgl gene expression in C. angulata. This study served as an experimental case to reveal how the genetic variations with G and (or) G × E effects propagate into the divergent pattern of plasticity in environmental adaptive traits, which provides new insights into predicting the adaptability of marine organisms to future climate changes.

Phylogenetic Perspectives and Ethnobotanical Insights on Wild Edible Plants of the Mediterranean, Middle East, and North Africa

This study investigates the phylogenetic and geographical distribution of wild food plants (WFPs) across 30 Mediterranean and North African (MENA) regions, focusing on the intersection of evolutionary lineage, ecological adaptation, and cultural utilization. A phylogenetic analysis of 111 genera of WFPs used in traditional diets reveals clusters reflecting shared ancestry, functional adaptations, and ecological resilience. Key regions such as Lebanon and Ikaria stand out as potential centers for the diversity of wild food plant use, suggesting that the Eastern Mediterranean may be a primary origin area, especially for species adapted to semi-arid climates. Major plant families including Lamiaceae, Rosaceae, and Fabaceae form distinct clusters that underscore their common ancestry and adaptability, making them foundational to traditional diets and medicinal applications across various environments. Geographical analysis indicates historical connections, such as those between Malta and Egypt, supporting the hypothesis that ancient trade routes influenced the spread and cultural exchange of wild food plant use across the Mediterranean. The study emphasizes the integration of phylogenetic and ethnobotanical perspectives, shedding light on how biodiversity, ecological adaptation, and cultural practices intersect in these regions. This research demonstrates that WFPs serve as both ecological and cultural assets, crucial for preserving traditional diets and supporting biodiversity conservation amid environmental changes. Integrating evolutionary and cultural knowledge can enrich ecological understanding and contribute to the sustainable use of plant resources in the MENA regions.

Adaptive Laboratory Evolution Uncovers Potential Role of a DNA Helicase Mutation in Torulaspora delbrueckii Increased Sulphite Resistance.

Wine industry has faced pressure to innovate its products. Saccharomyces cerevisiae has been the traditional yeast for producing alcoholic beverages, but interest has shifted from the conventional S. cerevisiae to non-Saccharomyces yeasts for their biotechnological potential. Among these, Torulaspora delbrueckii is particularly notable for its ability to enrich wine with novel flavours. During winemaking, sulphites are added to suppress spoilage microorganisms, making sulphite tolerance a valuable characteristic of wine yeasts. Adaptive laboratory evolution in liquid and solid media improved sulphite resistance in two T. delbrueckii strains, achieving, in the best case, a fourfold increase from 0.50 to 2.00 mM of sodium metabisulphite, highlighting the potential of these evolve strains for winemaking applications. Genomic analysis revealed SNPs/InDels in all the strains, including a novel unique missense mutation common to the four evolved isolates, but absent from the parental strains, located in chromosome VIII (protein TDEL0H03170, homologue of S. cerevisiae MPH1). These genes code for a protein catalogued as an ATP-dependent DNA helicase, known for its role in maintaining genome stability by participating in DNA repair pathways. We propose that this valine-to-serine mutation, common to all the evolved isolates, helps the evolved strains repair sulphite-induced DNA damage more effectively.

The potential of MAO inhibitors as chemotherapeutics in cancer: A literature survey.

Drug resistance in cancer is determined by genetic mutations and adaptations of tumor cells to drug treatments, raising a challenge in the treatment of cancer. Factors such as prolonged drug exposure, genetic variability among patients, and tumor heterogeneity have been established as contributors to rising incidence of drug resistance, prompting ongoing research into alternative therapies and combination treatments to overcome this challenge. Monoamine oxidases (MAOs), including both isoforms MAO-A and MAO-B, are mitochondrial enzymes responsible for the catabolism of monoamine neurotransmitters such as dopamine, norepinephrine, and serotonin. While these enzymes play a pivotal role in the nervous system, their role in tumorigenesis has garnered increasing attention in the last years. Recent studies, in fact, have highlighted the potential of MAO inhibitors (MAOIs) as antitumor agents, emphasizing their use as standalone treatments or in synergy with traditional anticancer therapies, focusing on pathways involved in tumorigenesis. This review aims to provide a comprehensive overview of MAOIs currently under study for their potential antitumor activity, focusing on their structural characteristics, mechanisms of action, and efficacy in preclinical and clinical settings, referencing key articles in the field.

Histological characterization of γδ T cells in cutaneous wound healing in Fraser's dolphins (Lagenodelphis hosei).

Cetaceans exhibit remarkable wound healing capabilities. However, the specific immune mechanisms underlying this process, particularly the role of γδ T cells, remains largely unexplored. In ruminants, pigs, and camelids, which are members of the order Cetartiodactyla alongside cetaceans, γδ T cells express a unique receptor called workshop cluster 1 (WC1). Despite cetaceans also belonging to this order, the presence of WC1 in their γδ T cells has not yet been reported. This study aims to investigate the distribution and potential function of γδ T cells in cetacean skin during homeostasis and wound healing. Using immunofluorescence and immunohistochemical staining, we identified γδ TCR+ and WC1+ cells in dolphin skin for the first time. These cells are predominantly located in the dermis and blubber, with an increased presence in healing wounds, suggesting their involvement in wound healing rather than pathogen defense. Furthermore, our findings revealed that γδ TCR+ cells constitute a small fraction of CD3+MHCII+ cells in dolphin skin, indicating their intricate role in cetacean immunology. Additionally, the appearance of WC1+ cells in cetaceans highlights unique immunological features within Cetartiodactyla. Comparative analysis demonstrates that γδ T cells in dolphins exhibit distinctive morphological and distributional characteristics compared to those in humans, mice, and ruminants, implying species-specific adaptations. These insights contribute to a deeper understanding of cetacean immunology and underscore the potential evolutionary adaptations that support their exceptional wound healing capabilities. Future research on the genomic and functional aspects of γδ T cells in cetaceans is essential to further elucidate their roles in immune response and wound healing.

Carbon dioxide suppresses filamentous growth in the human fungal pathogen Candida tropicalis.

A striking characteristic of the human fungal pathogen Candida albicans is its ability to switch between budding yeast morphology and the filamentous form, facilitating its adaptation to changing host environments. The filamentous growth of C. albicans is mediated by various environmental factors, such as carbon dioxide (CO2), N-acetylglucosamine (GlcNAc), serum, and high temperature. Despite extensive studies in C. albicans, the regulatory mechanism of filamentation in Candida tropicalis, a fungal species that is closely related to C. albicans, has not been well characterized. In this study, we reveal opposite roles of CO2 in regulating filamentation among Candida species: CO2 promotes filamentous growth in C. albicans and Candida dubliniensis, whereas it inhibits filamentation in C. tropicalis. Despite the critical role of the canonical cAMP pathway in filamentation, it is dispensable in CO2-regulated filamentation in C. tropicalis. A CO2-specific signaling is involved in the regulation of filamentous growth in C. tropicalis. Additionally, we identify two key elements involved in CO2 sensing in C. tropicalis: a single carbonic anhydrase (CA) Nce103 and the bZIP transcription factor Rca1. Both Nce103 and Rca1 are important for cellular growth in ambient air and negatively regulate filamentous development in response to CO2 in C. tropicalis. These findings reveal a distinct mechanism underlying CO2-regulated filamentation in C. tropicalis, contributing to a deeper understanding of its unique survival strategies in diverse environmental niches and providing new insights into the adaptive evolution of CO2 sensing mechanisms among various fungal pathogens.

Assessing genomic diversity and signatures of selection in Qingyuan Wapiti.

Red deer is a species of family Cervidae that is widely distributed in the world and is often raised to provide antlers, as a trophy or traditional medicine materials, and meat. Currently, the whole genomic data for red deer are very limited. Qingyuan Wapiti (QYW), China's first breed of red deer by artificial breeding, is well known for its high yield of antlers and large body size. The phylogenetic tree showed that QYW had a closer genetic relationship with Tarim red deer than European red deer. To explore the genetic diversity and selection signatures, the whole genome of 28 QYW individuals was sequenced, and 19 401 749 biallelic SNPs and 1 849 784 indels were obtained. The value of observed heterozygosity, expected heterozygosity, and nucleotide diversity were 0.258598, 0.268844, and 0.002193, respectively. Based on Tajima's D and integrated haplotype score analyses, the candidate regions containing 187 genes were detected, including PLD1, ANTXR1, PLCL1, CPE, and CTNNA3, which have been reported to be correlated with osteogenesis and mineralization, growth, and body size by previous studies. The results obtained in this study will contribute to elucidating the genetic mechanisms underlying the formation of excellent traits in QYW and provide the whole genome data for future exploration of genomic diversity and adaptation evolution of red deer worldwide.

Single-Cell Landscape of the Cochlea Revealed Cell-Type-Specific Diversification in Hipposideros armiger Based on PacBio Long-Read Sequencing

Echolocation represents one of the most rapid adaptive sensorimotor modulation behaviors observed in mammals, establishing bats as one of the most evolutionarily successful mammals. Bats rely on high-frequency hearing for survival, but our understanding of its cellular molecular basis is scattered and segmented. Herein, we constructed the first single-cell transcriptomic landscape of the cochlea in Hipposideros armiger, a CF-FM bat, using a PacBio-optimized genome and compared it with the results obtained from unoptimized original genomes. Sixteen distinct cell types were distributed across five spatial regions of the cochlea. Notably, through hematoxylin and eosin staining and fluorescence in situ hybridization, we identified new types of spiral ganglion neuron (SGN) cells in the cochlea of H. armiger. These SGN cells are likely critical for auditory perception and may have driven the adaptive evolution of high-frequency hearing in this species. Furthermore, we uncovered the differentiation relationships of among specific cell types, such as the transition from supporting cells to hair cells. Using the cochlear cell atlas as a reference, cell types susceptible to deafness-associated genes (in the human) were also identified. In summary, this study provides novel insights into the cellular and molecular mechanisms underlying the adaptive high-frequency hearing in bats and highlights potential candidate cell types and genes for therapeutic interventions in hearing loss.

Pan-genomics: Insight into the Functional Genome, Applications, Advancements, and Challenges

A pan-genome is a compilation of the common and unique genomes found in a given species. It incorporates the genetic information from all of the genomes sampled, producing a big and diverse set of genetic material. Pan-genomic analysis has various advantages over typical genomics research. It creates a vast and varied spectrum of genetic material by combining the genetic data from all the sampled genomes. Comparing pan-genomics analysis to conventional genomic research, there are a number of benefits. Although the most recent era of pan-genomic studies has used cutting-edge sequencing technology to shed fresh light on biological variety and improvement, the potential uses of pan-genomics in improvement have not yet been fully realized. Pangenome research in various organisms has demonstrated that missing genetic components and the detection of significant Structural Variants (SVs) can be investigated using pan-genomic methods. Many individual-specific sequences have been linked to biological adaptability, phenotypic, and key economic attributes. This study aims to focus on how pangenome analysis uncovers genetic differences in various organisms, including human, and their effects on phenotypes, as well as how this might help us comprehend the diversity of species. The review also concentrated on potential problems and the prospects for future pangenome research.

Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation.

Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which scratching exacerbates inflammation and whether scratching provides benefit to the host are largely unknown. We found that scratching was required for skin inflammation in mouse models dependent on FcεRI-mediated mast cell activation. Scratching-induced inflammation required pain-sensing nociceptors, the neuropeptide substance P, and the mast cell receptor MrgprB2. Scratching also increased cutaneous inflammation and augmented host defense to superficial Staphylococcus aureus infection. Thus, through the activation of nociceptor-driven neuroinflammation, scratching both exacerbated allergic skin disease and provided protection from S. aureus, reconciling the seemingly paradoxical role of scratching as a pathological process and evolutionary adaptation.

Nature AND nurture: enabling formate-dependent growth in Methanosarcina acetivorans.

Methanosarcinales are versatile methanogens, capable of regulating most types of methanogenic pathways. Despite the versatile metabolic flexibility of Methanosarcinales, no member of this order has been shown to use formate for methanogenesis. In the present study, we identified a cytosolic formate dehydrogenase (FdhAB) present in several Methanosarcinales, likely acquired by independent horizontal gene transfers after an early evolutionary loss, encouraging re-evaluation of our understanding of formate utilization in Methanosarcinales. To explore whether formate-dependent (methyl-reducing or CO2-reducing) methanogenesis can occur in Methanosarcinales, we engineered two different strains of Methanosarcina acetivorans by functionally expressing FdhAB from Methanosarcina barkeri inM. acetivorans. In the first strain, fdhAB was integrated into the N5-methyl- tetrahydrosarcinapterin:coenzyme M methyltransferase (mtr) operon, making it capable of growing by reducing methanol with electrons from formate. In the second strain, fdhAB was integrated into the F420-reducing hydrogenase (frh) operon, instead of the mtr operon, enabling its growth with formate as the only source of carbon and energy after adaptive laboratory evolution. In this strain, one CO2 is reduced to one methane with electrons from oxidizing four formate to four CO2, a metabolism reported only in methanogens without cytochromes. Although methanogens without cytochromes typically utilize flavin-based electron bifurcation to generate the ferredoxins needed for CO2 activation, we hypothesize that, in our engineered strains, reduced ferredoxins are obtained via the Rhodobacter nitrogen fixation complex complex running in reverse. Our work demonstrates formate-dependent methyl-reducing and CO2-reducing methanogenesis in M. acetivorans that is enabled by the flexible nature of the microbe working in tandem with the nurturing provided.