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Letter by Meng et al Regarding Article, “An Aberrant Resurgence of Endogenous Retroviruses Prompts Myocarditis and Heart Failure”

How to revive science in America

Second- and Third-Generation BCR-ABL Tyrosine Kinase Inhibitors and the Risk of Pulmonary Arterial Hypertension: A Prevalent New-User Design

BACKGROUND: BCR-ABL (fusion between the Abelson [Abl] tyrosine kinase gene at chromosome 9 and the break point cluster [Bcr] gene at chromosome 22) tyrosine kinase inhibitors (TKIs) have been increasingly linked to pulmonary arterial hypertension (PAH) since 2009, although supporting evidence is limited. Our objective was to evaluate the risk of PAH associated with second- and third-generation BCR-ABL TKIs compared with imatinib in adults. METHODS: We employed a prevalent new-user design that emulates a randomized trial within the French national health care database population between 2008 and 2024. Thus, subjects initiating a second- and third-generation BCR-ABL TKI were matched on time and propensity score with users of the first-generation BCR-ABL TKI, imatinib. Patients were followed to occurrence of the primary outcome (ie, new onset of PAH), switch to another BCR-ABL TKI, death from any cause, end of registration within the database, or end of the study period, whichever came first. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression models, and incidence rates and corresponding 95% CIs were calculated using the Poisson distribution. RESULTS: Six thousand six hundred twenty-five dasatinib (age 59.7±15.2 years, 44.0% women), 5205 nilotinib (age 55.4±15.0 years, 44.2% women), 2421 bosutinib (age 63.8±14.2 years, 42.1% women),1358 ponatinib (age 57.3±14.9 years, 46.1% women), and 922 asciminib (age 64.3±13.8 years, 43.7% female) new users were each matched with the maximum of available imatinib users on time-conditional propensity score and on duration of prior imatinib use (prevalent users). Dasatinib use was associated with a 9-fold increased risk of PAH compared with imatinib (1829 versus 43 events per million persons per year; HR=8.89 [95% CI, 5.30–14.92]). Bosutinib and ponatinib were associated with HRs of 10.76 (95% CI, 4.68–24.73) and 7.74 (95% CI, 2.33–25.70) respectively, with most cases occurring in patients previously exposed to dasatinib. Nilotinib and asciminib were not associated with an increased risk of PAH. CONCLUSIONS: This study, designed to emulate a randomized trial, suggests that, in French patients with chronic myeloid leukemia treated with BCR-ABL TKIs, dasatinib use is associated with a higher risk of PAH compared with imatinib, while bosutinib and ponatinib exposure may aggravate or trigger a recurrence of PAH in patients with preexisting dasatinib exposure. Whether bosutinib and ponatinib could induce PAH without preexposure to dasatinib remains to be explored.

VIBES: A multiscale modeling approach integrating within-host and between-hosts dynamics in epidemics

Infectious disease spread is a multiscale process composed of within-host (biological) and between-host (social) drivers and disentangling them from each other is a central challenge in epidemiology. Here, we introduce VIBES, a multiscale modeling framework that explicitly integrates viral dynamics based on patient-level data with population-level transmission on a data-driven network of social contacts. Using SARS-CoV-2 as a case study, we analyze three emergent epidemic properties, namely the generation time, serial interval, and presymptomatic transmission. First, we established a purely biological baseline, thus independent of the reproduction number ( R ), from the within-host model, estimating a generation time of 6.3 d for symptomatic individuals and 43.1% presymptomatic transmission. Then, using the full model incorporating social contacts, we found a shorter generation time (5.4 d at R = 3.0) and an increase in presymptomatic transmission (52.8% at R = 3.0), disentangling the impact of social drivers from a purely biological baseline. We further show that as pathogen transmissibility increases ( R from 1.3 to 6), competition among infectious individuals shortens the generation time and serial interval by up to 21% and 13%, respectively. Conversely, a social intervention, like isolation, increases the proportion of presymptomatic transmission by about 30%. Our framework also estimates metrics that are challenging to obtain empirically, such as the generation time for asymptomatic individuals (5.6 d; 95%CI: 5.1 to 6.0 at R = 1.3). Our findings establish multiscale modeling as a powerful tool for mechanistically quantifying how pathogen biology and human social behavior shape epidemic dynamics as well as for assessing public health interventions.

Elevated Pulmonary Artery Wedge Pressure in Group 1 Pulmonary Hypertension

BACKGROUND: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy ( P <0.0002), left ventricular strain impairment ( P <0.0001), and decreased left ventricular compliance ( P <0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction ( P <0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P <0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P <0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Maternal Krüppel-like factor 2 (KLF2)+ CD4 T cells promote fertility and fetal tolerance

Pregnancy requires expanded maternal tolerance to semiallogeneic fetal-expressed antigens to protect against fetal loss and other pregnancy complications. Our understanding of how this biological imperative works remains uncertain. Here we show pregnancy primes expansion of antigen-experienced Krüppel-like factor 2 (KLF2)+ CD4 T cells with fetal specificity, and that these maternal cells play an essential role in optimal fertility and protecting against fetal resorption. Antigen-experienced KLF2+ CD4 cells purified from pregnant dams are poised for IL10 production and suppress responder T cell proliferation in coculture. Mice with conditional loss of KLF2 in T cells become pregnant less efficiently after allogeneic mating with genetically discordant males, but not after syngeneic mating with genetically identical males. Impaired fertility is associated with diminished and variable early pregnancy progesterone levels, whereas progression from mating to pregnancy is restored with exogenous progesterone. To bypass fertility defects, complementary experiments show that initiating induced KLF2 deletion in CD4 T cells midgestation causes fetal resorption associated with expansion of activated fetal-specific CD8 effector T cells across maternal tissues, particularly in the uterine draining lymph node and at the maternal–fetal interface. Reciprocally, these phenotypes are overturned with CD8 T cell depletion or in mice reconstituted with CD4 cells from wild-type donors which upregulate KLF2 expression in pregnant recipients. These findings demonstrate that maternal KLF2+ CD4 T cells promote fetal tolerance and fertility, particularly during allogeneic pregnancy.

Myocardial Infarction, Precision-Engineered T Regulatory Cells to the Rescue

Targeting the ANGPTL4/NRP1/ABL1/RAD51 axis reverses cisplatin resistance by impairing DNA damage repair in head and neck cancer

Drug chemoresistance remains a major reason of treatment failure in cancer patients. In head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer worldwide, cisplatin chemotherapy remains the gold standard for advanced tumors but often faces loss of responsiveness and the drawback of relapse. We previously showed that the metabolic and angiogenic factor angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of oral dysplasia and HNSCC. We also found that through interaction with Neuropilin 1 (NRP1), ANGPTL4 activates proliferative and migratory pathways that contribute to HNSCC development. Using HNSCC xenografts, patient tumor-derived organoids, tumor spheroids, and HNSCC cell lines, CAL27, HN13, and HN4, here we provide evidence of the role of ANGPTL4 in the development of platinum-based chemoresistance in HNSCC through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting phosphorylation of RAD51 recombinase in Tyr 315/54 through an NRP1/ABL1-dependent mechanism. Pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results reveal a role for ANGPTL4 in RAD51-dependent DNA repair and suggest that ANGPTL4/NRP1/ABL1/RAD51 may serve as an alternative therapeutic target for HNSCC.

Engineered Regulatory T Lymphocytes Promote Infarcted Heart Repair

BACKGROUND: Myocardial infarction (MI) initiates a dysregulated healing process characterized by excessive fibrosis and unresolved inflammation, resulting in suboptimal cardiac repair in clinical settings. Regulatory T lymphocytes (Tregs) naturally orchestrate cardiac repair after MI, but their therapeutic potential is limited by inefficient homing to ischemic myocardium. We hypothesize that FAP (fibroblast activation protein)–specific CAR (chimeric antigen receptor) engineering overcomes this barrier by enabling precise delivery of Tregs to FAP⁺-enriched infarct zones, thereby focally amplifying reparative activity within injured myocardium. METHODS: In murine MI and ischemia–reperfusion models, C57BL/6J mice were injected with lentivirus-engineered FAP CAR Tregs (FCTRs) or mock Tregs derived from wild-type, IL-10 (interleukin-10) knockout ( IL-10 −/− ) or Areg (amphiregulin) knockout ( Areg −/− ) donors after infarction. The cardiac outcomes and underlying mechanisms mediated by FCTRs were thoroughly analyzed. Systemic toxicity was evaluated to ensure safety. RESULTS: Intravenous injections of FCTRs on day 3 after injury led to targeted engraftment in the damaged cardiac tissue. Compared with controls treated with vehicle or mock Tregs, mice receiving FCTRs exhibited remarkable cardiac functional recovery in both MI and ischemia–reperfusion models by day 14, accompanied by reduced fibrosis and decreased inflammation, all achieved without compromising the integrity of cardiac tissue. Absence of IL-10 in the engineered CAR Tregs abrogated their therapeutic efficacy, whereas the ablation of Areg showed no functional impairment. We further demonstrated that the beneficial effects of FCTRs depended on IL-10 production, which inhibited pathogenic myofibroblast differentiation by suppressing Smad2/3-dependent signaling. In addition, IL-10 secretion by these engineered Tregs promoted the polarization of inflammatory monocytes into reparative M2 macrophages and resolved excessive inflammatory responses. No treatment-related adverse effects were observed. CONCLUSIONS: We pioneered FAP-targeted CAR Tregs as a dual-action precision therapy resolving post-MI fibrosis and inflammation through IL-10–dependent mechanisms. By spatiotemporally suppressing myofibroblast differentiation and remodeling immune niches, this strategy prevents maladaptive remodeling while accelerating functional recovery, establishing a translational platform for fibrotic diseases across organ systems.

VAMP8 function reveals tight linkage between endocytic recycling and endocytosis

Clathrin-mediated endocytosis (CME) is a multistage process that involves the initiation and stabilization of clathrin-coated pits (CCPs) that invaginate and finally detach from the plasma membrane to form clathrin-coated vesicles (CCVs). Given that Soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins are essential for downstream vesicle targeting and fusion events, their recruitment into nascent CCVs has been suggested to be a prerequisite for CME progression. However, which and how SNARE proteins regulate CME remains to be explored. Here, we showed that siRNA-mediated knockdown of the R-SNARE, vesicle-associated membrane protein 8 (VAMP8) impairs CCP initiation, stabilization, and invagination and strongly inhibits CME. Mechanistically, recruitment of VAMP8 to CCVs is not required for CME. Instead, depletion of VAMP8 inhibits recycling of endocytic cargoes and as exemplified here by transferrin receptor, skews their trafficking toward lysosomal degradation. VAMP8 depletion therefore indirectly impairs CCV formation and inhibits CME by depleting endocytic cargo. Overall, our study provides insights into the crosstalk between endocytosis and endocytic recycling of CME cargo and demonstrates the critical role for cargo recruitment in stabilizing nascent CCPs to regulate CME.

Response by Xiong and Zhang to Letter Regarding Article, “An Aberrant Resurgence of Endogenous Retroviruses Prompts Myocarditis and Heart Failure”

Large future genetic diversity losses are predicted from conservation indicators even with habitat protection

Genetic diversity within species underpins evolutionary adaptation and has recently been included as a target for protection in the United Nations’ Global Biodiversity Framework (GBF). Yet, we lack mathematical tools to estimate past genetic diversity loss across species—or predict future losses—based on demographic proxies used in conversation policy. To fill this gap, we developed a spatiotemporal framework to predict the dynamics of genetic diversity under realistic habitat change scenarios, calibrated with population-scale genomic data from 29 plant and animal species. To estimate how much genetic diversity has already been lost, we analyzed habitat area and population size losses for 4,611 species from the last five decades, using data from the Living Planet Index, the Red List, and new GBF indicators. We estimate that species have already lost 1 to 13% of π genetic diversity. Furthermore, we predict that genetic diversity losses lag behind population and habitat area declines, such that an average of 6 to 45% of genetic diversity will be lost under different scenarios even if population sizes or habitats do not decline further. Our results highlight that safeguarding existing habitats is insufficient to maintain the genetic health of species, and that genetic monitoring from proxy indicators will only detect major genetic diversity losses after it is already too late.

Response by Hundemer and Vaidya to Letter Regarding Article, “Subclinical Primary Aldosteronism and Major Adverse Cardiovascular Events: A Longitudinal Population-Based Cohort Study”

Multigenerational and gender-symmetric transmission of migration behaviors in historical Quebec

Migration decisions are embedded in social and family trajectories that escape traditional data sources, which tend to observe individuals in isolation. Genealogical microdata now make it possible to trace these dynamics over long time horizons. This paper documents how prior generations’ migration histories shape future internal migration behavior, leveraging rich historical microdata spanning over two centuries and multiple generations at the scale of an entire population (Quebec, Canada; 1621–1861). As the cultural norm preserved women’s maiden names throughout the life course, genealogies could be assembled as exhaustively for women as for men. Using residential trajectories reconstructed from these linked vital data, the study shows that the mobility of married couples depends on both spouses’ parents’ and grandparents’ migration histories. Descendants of migratory people are substantially more likely than their peers from sedentary families to migrate themselves, the effect of the grandparental generation being about half that of the parental generation. These effects compound such that couples with multiple migratory ascendants are even more likely to migrate. Moreover, husbands’ and wives’ migration backgrounds are equally predictive of their joint mobility decisions, suggesting a substantial role of women in shaping couples’ mobility and challenging the conventional assumption that migration decisions were historically made by men. These results reveal deep family history as an underexplored axis of migrant selection. The long-lasting influence of family should be integrated in migration theories.

Correction for Liaño-Pons et al., Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment

Controlled propagation of soliton bullets in an engineered strain field

Predicting and controlling the propagation of nonlinear responses in materials is critical to a range of fields, from the manipulation of single electrons in quantum optics to the understanding of crack propagation and failure of quasi-brittle materials. Solitons, which are highly localized strain patterns that propagate and persist due to nonlinear feedback mechanisms, can be produced in liquid crystal (LC) films under high-frequency AC electric fields. In previous work using uniformly oriented films of LC, soliton bullets propagated in one preset direction perpendicular to the far-field orientation of the LC director. Here, we show that confinement of the LC between asymmetric surfaces and the introduction of strain can provide a versatile mechanism to modulate the propagation direction of solitons. Specifically, we find that soliton bullets propagate along two oblique axes, where the angle can be dynamically modulated with the electric field frequency. The origins of this behavior are understood through theory and simulations, where the forces driving soliton motion are analyzed. Importantly, asymmetric flexoelectric torques lead to frequency-dependent oblique trajectories in the presence of hybrid LC anchoring, with numerical simulations predicting asynchronous out-of-plane fluctuations that are verified in experiments. Overall, our results highlight the interplay between the nonlinear action of external fields and the far-field strain on soliton propagation. They also show that confinement can be used to control the direction of propagation of nonlinear signals and demonstrate how LCs can be used as model systems to test and predict the effects of nonlinear excitations in new material designs.

Energy landscape statistics and thermodynamics of a machine-learned model of water

Water’s anomalous thermodynamic behavior arises from the presence of intricate hydrogen-bond networks that are highly sensitive to many-body interactions, challenging molecular modeling for decades. The ongoing machine learning revolution has opened the possibility of performing quantum-accurate liquid-structure calculations at affordable computational cost. Beyond reproducing water’s thermodynamic properties with high fidelity, such simulations provide a stringent benchmark for theoretical models and a route to deeper physical understanding. We use the recently developed machine-learned Deep Potential Many-Body Polarizable water model to show that the free energy of supercooled water can be accurately modeled with the potential energy landscape formalism. The resulting equation of state predicts the presence of a liquid–liquid critical point in excellent agreement with recent estimates. Together with previous studies based on empirical classical water potentials, it confirms that the potential energy landscape of water is Gaussian, providing a unifying framework for extracting thermodynamic behavior across model complexity, from empirical force fields to quantum-trained neural network models.

Monoclonal antibodies from COVID-19 convalescent patients target cryptic epitopes for broad SARS-CoV-2 neutralization

The COVID-19 pandemic, which has resulted in over seven million global fatalities, poses a substantial threat to public health and precipitated a global economic crisis. Emerging variants of concern (VOCs) with enhanced transmissibility and improved immune evasion may compromise the efficacy of current antiviral and immunotherapies, necessitating comprehensive investigations into the immune response to SARS-CoV-2. The conformational dynamics of the receptor binding domain in SARS-CoV-2 spike and the presentation of neutralizing antibody epitopes influence viral transmission and infection rates. In this study, we have identified highly conserved non-receptor-binding motif epitopes for two potent monoclonal antibodies (mAbs), TAU-1109 and TAU-2310, isolated from convalescent human patients, which contribute to the broad neutralizing activity of these mAbs against all the circulating VOCs, including the recently emerged Omicron subvariants. We employed high-resolution structural data in conjunction with systematic biochemical investigation to elucidate the neutralization mechanism of TAU-1109 and TAU-2310. The mechanism involves antibody-mediated destabilization of the spike trimer, resulting in the premature shedding of the S1 subunit and rendering the spike incapable of mediating host cell entry. The identification of conserved cryptic epitopes in our study advances the mechanistic understanding of immune response against SARS-CoV-2, providing alternative avenues for the development of universal therapeutic antibodies and vaccines to combat COVID-19.

Uncovering the embodied dimension of the wandering mind

When at rest, the mind becomes preoccupied with self-generated thoughts, commonly known as mind-wandering. While the social, autobiographical, and temporal features of these thoughts have been extensively studied, little is known about how frequently the wandering mind turns toward the interoceptive and somatic body. To map this underexplored component of “body-wandering,” we conducted a large-scale neuroimaging study in 536 healthy participants, expanding a retrospective multidimensional experience sampling approach to include probes targeting visceral and somatomotor thoughts. Our findings reveal a robust interindividual dimension of body-wandering characterized by negative affect, high autonomic arousal, and a reduction in socially oriented thoughts. Despite this negative tone, individual differences in the propensity for body-wandering thoughts were associated with lower self-reported symptoms of ADHD and depression. Multivariate functional connectivity analyses further revealed that affective, body-oriented thoughts are related to a pattern of thalamocortical connectivity interlinking somatomotor and interoceptive-allostatic cortical networks. Collectively, these results demonstrate that self-generated thoughts exhibit core embodied features which are linked to the ongoing physical and emotional milieu of the visceral body.

Receptor sequence divergence, gain, loss, duplication, and neofunctionalization drive olfactory adaptation in <i>Drosophila suzukii</i>

Shifts in ecological niches are often driven by evolutionary changes in the olfactory system, yet the underlying mechanisms remain poorly understood. To investigate this, we used Drosophila suzukii , an invasive fruit pest, as a model. Unlike most Drosophila species, which prefer overripe fruit, D. suzukii strongly prefers laying eggs in ripe fruit. We found that this shift is accompanied by pronounced changes in the odorant tuning of only a few olfactory receptor neurons (ORNs) compared to Drosophila melanogaster . Some changes are shared with its relative Drosophila biarmipes , whereas others are unique to D. suzukii . These shifts resulted not only from receptor sequence divergence but also from additional mechanisms. In one ORN, a second odorant receptor ( Or ), distinct from the ancestral Or , mediates detection of a leaf-derived odorant, while a single amino acid substitution—likely acting with additional changes—in the ancestral Or fine-tunes sensitivity to fruit-ripening esters. In two additional ORNs, four gene duplicates derived from an ancestral Or mediate tuning shifts: Two duplicates maintain responses similar to the original ORN, while two tandem duplicates confer responses in a preexisting ORN that has lost its ancestral Or . This neofunctionalization is unique to D. suzukii . Finally, we show that two of the receptors underlying these innovations are required for attraction to ripe fruit but are dispensable for egg-laying preference. Our findings reveal how receptor sequence divergence, coexpression, loss, duplication, and neofunctionalization drive sensory adaptation and ecological specialization and provide a foundation for identifying additional attractants and repellents to control D. suzukii .