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Correction for Eggertsen et al., Logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy

Trait-space patterning is dictated by the tempo and mode of mutation

In large, natural ecosystems, many ( ≳ 1) phenotypically relevant mutants can emerge over the characteristic turnover time of the population. When this is the case, there can be ‘eco-evolutionary feedback’ between the dynamical processes that underlie mutation, selection and ecology. We show that, owing to such feedback, the precise details of the mutational process can have a qualitative impact on the long-term behavior of an eco-evolutionary system, in contrast to the classical population genetic assumption that all mutations can be modeled with an effective, homogeneous rate. We demonstrate this in the context of a version of MacArthur’s consumer-resource model in which consumers mutate along a resource preference trait-space. Starting from a stochastic individual-based model, we simulate the system in the case where mutations are exogenously generated at a fixed rate (e.g. via external mutagens) and in the case where mutations are coupled to replication (e.g. via DNA copying errors). We find that, surprisingly, replication-coupled mutations are capable of generating a patterned phase in the limit of fast ecological relaxation – precisely the regime where classical population genetic models are expected to operate. We derive a mean-field description of the stochastic model and show that the patterned phase comes about due to a Turing-like mechanism driven by the non-reciprocal and nonlinear nature of replicative mutations. Furthermore, we show that additional interactions like those due to host defense mechanisms can extend the patterned regime to arbitrarily high dimensional phenotype spaces. We demonstrate that these results are robust to demographic noise and model choices and we discuss systems in which this phenomenology might be relevant.

Partner dependency alters patterns of coevolutionary selection in mutualisms

Coevolution is a ubiquitous driver of diversification in both mutualistic and antagonistic interactions between species. In mutualisms, coevolution can result in trait complementarity between partners that facilitates their persistence. Despite its importance, most of what we know about coevolution in mutualism comes from obligate interactions, whereas we know comparatively little about facultative interactions, arguably the most common type of mutualism. To evaluate coevolutionary dynamics in facultative mutualism and test how it compares with obligate mutualisms, we used a synthetic yeast mutualism where the partners exchange essential nutrient resources. We manipulated mutualism dependency by controlling the availability of mutualistic resources in the environment and measured coevolution via time-shift assays and tracking the evolution of mutualistic traits over time. In addition, we genotyped the evolved and ancestral mutualists to test for differences in the strength of coevolutionary selection between facultative and obligate mutualisms. We found evidence of coevolution in both facultative and obligate mutualisms, but coevolution was weaker and slower in facultative mutualisms. We also found evidence for evolution of trait complementarity in obligate mutualisms but not in facultative mutualisms. Furthermore, obligate mutualists had more SNPs under positive selection than facultative mutualists. Together, these results provide strong evidence that mutualism dependency impacts both the strength of coevolution and the rate of trait evolution.

Macrophages release neuraminidase and cleaved calreticulin for programmed cell removal

Calreticulin (CALR) is primarily an endoplasmic reticulum chaperone protein that also plays a key role in facilitating programmed cell removal (PrCR) by acting as an “eat-me” signal for macrophages, directing their recognition and engulfment of dying, diseased, or unwanted cells. Recent findings have demonstrated that macrophages can transfer their own CALR onto exposed asialoglycans on target cells, marking them for PrCR. Despite the critical role CALR plays in this process, the molecular mechanisms behind its secretion by macrophages and the formation of binding sites on target cells remain unclear. Our findings show that CALR undergoes C-terminal cleavage upon secretion, producing a truncated form that functions as the active eat-me signal detectable on target cells. We identify cathepsins as potential proteases involved in this cleavage process. Furthermore, we demonstrate that macrophages release neuraminidases, which modify the surface of target cells and facilitate CALR binding. These insights reveal a coordinated mechanism through which lipopolysaccharide (LPS)-activated macrophages regulate CALR cleavage and neuraminidase activity to mark target cells for PrCR. How they recognize the cells to be targeted remains unknown.

Calcineurin controls the cytokinesis machinery during thermal stress in <i>Cryptococcus deneoformans</i>

Calcineurin is a highly conserved phosphatase that plays a central role in sensing calcium and governing transcriptional, posttranscriptional, and posttranslational signaling networks. Calcineurin is a heterodimer consisting of a catalytic A subunit and a regulatory B subunit. Through downstream effectors, calcineurin signaling drives myriad responses in different organisms. In the fungal pathogenic Cryptococcus species complex that infects humans, calcineurin governs thermotolerance and is essential for growth at high temperature and pathogenesis. In Cryptococcus deneoformans , the underlying molecular functions of this critical signaling cascade are not well understood. In this study, we conducted a genetic screen and identified genetic changes that suppress the requirement for calcineurin during high-temperature growth. Our results identified two mechanisms that bypass the requirement for calcineurin function. The first mechanism involves segmental aneuploidy via both amplification as well as loss of chromosome fragments. The second mechanism involves dominant amino acid substitution mutations in the genes encoding three proteins, Chs6, Imp2, and Cts1, orthologs of components of the Ingression Progression Complex required for septation and budding in Saccharomyces cerevisiae . Loss of calcineurin activity causes chitin and chitosan accumulation and severe budding defects, whereas suppressor mutations largely restore growth and cytokinesis in the absence of calcineurin. These findings reveal that the calcineurin signaling cascade controls a conserved cytokinesis machinery at the mitotic exit network during thermal stress.

Galvanotactic directionality of cell groups depends on group size

Motile cells migrate directionally in the electric field (EF) in a process known as galvanotaxis, an important phenomenon in wound healing and development. We previously reported that individual fish keratocyte cells migrate to the cathode in EFs, that inhibition of PI3 kinase (PI3K) reverses single cells to the anode, and that large cohesive groups of either unperturbed or PI3K-inhibited cells migrate to the cathode. Here, we report that small uninhibited cell groups move to the cathode, while small groups of PI3K-inhibited cells move to the anode. Small groups move faster than large groups, and groups of unperturbed cells move faster than PI3K-inhibited cell groups of comparable sizes. The shapes and sizes of large groups change little when they start migrating, while size and shapes of small groups change significantly, and lamellipodia disappear from the rear edges of these groups. The computational model, according to which cells inside and at the edge of the group interpret directional signals differently, explains the observations. Namely, cells in the group interior are directed to the cathode independently whether they are PI3K-inhibited or not. Meanwhile, the edge cells behave like individual cells: They are directed to the cathode in uninhibited groups and to the anode in PI3K-inhibited groups. As a result, all cells drive uninhibited groups to the cathode, while larger PI3K-inhibited groups are directed by cell majority in the group interior to the cathode, while majority of the edge cells in small groups win the tug-of-war driving these groups to the anode.

Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small-cell lung cancer

Small-cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by rapid evolution from chemosensitivity to chemoresistance and limited treatment options. However, the mechanisms underlying this evolution remain poorly understood. Here, we show that Retinoid X receptor γ (RXRγ) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXRγ serves as an essential factor driving chemoresistance in SCLC. RXRγ forms phase-separated droplets with LSD1 in the nucleus, which enhances RXRγ-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXRγ antagonist disrupts RXRγ–LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXRγ target gene network. Finally, RXRγ antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, resulting in a substantial extension of survival in mouse models. Thus, these results establish RXRγ as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.

The evolution of thermal performance curves in response to rising temperatures across the model genus yeast

The maintenance of biodiversity crucially depends on the evolutionary potential of populations to adapt to environmental change. Accelerating climate change and extreme temperature events urge us to better understand and forecast evolutionary responses. Here, we harnessed the power of experimental evolution with the microbial model system yeast ( Saccharomyces spp. ) to measure the evolutionary potential of populations to adapt to future warming, in real-time and across the entire phylogenetic diversity of the genus. We tracked the evolution of thermal performance curves (TPCs) in populations of eight genetically and ecologically diverse species under gradually increasing temperature conditions, from 25 to 40 °C, for up to 600 generations. We found that evolving toward higher critical thermal limits generally came at a cost, causing a decrease in both thermal tolerance and maximum growth performance. The evolution of TPCs varied significantly between species with strong genotype-by-environment interactions, revealing two main trajectories: i) Warm-tolerant species showed an increase in both optimum growth temperature and thermal tolerance, consistent with the “hotter is wider” hypothesis. ii) Cold-tolerant species on the other hand evolved larger thermal breadth and higher thermal limits, but suffered from reduced maximum performance overall, consistent with the generalist or “a jack of all temperatures is a master of none” hypothesis. In addition, cold-tolerant species never reached the warm-tolerant species’ upper thermal limits. Our results show that adaptive strategies to increasing temperatures are complex, highlighting the need to consider both within and between species diversity when predicting and managing the impacts of climate change on populations.

Effective polarization in potassium channel simulations: Ion conductance, occupancy, voltage response, and selectivity

Potassium (K + ) channels are widely distributed in many types of organisms. They combine high efficiency (~100 pS) and K + /Na + selectivity by a conserved selectivity filter (SF). Molecular Dynamics (MD) simulations can provide detailed, atomistic mechanisms of this sophisticated ion permeation. However, currently there are clear inconsistencies between computational predictions and experimental results. First, the ion occupancy of the SF in simulations is lower than expected (~2.5 in MD compared to ~4 in X-ray crystallography). Second, in many reported MD simulations of K + channels, K + conductance is typically an order of magnitude lower than experimental values. This discrepancy is in part because the force fields used in MD simulations of potassium channels do not account for polarization. One of the proposed solutions is the Electronic Continuum Correction (ECC), a force field modification that scales down formal charges, to introduce the polarization in a mean-field way. When the ECC is used in conjunction with the Charmm36m force field, the simulated K + conductance increases 13-fold. Following the analysis of ion occupancy states using Hamiltonian Replica Exchange simulations, we propose a parameter set for Amber14sb, that also leads to a similar increase in conductance. These two force fields are then used to compute the full current–voltage (I-V) curves from MD simulations, approaching quantitative agreement with experiments at all voltages. In general, the ECC-enabled simulations are in excellent agreement with experiment, in terms of ion occupancy, conductance, current–voltage response, and K + /Na + selectivity.

Knowledge of politician stock trading reduces congressional legitimacy and compliance with the law

Institutional legitimacy is essential for democracies, yet public trust and confidence in the United States Congress are at an all-time low. A significant predictor of attitudes toward Congress is perceptions of corruption, with perceptions of corruption in government linked to less legitimacy. This study tests whether knowledge of Congressional stock trading affects legitimacy and compliance with Congressional authority. In a preregistered experiment with US citizens ( n = 506), participants who read a report detailing how Congressmembers made higher-than-expected profits from stock trading in 2024 reported increased perceptions of corruption and decreased legitimacy in Congress. They also viewed laws passed by Congress as less fair and were less willing to comply with such laws. Perceptions of Congressional legitimacy mediated the effect of stock trading knowledge on willingness to comply with congressional laws and perceptions of congressional laws as fair. A preregistered follow-up experiment ( n = 664) shows that these effects are not driven by how much Congressmembers profit but by how trading negatively affects broader perceptions of legitimacy. These findings highlight the detrimental effects of Congressional stock trading on perceptions of legitimacy and respect for the law.

Ancient DNA suggests a historical demographic decline and genetic erosion in the Atlantic bluefin tuna

Overexploitation has depleted fish stocks during the past century; nonetheless, its genomic consequences remain poorly understood for most species. Characterizing the spatiotemporal patterns of these consequences may provide baseline estimates of past diversity and productivity to aid management targets, help predict future dynamics, and facilitate the identification of evolutionary factors limiting fish population recovery. Here, we evaluate human impacts on the evolution of the iconic Atlantic bluefin tuna ( Thunnus thynnus ), one of the longest and most intensely exploited marine fishes, with a tremendous cultural and economic importance. We sequenced whole genomes from modern (n = 49) and ancient (n = 41) specimens dating up to 5,000 y ago, uncovering several findings. First, we identify temporally stable patterns of population admixture, as bluefin tuna caught off Norway and in the eastern Mediterranean share a greater degree of ancestry with Gulf of Mexico bluefin tuna than western and central Mediterranean bluefin tuna. This suggests that Atlantic spawning areas are important mixing grounds for the genetic diversity of Mediterranean bluefin tuna. We model effective population size to show that Mediterranean bluefin tuna began to undergo a demographic decline by the year 1900 to an extent not observed across the previous millennia. Coinciding with this, we found that heterozygosity and nucleotide diversity were significantly lower in modern (2013 to 2020) than ancient (pre-1941) Mediterranean bluefin tuna, suggesting that bluefin tuna underwent a genetic bottleneck. With this work, we show how ancient DNA provides unique perspectives on ecological complexity with the potential to inform the management and conservation of fishes.

Can AI weather models predict out-of-distribution gray swan tropical cyclones?

Predicting gray swan weather extremes, which are possible but so rare that they are absent from the training dataset, is a major concern for AI weather models and long-term climate emulators. An important open question is whether AI models can extrapolate from weaker weather events present in the training set to stronger, unseen weather extremes. To test this, we train independent versions of the AI weather model FourCastNet on the 1979–2015 ERA5 dataset with all data, or with Category 3–5 tropical cyclones (TCs) removed, either globally or only over the North Atlantic or Western Pacific basin. We then test these versions of FourCastNet on 2018–2023 Category 5 TCs (gray swans). All versions yield similar accuracy for global weather, but the one trained without Category 3–5 TCs cannot accurately forecast Category 5 TCs, indicating that these models cannot extrapolate from weaker storms. The versions trained without Category 3–5 TCs in one basin show some skill forecasting Category 5 TCs in that basin, suggesting that FourCastNet can generalize across tropical basins. This is encouraging and surprising because regional information is implicitly encoded in inputs. Given that current state-of-the-art AI weather and climate models have similar learning strategies, we expect our findings to apply to other models. Other types of weather extremes need to be similarly investigated. Our work demonstrates that novel learning strategies are needed for AI models to reliably provide early warning or estimated statistics for the rarest, most impactful TCs, and, possibly, other weather extremes.

Forecasting range shifts of dioecious plants under climate change

Global climate change has triggered an urgent need for predicting the reorganization of Earth’s biodiversity. For dioecious species (those with separate sexes), it is unclear how commonly unique climate sensitivities of females and males could influence projections for species-level responses to climate change. We developed demographic models of range limitation, parameterized from geographically distributed common garden experiments, with females and males of a dioecious grass species ( Poa arachnifera ) throughout and beyond its range in the south-central U.S. We contrasted predictions of a standard female-dominant model with those of a two-sex model that accounts for feedbacks between sex ratio and vital rates. Both model versions predict that future climate change will induce a poleward shift of niche suitability beyond current northern limits. However, the magnitude of the poleward shift was underestimated by the female-dominant model because females have broader temperature tolerance than males but become mate-limited under female-biased sex ratios, which are forecasted to become more common under future climate. Our results illustrate how explicitly accounting for both sexes can enhance population viability forecasts and conservation planning for dioecious species in response to climate change.

Inflammatory cytokine upd3 induces axon length–dependent synapse removal by glia

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors but the cellular and molecular bases for neurite length-dependent vulnerability of neurons to degeneration is largely unknown. Using Drosophila sensory neurons as a model system we show that neuronal activation of the integrated stress response triggers expression of the Interleukin-6 homolog unpaired 3 ( upd3 ), which is both necessary and sufficient for axon length–dependent degeneration of presynapses. Upd3 activates phagocytic glia, triggering phagocytic removal of presynapses preferentially on neurons with long axons, thus revealing an intrinsic axon length–dependent vulnerability to glial insult. Finally, we found that axon length–dependent presynapse loss in fly models of human NDDs utilized this pathway, requiring upd3 and glial expression of the phagocytic receptor draper. Our studies identify inflammatory cytokine signaling and glial phagocytosis as key determinants of axon length–dependent vulnerability, thus mechanistically linking these hallmarks of NDDs.

Arteries are finely tuned thermosensors regulating myogenic tone and blood flow

In response to changing blood pressure, arteries adjust their caliber to control blood flow. This vital autoregulatory property, termed vascular myogenic tone, stabilizes downstream capillary pressure. Here, we reveal that tissue temperature, combined with intraluminal pressure, critically determines myogenic tone. Heating steeply activates tone in skeletal muscle, gut, brain, and skin arteries with temperature coefficients ( Q 10 ) of ~11 to 20. Each of these tissues has a distinct resting temperature, and we find that arterial thermosensitivity is tuned to this temperature, making myogenic tone sensitive to small thermal fluctuations. Interestingly, temperature and intraluminal pressure are sensed largely independently and the signals integrated to trigger myogenic tone. We demonstrate that thermosensitive channels TRPV1 and TRPM4 mediate heat-induced tone in skeletal muscle arteries with discrete temperature sensitivities. Similarly, TRPM4 contributes to heat-induced tone in gut and brain arteries. The half-maximal responses occur at approximately 31 °C for TRPV1 and 33 °C for TRPM4. Variations in tissue temperature are known to alter blood fluidity and therefore vascular conductance; remarkably, thermosensitive tone counterbalances this effect, thus protecting capillary integrity and fluid balance. In conclusion, thermosensitive myogenic tone is a fundamental homeostatic mechanism regulating tissue perfusion.

Stathmin-2 enhances motor axon regeneration after injury independent of its binding to tubulin

Stathmin-2 (also known as SCG10 ) is encoded by the STMN2 gene, whose mRNA is one of the most abundantly expressed in human motor neurons. In almost all instances of ALS and other TDP-43 proteinopathies, stathmin-2 encoding mRNAs are cryptically spliced and polyadenylated in motor neurons, a pathogenic consequence of nuclear loss of function of the RNA binding protein TDP-43. While stathmin-2 has been shown to enhance regeneration after axonal injury to axons of cultured motor neurons, here, we show that after crush injury within the adult murine nervous system of wild-type or stathmin-2-null mice, the presence of stathmin-2 reduces axonal and neuromuscular junction degeneration and stimulates reinnervation and functional recovery. Mechanistically, although stathmin-2 has been proposed to function through direct binding to α/β tubulin heterodimers and correspondingly to affect microtubule assembly and dynamics, stathmin-2’s role in axon regeneration after axotomy is shown to be independent of its tubulin binding abilities.

Pattern formation along signaling gradients driven by active droplet behavior of cell swarms

Gradients of extracellular signals organize cells in tissues. Although there are several models for how gradients can pattern cell behavior, it is not clear how cells react to gradients when the population is undergoing 3D morphogenesis, in which cell–cell and cell–signal interactions are continually changing. Dictyostelium cells follow gradients of their nutritional source to feed and maintain their undifferentiated state. Using lightsheet imaging to simultaneously monitor signaling, single-cell, and population dynamics, we show that the cells migrate toward nutritional gradients in swarms. As swarms advance, they deposit clumps of cells at the rear, triggering differentiation. Clump deposition is explained by a physical model in which cell swarms behave as active droplets: cells proliferate within the swarm, with clump shedding occurring at a critical population size, at which cells at the rear no longer perceive the gradient and are not retained by the emergent surface tension of the swarm. The model predicts vortex motion of the cells within the swarm emerging from the local transfer of propulsion forces, a prediction validated by 3D tracking of single cells. This active fluid behavior reveals a developmental mechanism we term “musical chairs” decision-making, in which the decision to proliferate or differentiate is determined by the position of a cell within the group as it bifurcates.

Population size interacts with reproductive longevity to shape the germline mutation rate

Mutation rates vary across the tree of life by many orders of magnitude, with fewer mutations occurring each generation in species that reproduce quickly and maintain large effective population sizes. A compelling explanation is that large effective population sizes facilitate selection against weakly deleterious “mutator alleles” such as variants that modulate cell division or interfere with the molecular efficacy of DNA repair. However, while the fidelity of a single cell division largely determines microorganisms’ mutation rates, the relationship of the mutation rate to the molecular determinants of DNA damage and repair is more complex in multicellular species with long generation times. Since long generations leave more time for mutations to accrue each generation, we posit that a long generation time likely amplifies the fitness consequences of any damage agent or DNA repair defect that creates extra mutations in the spermatogonia or oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for avoiding and repairing mutations in their reproductive cells. Consistent with this, we show that mutation rates in the reproductive cells are inversely correlated with generation time; in contrast, the number of germline mutations that occur during prepuberty development trends weakly upward as generation time increases. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold.

Physical exercise activates a PVN–NAc oxytocin circuit to relieve stress-induced depressive-like behaviors

Physical exercise is known to reduce depression, but the underlying brain mechanisms remain unclear. Based on a chronic restraint stress model in mice, we showed that 4-wk treadmill exercise profoundly maintained normal neural activity in the nucleus accumbens (NAc), in association with the prevention of depressive-like behaviors. Microarray analysis conducted in the NAc revealed that the oxytocin (OT) receptor displayed the most significant differential expression, implying a crucial involvement of OT signaling in exercise-induced antidepressant effects. In vivo fiber photometry revealed disrupted OT release in the NAc and altered activity of OT neurons in the paraventricular nucleus (PVN) and their projections to the NAc in stressed mice, which were restored by exercise. Moreover, we found that stress-induced depressive-like behaviors were prevented by activation of the PVN–NAc OT circuit. Additional inhibition of the PVN–NAc OT circuit blocked the antidepressant effects of exercise in stressed mice. In summary, our findings reveal a critical role of the PVN–NAc OT circuit in regulating depressive-like behaviors, which is required for the antidepressant effects of exercise. This neural circuit mechanism provides an explanation for brain network adaptations upon exercise and also suggests a promising therapeutic target for depression.

Click-constructed modular signal aptamer chimeras enable receptor-independent degradation of membrane proteins

Cell-membrane proteins are critical mediators of signal transduction, playing essential roles in disease occurrence and progression. The emerging LYTACs (Lysosome-targeting chimeras) technology combines drug-targeting strategies with lysosomal degradation, providing a novel approach to drug development and offering new possibilities for disease therapy. However, the clinical applicability of current LYTAC degraders is limited by the variable expression of lysosome-targeting receptors (LTRs) in tissues. To overcome this limitation, we herein hijacked a YXXØ sorting signal that derived from lysosome-associated membrane protein 2a (LAMP-2a) to develop a signal aptamer platform (SApt), which exhibits high specificity for targeting membrane proteins and inducing efficient lysosomal degradation. SApts were synthesized by conjugating the YXXØ signal peptide to the aptamer’s terminus through a click reaction. Our study demonstrated that SApts efficiently degrade disease-associated membrane proteins, such as PTK7, Met, and NCL, based on the inherent signals rather than specific LTR. The potent antitumor efficacy of SApts was further confirmed in a xenograft tumor model, where in vivo degradation of PTK7 was observed. Collectively, our work provides insights into the development of a simple and universal lysosomal degradation platform with potential translational value in clinical treatment.