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Could humans and AI become a new evolutionary individual?

Long-term evolutionary persistence of a cryptic color polymorphism in frogs

Color polymorphism can influence the evolutionary fate of cryptic species because it increases populations’ chances of survival in heterogenous or variable environments. Yet, little is known about the molecular and evolutionary mechanisms underlying the persistence of cryptic color polymorphisms, or the impact these polymorphisms have on the macroevolutionary dynamics of lineages. Here, we examine the evolutionary history of the most widespread cryptic color polymorphism in anurans, involving green and brown morphs. Using an order-scale comparative analysis, we show that these morphs can coexist within species over long evolutionary periods and that polymorphic lineages switch habitat more frequently and have greater diversification rates than other groups. We then identify the locus responsible for the green/brown polymorphism in a group of African grass frogs, and demonstrate that it evolves under long-term balancing selection, resulting in trans-specific polymorphism. These results provide a microevolutionary mechanism for the long-term persistence of multiple color morphs within species observed at a macroevolutionary scale. This study underscores the importance of cryptic color polymorphism in the ecology and evolution of anurans, and provides a framework for future research on the genetic architecture and selective forces underlying cryptic coloration traits.

CpG-A induces liquid–liquid phase separation of HMGB1 to activate the RAGE-mediated inflammatory pathway

High-mobility group box protein 1 (HMGB1) is a chromatin-associated nonhistone protein widely distributed in the nucleus of eukaryotic cells. It is transported extracellularly as a proinflammatory mediator or late warning protein to induce immune and inflammatory reactions upon stimuli such as microbial infection. Here, we have found that HMGB1 directly interacts with bacterial DNA analogue CpG-A in the extracellular environment to undergo liquid–liquid phase separation (LLPS) via its positively charged DNA-binding domain. We have demonstrated that the receptor for advanced glycosylation end products (RAGE) responds to stimulation of the extracellular HMGB1-CpG-A complex and triggers phase separation of the downstream adaptor protein, Src76kDa structural domain leukocyte protein (SLP76), which promotes activation of the MAPK pathway and release of inflammatory cytokines. These results not only designate that LLPS serves as a gain-of-function mechanism involved in the axis of DNA-HMGB1 stimulated RAGE-SLP76 signaling pathway but also provide evidence that the activity of HMGB1 is regulated by LLPS, highly relevant to immune responses of inflammatory cells toward microbial infection. Especially, the finding that the intracellular SLP76 forms condensates with the cytosol domain of RAGE may represent a general downstream phenomenon when an inflammatory cell membrane receptor is activated.

Correction: Epidemiological factors associated with Turtle fraservirus 1 (TFV1) in freshwater turtles in Florida, USA

DNA polymerase α-primase can function as a translesion DNA polymerase

Replication of cellular chromosomes requires a primase to generate short RNA primers to initiate genomic replication. While bacterial and archaeal primase generate short RNA primers, the eukaryotic primase, Polα-primase, contains both RNA primase and DNA polymerase (Pol) subunits that function together to form a >20 base hybrid RNA–DNA primer. Interestingly, the DNA Pol1 subunit of Polα lacks a 3’-5’ proofreading exonuclease, contrary to the high-fidelity normally associated with DNA replication. However, Polδ and Polε synthesize the majority of the eukaryotic genome, and both contain 3’-5’ exonuclease activity for high fidelity. Nonetheless, even the small amount of DNA produced by Pol1 in each of the many RNA/DNA primers during chromosome replication adds up to tens of millions of nucleotides in a human genome. Thus, it has been a longstanding question why Pol1 lacks a proofreading exonuclease. We show here that Polα is uniquely capable of traversing common oxidized or hydrolyzed template nucleotides and propose that Polα evolved to bypass these common template lesions when they are encountered during chromosome replication. Additionally, we show a unique ability of replication factor C (RFC) to stimulate Polδ lesion bypass, independent of its sliding clamp. This suggests that there may be a coordination between Polδ and RFC that does not involve RFC loading of PCNA.

Correction: Systemic immune-inflammation index is associated with clinical outcome of acute ischemic stroke patients after intravenous thrombolysis treatment

Is Nav1.8-specific inhibition the only path? Preferential Nav blockers offer a compelling alternative

The timing of the Castelnovisation of southwestern Europe: A Bayesian modelling insight from the Romagnano Loc III rock shelter sequence (Trento, Italy)

This paper provides a review of the Mesolithic sequence at the Romagnano loc III site through Bayesian modelling, combining the radiocarbon dates obtained in the 1970s with more recent 14C dates. The results suggest a chronology associated with the Castelnovian complex that predates those identified in other areas of Southwestern Europe, thus offering a new working hypothesis regarding the origin of this complex. Finally, these findings are discussed within the broader context of the origin and expansion of the Blade Trapeze Complex in Southwestern Europe indicating that the emergence of this new complex was a multifaceted process that can only be fully understood through a comprehensive global approach.

Sensitization of cancer cells to DNA-damaging agents by expression of the REV1 C-terminal domain: Implications for chemotherapy

The mutagenic translesion synthesis (TLS) pathway, which is critically dependent on REV1’s ability to recruit inserter TLS polymerases and the POLζ extender polymerase, enables cancer cells to bypass DNA lesions while introducing mutations that likely contribute to the development of chemotherapy resistance and secondary malignancies. Targeting this pathway represents a promising therapeutic strategy. Here, we demonstrate that the expression of the C-terminal domain (CTD) of human REV1, a ca. 100 amino acid scaffold essential for TLS polymerase interactions, disrupts REV1/POLζ-dependent TLS in mammalian cells. Inducible expression of REV1-CTD in multiple human and murine cancer cell lines sensitizes cells to DNA-damaging agents such as cisplatin, benzo[a]pyrene diol epoxide, and methyl methanesulfonate, without intrinsic cytotoxicity. REV1-CTD expression increases genomic instability, decreases mutagenesis, and enhances G2 arrest following genotoxic stress. Mutational disruption of the CTD’s interaction interfaces abrogates these effects, confirming a dominant-negative mechanism via sequestration of TLS components. In a xenograft mouse model, REV1-CTD expression markedly enhances cisplatin efficacy, significantly reducing tumor burden. These findings establish the REV1-CTD as an effective dominant-negative inhibitor of TLS and support its development as a therapeutic agent delivered to cancer cells to enhance the efficacy of genotoxic chemotherapy.

A single PCR-sequencing method to establish the frequency of kdr alleles in the stable fly, Stomoxys calcitrans: application to seven livestock farms from south of France

The stable fly, Stomoxys calcitrans, is a cosmopolite pest causing direct and indirect nuisances on livestock, due to painful bite, harassment, blood despoliation and biological or mechanical transmission of viruses, bacteria and parasites. Its control is mainly based on direct applications of pyrethroid insecticides on livestock, although evidences show limited efficiency due to short term effects and high levels of phenotypic and genotypic resistance. Diagnosis of genetic resistance is currently based on a series of point mutation PCRs showing limitations. Based on fly specimens trapped in southern France, this study aims to establish a new diagnosis method to investigate kdr allele frequencies in livestock farms. A total of 144 S. calcitrans specimens were collected from seven farms (1 with insecticide usage, and 6 without) and processed individually through a single PCR using newly designed primers amplifying a 340 bp fragment including the mutation site of the voltage-sensitive sodium channel domain II; PCR products were then sequenced. Among the 104 individuals successfully sequenced, the methodology allowed to detect the wild-type, kdr-his and kdr genotypes encoding for leucine, histidine and phenylalanine, respectively. Although the wild-type was the most prevalent, resistance alleles were detected in all farms, especially at the veterinary school, where insecticides are commonly used. These results highlight that genotypic insecticide resistance in S. calcitrans populations is widespread. This single PCR-sequencing method, simple, cost-effective and reliable, will allow determining prevalence, distribution and resilience of genotypic pyrethroid insecticide resistance, a primary data to support a conversion from chemical vector control toward environmental-friendly strategies.

Relationship dynamics and behavioral adaptations in the control of the 2022 mpox epidemic

We analyzed the patterns of transmission in the 2022 clade IIb mpox epidemic as it unfolded in the European population of men who have sex with men (MSM). We developed an agent-based model that simulates sexual pair formation, incorporating both brief and longer-term sexual relationships. The model implements survey data on the sexual behavior of MSM and accounts for the highly heterogeneous nature of the sexual contact network within this community. When simulating the mpox epidemic, the model reproduces the reported numbers of sexual partners of mpox-infected individuals. We find that infection-derived immunity had little impact on ending the European outbreak. Instead, we suggest that the marked decrease in serial interval observed across the epidemic reflects a substantial increase in self-isolating behavior among infected persons and that this is sufficient to explain the early control of the epidemic. Our work highlights the critical interplay between relationship dynamics and adaptive behaviors in shaping mpox epidemic patterns and achieving control in 2022. Despite continued propagation of clade IIb mpox, the European MSM population remains protected by immunity, primarily vaccine-induced.

Exploring the implementation of an evidence-based health promotion intervention for women experiencing intimate partner violence (iHEAL) in diverse contexts: Study Protocol

Objectives This participatory, mixed methods study will explore how iHEAL, a woman-led, nurse-delivered health promotion intervention for women who have experienced intimate partner violence (IPV), can be implemented in real-world, community-based health care settings located in 3 Canadian provinces. Grounded in the Active Implementation Frameworks, the study’s primary aim is to identify the processes, resources and supports necessary to implement and sustain this novel program with fidelity while maintaining its benefits for women. Methods/Design Over 2.5 years, each organization will plan for and deliver the iHEAL program, supported by an iHEAL Consultant. To explore implementation processes and fidelity, successes and challenges, and any value-added of iHEAL to organizations and/or communities, qualitative interviews will be conducted with 3 groups of participants: 1) organizational leaders; 2) implementation/delivery team members (nurses and supervisors); and 3) external stakeholders or agencies supporting iHEAL through referrals or other collaboration. High level notes capturing key issues and decisions at planning meetings will supplement these data. Administrative program data will be collected to assess program reach, participant engagement, and aspects of fidelity. Women participating in iHEAL will also be invited to complete pre/post intervention surveys to assess changes in key outcomes, with a subsample of 60 women to be interviewed about their experiences of iHEAL and suggestions for strengthening the program. Qualitative data will be analyzed using Rapid Team Based Qualitative Analysis and Reflective Thematic Analysis. Quantitative data will be summarized using descriptive statistics; pre-post intervention changes in outcomes collected in women’s surveys will be analyzed using paired t-tests. Ethical approval has been obtained, and all participants will provide informed consent. Significance The findings of this research are expected to yield insights about organizational factors that shape the delivery of iHEAL and support the development of guidance materials for future iHEAL implementation and scale up.

Evolution of cross-tolerance to metals in yeast

Organisms often face multiple selective pressures simultaneously (e.g., mine tailings with multiple heavy metal contaminants), yet we know little about when adaptation to one stressor provides cross-tolerance or cross-intolerance to other stressors. To explore the potential for cross-tolerance, we adapted Saccharomyces cerevisiae to high concentrations of six single metals in a short-term evolutionary rescue experiment. We then measured cross-tolerance of each metal-adapted line to the other five metals. We tested three predictors for the degree of cross-tolerance, based on similarity in 1) the physiochemical properties of each metal pair, 2) the overlap in genes known to impact tolerance to both metals, and 3) their co-occurrence in the environment. None of these predictors explained significant variation in cross-tolerance. Instead, the strongest predictor was the metal in which adaptation occurred: Cobalt-adapted lines performed well in most metals (generalists) while manganese-adapted lines typically performed poorly (specialists). To determine the genetic basis, we sequenced the genomes of 109 metal-adapted lines. Broader cross-tolerance characterized lines bearing mutations affecting phosphorus metabolism, with three genes related to phosphate metabolism bearing several independent mutations ( PHO84 , SIW14 , VTC4 ). Thus, while a genome-wide analysis failed to predict cross-tolerance, a subset of genes facilitated growth in multiple metals. We also observed two “mutator” lines (both in manganese) and report evidence that cadmium, cobalt, and manganese altered the mutation spectrum. While it is challenging to predict how evolutionary adaptation to one stressor will impact tolerance to other stresses, our work helps reveal the environments and pathways that contribute to cross-tolerance among metals.

Osmolality as a strong predictor of COVID-19 mortality and its possible links to other biomarkers

Osmolality, concentration of solute particles, was rarely used for prognosis for COVID-19. By analyzing blood samples of more than 1300 COVID-19 patients from Tokat, Turkey (including 100 surviving and 30 deceased inpatients), we found calculated osmolality to be an excellent prognostic biomarker for mortality and significantly associated with hospitalization, independent from gender and age. Although calculated osmolality is defined as a weighted sum of sodium, glucose, and urea, the three are not necessarily independent. Other blood test biomarkers, ferritin, creatine, and chloride are also correlated with osmolality after conditioning on age. By applying a combination of collider analysis and mediation analysis, we design a pipeline to construct a causal model among all these variables in their relationship to osmolality. We confirm that while glucose and sodium are independent contributors of osmolality, glucose and urea, urea and sodium are correlated. We also conclude that ferritin and creatine are associated with osmolality through urea, and chloride’s association to osmolality is through sodium.

Critical exponents of the spin-glass transition in a field at zero temperature

We analyze the spin-glass transition in a field in finite dimension D below the upper critical dimension directly at zero temperature using a recently introduced perturbative loop expansion around the Bethe lattice solution. The expansion is generated by the so-called M -layer construction, and it has 1 / M as the associated small parameter. Computing analytically and numerically these nonstandard diagrams at first order in the 1 / M expansion, we construct an ϵ -expansion around the upper critical dimension D uc = 8 , with ϵ = D uc − D . Following standard field theoretical methods, we can write a β function, finding a new zero-temperature fixed-point associated with the spin-glass transition in a field in dimensions D < 8 . We are also able to compute, at first order in the ϵ -expansion, the three independent critical exponents characterizing the transition, plus the correction-to-scaling exponent.

Alternative splicing and residual function potentially expand the therapeutic landscape of the CFTRdele2ins182 variant

This study investigates the molecular and functional consequences of rare CFTR variants, particularly focusing on the complex allele [186-13C > G; 1898 + 3A > G] and the CFTRdele2ins182 rearrangement. Using patient-derived nasal epithelial cells, the research characterized the transcripts produced by these variants, revealing that CFTRdele2ins182, previously considered a null allele, generates alternative mRNA isoforms, one of which potentially encodes a partially functional CFTR protein. Functional assays in both heterologous and patient-derived cell models explored the impact of CFTR modulators on these variant proteins. While some rescue of CFTR activity was observed with specific modulator combinations in certain variants, the study highlights the complexity of genotype-phenotype correlations in CF and emphasizes the importance of personalized functional characterization of rare CFTR variants to guide therapeutic strategies. The findings suggest that even variants thought to be null alleles may produce proteins with residual function, opening avenues for developing targeted therapies for a broader range of CF patients.

Spontaneous glutamate release activates mGluR signaling to drive rapid antidepressant responses

Major depressive disorder affects millions worldwide, yet current treatments require prolonged administration. In contrast, ketamine produces rapid antidepressant effects by blocking spontaneous N-Methyl-D-Aspartate (NMDA) receptor signaling, which lifts the suppression of protein synthesis and triggers homeostatic synaptic plasticity. Here, we identify a parallel signaling pathway involving metabotropic glutamate receptor 5 (mGluR5) that promotes rapid antidepressant-like effects. We show that enhancing the endogenous mGluR5 signaling produces synaptic potentiation in the hippocampus and triggers the rapid antidepressant effect, similar to ketamine. Importantly, blocking mGluR5 prevents ketamine’s effects, revealing a synergy between the two pathways. At the cellular level, spontaneous calcium transients mediated by mGluR5 activate the phosphatase calcineurin and promote eukaryotic elongation factor 2 (eEF2) dephosphorylation, increasing BDNF translation to drive synaptic plasticity. We show that quantal glutamate release activates two spatially segregated Ca 2+ signals—NMDAR- and mGluR5-driven—which exert opposing effects on protein synthesis. Together, these findings highlight mGluR5 as a promising therapeutic target for rapid antidepressant action, harnessing the complex nanoscale organization of synapses.

Uncorrected refractive errors, visual impairment and need for spectacles among children and adolescents in eastern, China

Background Uncorrected refractive errors (URE) are the leading preventable cause of visual impairment (VI) in children globally, with China facing a critical dual challenge of high myopia prevalence and insufficient spectacle coverage among youth. Despite eastern China’s rapid development, population-based data on URE, VI, and need for spectacles remain scarce, particularly regarding the understudied role of anisometropia and subtype-specific refractive risks. This study evaluates these unmet needs to inform targeted interventions. Methods A cross-sectional school-based study was conducted in Nantong, China, including participants 7–19 years of age. All participants underwent assessments of their uncorrected visual acuity, presenting visual acuity (PVA), and best-corrected visual acuity. URE was defined as PVA worse than 0.3 logMAR (6/12 Snellen) with ≥1 line improvement (≥0.1 logMAR) after correction in either eye.VI was defined as PVA < 6/12 in the better eye. Need for spectacles was defined as the total prevalence of refractive error requiring correction, including unmet, under-met, and met needs. Non-cycloplegic autorefraction was assessed for each participant. Results Of the 9,864 participants, 9,438 were included in the analysis. The total prevalence of URE, VI and need for spectacles was 15.7% (95% CI: 15.0–16.5; n = 1,485),4.9% (95% CI: 4.9–5.3; n = 459) and 55.9% (95% CI: 54.9–56.9; n = 5,275), respectively. Multivariate analysis showed that factors such as female sex (aOR: 1.24, 95% CI: 1.09–1.40), wearing spectacles (aOR: 0.16, 95% CI: 0.14–0.19), older age groups (e.g., aOR: 3.92 for 13–14 years), hyperopia (aOR: 13.08, 95% CI: 7.67–22.31), myopia (aOR: 18.65, 95% CI: 12.54–27.77), and anisometropia (aOR: 1.87, 95% CI: 1.64–2.12) were associated with URE. For VI, significant associations included female sex (aOR: 1.20, 95% CI: 0.98–1.47), hyperopia (aOR: 7.23, 95% CI: 1.60–32.61), myopia (aOR: 53.04, 95% CI: 19.68–142.95), and rural residence (aOR: 1.53, 95% CI: 1.25–1.87). Factors such as older age (highest aOR: 11.77 for 19 years), female sex (aOR: 1.58, 95% CI: 1.42–1.77), hyperopia (aOR: 16.56, 95% CI: 10.97–25.01), myopia (aOR: 28.88, 95% CI: 21.83–38.19), astigmatism (aOR: 2.50, 95% CI: 2.22–2.82), and anisometropia (aOR: 1.37, 95% CI: 1.21–1.55) were associated with need for spectacles. Conclusion Although the prevalence of VI among children and adolescents in eastern China was low, the prevalence of URE and the need for spectacles were high. Myopia was the most important risk factor for URE, VI, and need for spectacles, and the impact of anisometropia on URE, VI, and need for spectacles cannot be ignored. Further research on adjusting intervention strategies is needed to eliminate preventable visual impairments.

From molecular damage and viscoelasticity to interfacial fracture in soft polymer networks: Insights from mechanochemistry

Many soft, tough materials have emerged in recent years, paving the way for advances in wearable electronics, soft robotics, and flexible displays. However, understanding the interfacial fracture behavior of these materials remains a significant challenge, owing to the difficulty of quantifying the respective contributions from viscoelasticity and damage to energy dissipation ahead of cracks. This work aims to address this challenge by labeling a series of polymer networks with fluorogenic mechanophores, subjecting them to T-peel tests at various rates and temperatures, and quantifying their force-induced damage using a confocal microscope. The results challenge longstanding assumptions underlying linear viscoelastic fracture theories, revealing a complex interplay between viscoelasticity and damage governed by the Weissenberg number, W i . Specifically, they suggest a molecular picture in which the interfacial toughness increases due to polymer chain breakage and enlarged strains when W i < 0.3 , and significant chain friction and network stiffening when W i > 0.3 , with the damage being negligible in the limits of W i ≪ 0.3 and W i ≫ 0.3 either due to insufficient strains at the peel front or because of excessive stress at weak interfacial bonds. Overall, these results illustrate the molecular and mesoscopic mechanisms underpinning interfacial fracture, aiding to refine current viscoelastic fracture theories and accelerating the development of advanced polymer networks for increasingly demanding applications.

Optimized processing of Gardenia Fruits with ginger juice: Unveiling therapeutic mechanisms for cholestatic liver injury through TLR4/NF-κB, FXR/PPAR-α, and PI3K/AKT/GSK-3β

The study aimed to optimize the processing conditions of Gardeniae Fructus with ginger juice (GFPG) and confirm its therapeutic effects and pharmacological mechanisms on cholestatic liver injury. Processing conditions were optimized using response surface methodology (RSM) and thermal analysis, focusing on geniposide content as a key active compound. Variables included processing time, moistening time, and the solid-liquid ratio. Optimal conditions were: ginger juice to Gardeniae Fructus ratio of 8:1 (w/v), processing temperature of 208 °C, moistening time of 3 hours, and processing time of 5 minutes. Pharmacological mechanisms were analyzed through network pharmacology, molecular docking, and experimental validation using alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury in mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cell models. In vivo, GFPG extract alleviated ANIT-induced cholestatic liver injury by improving liver function markers (AST, ALT, TBA, TBIL, DBIL) and modulating TLR4/NF-κB, FXR/PPAR-α, and PI3K/AKT/GSK-3β pathways. In vitro, it reduced LPS-induced production of inflammatory mediators (NO, TNF-α, IL-6, IL-1β) through TLR4/NF-κB pathway inhibition. This study established optimal processing methods for GFPG using RSM and thermal analysis, providing robust quantitative parameters. GFPG demonstrated significant therapeutic effects in cholestatic liver injury models, indicating its potential as a candidate for developing treatments for cholestatic hepatitis.