Browse Articles
Discover research articles across all indexed journals
On the potential for strategic behavior in jurisdictional REDD+
Given well-known credibility issues in project-based avoided-deforestation credits and over $3 billion in committed credit purchases under ART TREES, the voluntary carbon market is increasingly moving toward jurisdictional approaches to Reducing Emissions from Deforestation and Forest Degradation (REDD+) as a source of credits. We test whether existing approaches to jurisdictional REDD+ create new incentives for strategic behavior that could undermine the additionality of these credits. Using global remotely sensed forest change data from all jurisdictions eligible for jurisdictional REDD+ programs in the voluntary carbon market, we examine existing jurisdictional baseline approaches. We find that jurisdictional approaches create predictable opportunities for jurisdictions to generate credits without requiring new policy action, while discouraging the enrollment of jurisdictions with increasing rates of deforestation. We show that two simple metrics predict over 30% of baseline errors and that if jurisdictions condition their enrollment on such metrics, they could generate millions of nonadditional credits. Despite this, we do not find systematic evidence that jurisdictions have exploited this information thus far. However, approximately half of enrolled jurisdictions exhibit significant temporary increases in deforestation immediately before crediting begins. This suggests anticipatory forest clearing by private landowners expecting future restrictions with Jurisdictional REDD+ enrollment. As jurisdictional REDD+ credits account for a growing share of voluntary carbon markets, these findings reveal both reassuring governance outcomes and critical vulnerabilities requiring methodological reform.
Detecting gene–environment interactions to guide personalized intervention: Boosting distributional regression for polygenic scores
Polygenic risk scores can be used to model the individual genetic liability for human traits. Current methods primarily focus on modeling the mean of a phenotype while neglecting the variance. However, genetic variants associated with phenotypic variance can provide important insights into gene–environment interaction studies. We propose snpboostlss, a cyclical gradient boosting algorithm for a Gaussian location-scale model to jointly derive sparse polygenic models for both the mean and the variance of a quantitative phenotype. To improve computational efficiency on high-dimensional and large-scale genotype data (large n and large p ), we only consider a batch of most relevant variants in each boosting step. We investigate the effect of statins therapy (the environmental factor) on low-density lipoprotein in the UK Biobank cohort using the snpboostlss algorithm. We find evidence of an interaction between statins usage and the polygenic risk scores for phenotypic variance in both cross-sectional and longitudinal analyses. Particularly, following the spirit of target trial emulation, we observe that the treatment effect of statins was more substantial in people with higher polygenic risk scores for phenotypic variance, indicating gene–environment interaction. When applying to body mass index, the newly constructed polygenic risk scores for variance show significant interaction with physical activity and sedentary behavior. Therefore, the polygenic risk scores for phenotypic variance derived by snpboostlss have potential to identify individuals that could benefit more from environmental changes (e.g. medical intervention and lifestyle changes).
Chronic infection perturbs the affinity hierarchy of antiviral B cells
A key function of the germinal center (GC) reaction consists in the preferential expansion and enrichment of high-affinity B cell clones. Whether and how persistent viral infection thwarts this purpose remains ill-defined. Here, we transferred monoclonal lymphocytic choriomeningitis virus–specific B cells into persistently infected hosts. High-affinity B cells expanded vigorously, forming GCs and abundant antibody-secreting cells. When failing to clear viremia or to drive viral mutational escape, the expanded B cell population contracted, ending in its quasi-complete disappearance from the spleen, a process we termed “attrition.” In stark contrast, low-affinity B cells expanded and persisted irrespective of high viral loads. B cell attrition was associated with phenotypic and transcriptional alterations including a prominent Blimp-1 transcriptional signature in high-affinity GC B cells. Blimp-1-deficient B cells were resistant to attrition, suggesting a B cell–intrinsic process. Moreover, exogenously supplied antibody feedback prevented attrition, suggesting that the latter may have resulted from excessive antigenic stimulation. Our findings suggest that in chronic viral infection, the incessant exposure to overwhelming amounts of antigen perturbs B cell affinity hierarchies by preferentially dysregulating high-affinity B cells.
ASB9 promotes ubiquitin-mediated degradation of TNP2 to facilitate histone-to-protamine transition in humans and mice
During spermiogenesis, nuclear remodeling occurs where histones are sequentially replaced by transition proteins (TNPs) and protamines, a process essential for sperm maturation. Although the degradation of histones and TNPs is thought to be essential for sperm nuclear remodeling, the underlying mechanisms, particularly those governing TNP degradation, remain poorly understood. In this study, we investigated the role of the ankyrin repeat-containing SOCS box protein 9 (ASB9) during spermiogenesis and found that its deficiency causes TNP2 retention, leading to a failure of the histone-to-protamine transition in both humans and mice. This disruption consequently causes male infertility, characterized by sperm head malformation and impairments in fertilization and early embryonic development. Mechanistically, we found that ASB9 assembles a testis-specific Cullin-RING ligase (CRL) complex—TNP2–ASB9–ELOB/C–CUL5–RBX1—that mediates the ubiquitin-dependent degradation of TNP2 to facilitate the histone-to-protamine transition during spermiogenesis. Collectively, our study uncovers the mechanism underlying TNP2 degradation and highlights the critical role of ASB9 in male fertility through the CRL complex-mediated ubiquitination pathway, thereby expanding the fundamental understanding of nuclear remodeling during spermiogenesis.
Spirocyclic β-lactone secondary metabolites modulate spliceosome function
Spirocyclic β-lactones (SβLs) are ring-strain activated natural products produced by actinomycetota, possessing potent and selective cytotoxicity, and with an unknown pharmacological mechanism. To further the understanding of their mechanism of action and the discovery of new SβLs, we obtained a series of known and previously not isolated SβLs from Streptomyces platensis , which contained a cryptic SβL-producing gene cluster. Utilizing single cell Multiplexed Activity Metabolomics to assess a panel of regulated cell injury and cell death markers in metabolomic arrays tested against MV-4-11 cells, phosphoprotein-S6 phosphorylation inhibition was observed for several metabolomic features, prompting us to prioritize these metabolites for structure elucidation. Several compounds were isolated including one new variant, permitting correlation of a cryptic biosynthetic gene cluster entry for oxazolomycin D (OxD) family metabolites. Cytotoxicity and flow cytometric structure–activity relationships for isolated analogs were determined using an expanded phospho-flow metabolism marker panel suggesting that SβLs possess two pharmacophores: a mixed polyketide component, involved in target engagement and inhibition, and a nonribosomal peptide synthetase-derived covalent β-lactone warhead, contributing to cytotoxicity. Global cellular thermal proteome profiling analysis of OxD treated cells implicated potent interaction with and modulation of spliceosome associated proteins. Spliceosome-associated functional changes were validated by alternate splicing analysis upon induction by OxD. As aberrant RNA splicing occurs in nearly all cancer types, the spliceosome-associated cellular response profiles of OxD define an unexplored opportunity for therapeutic development in cancers dependent upon alternative splicing.
Graph statistics theory of individualized quantitative genetics under haplotype-resolved genome assembly
Quantitative genetics is essential for genetic dissection of complex traits, yet the existing theory fails to illustrate a comprehensive landscape of genetic control mechanisms driving phenotypic variation and evolution. Here, we develop a statistical approach to assemble all genome loci into omnigenic interactome networks from diplotyped sequencing data. Such networks can not only capture dominance, epistasis, and pleiotropy and leverage these genetic concepts as bidirectional, signed, and weighted interactions among alleles and nonalleles, but also establish a framework for dissecting the genetic architecture of any single individual. While traditional approaches can only estimate coarse-grained genetic parameters at the population level, our approach can portray a fine-grained picture involving how each allele acts and interacts with every other allele for a single individual, thus facilitating its genome editing and genome engineering. By analyzing transcriptomic data of two diplotyped cultivars of a woody plant, our approach can interpret the genetic mechanisms underlying this species’ cold resistance and interorgan communication. Our network-centric approach, generalized as a graph statistics theory, builds the foundation of individualized quantitative genetics, a theory that can make genetics even more transformational to precision breeding or precision medicine.
Descent from a common ancestor restricts exploration of protein sequence space
How functional protein sequences are distributed in sequence space is fundamentally important for evolutionary theory and protein design, particularly if a large diversity of protein functions are hidden in evolutionarily unexplored areas of the sequence space. However, this question is understudied in part because experimental and computational studies use extant sequences as a starting point to study sequence space. Here, we study whether extant sequences are representative of the entire functional sequence space. Across thousands of protein families from vertebrates and bacteria we calculate the dimensionality and the volume of sequence space occupied by extant homologs. We find that the observed dimensionality and volume of extant sequence space are minuscule, many orders of magnitude smaller than what we estimated using a model of protein evolution. Simulating sequence evolution we then quantify the impact of phylogeny, selection, and epistasis on restricting the evolutionary exploration of sequence space. We find that sequence evolution from a single common ancestor, or a single point of origin in sequence space, is by far the largest limiting factor that reduces the dimensionality and volume of extant sequence space. These results indicate that there are vast areas of functional sequence space that have not been explored in evolution because of the excessive restrictions on natural exploration of the protein sequence space imposed by the point of origin effect. We suggest that protein design methods that rely on extant sequences may be limited in their ability to discover truly novel functions.
Non-ergodicity in ecology and evolution
Stochasticity plays an important role in all biological systems. The standard way to deal with stochasticity involves averaging over an ensemble of independent realizations. However, such mean statistics need not accurately reflect the typical outcomes in any finite sample unless the system satisfies the property of ergodicity, which guarantees that each trajectory will over time experience the same statistics as the entire ensemble. Here, we argue that, in contrast, non-ergodicity might instead be the rule rather than exception in real biological systems and investigate its implications for eco-evolutionary dynamics through three case-studies. First, we show how demographic stochasticity leads to ergodicity breaking where the asymptotic growth rate carries a signature of the initial condition. This motivates us to define a mutant establishment threshold, which quantifies a critical population size above which the typical mutant population starts to grow. Second, we consider environmental stochasticity and demonstrate that eco-evolutionary feedback can lead to non-ergodic dynamics, which has the important consequence that the fitness of a genotype cannot be simply averaged over the environments. Finally, we show how in a metapopulation structure the evolutionary dynamics within a typical subpopulation can deviate from the ensemble dynamics in the entire metapopulation, which is sufficient to explain the evolution and persistence of cooperation despite a fitness cost.
Deuterated perovskite for room temperature spin device
Moiré excitons in generalized Wigner crystals
Moiré superlattices of transition-metal dichalcogenide bilayers host strong Coulomb interactions residing in narrow electron bands, leading to correlated insulating states at fractional carrier doping densities, known as generalized Wigner crystals. In excited states, the formation of moiré excitons can be fundamentally shaped by the Wigner-crystal ground states, manifesting an intricate interplay between electronic and excitonic correlations. However, the microscopic description of these Wigner crystalline excitons (WCEs) remains elusive, largely subject to speculations, and is further needed for the understanding of exotic excitonic phases (e.g., exciton insulators and exciton density waves) and their unique properties (e.g., anomalous exciton diffusion). Here, using first-principles many-body GW –Bethe–Salpeter equation calculations, we directly reveal the internal structures of WCEs in angle-aligned MoSe 2 /MoS 2 moiré heterostructure at hole fillings of 1/3 and 2/3. Our results uncover the propagation of correlation effects from the ground state to excited states, shaping the real-space characteristics of WCEs. The strong two-particle excitonic correlations dominate over the kinetic energy of free electron–hole pairs, in analog to the strong single-particle correlations of flat bands. We propose that such unusual excited-state correlation effects of WCEs can be experimentally probed by photocurrent tunneling microscopy (PTM). Our work provides a microscopic understanding of strongly correlated WCEs, suggesting them as a highly tunable mixed boson-fermion platform to study many-body interactions and phenomena.
Spectral signature of periodic modulation and shifting of pseudogap state in moiré system
Background selection in recombining genomes and its consequences for the maintenance of variation in complex traits
Background selection (BGS)—the reduction of linked neutral diversity via the purging of deleterious mutations—is a pervasive force in genomic evolution. However, its impact on complex phenotypes remains poorly understood because classical theory treats fitness effects as fixed rather than emerging from a phenotype-to-fitness map. Here, we investigate the impact of BGS across three phenotypic selection frameworks: exponential directional, a liability threshold model, and stabilizing selection. First, we develop an effectively nonrecombining block approximation for the site frequency spectrum (SFS) and show that this framework accurately describes the skew in the SFS in the weak mutation regime typical of humans. Second, we show that phenotypic impacts of BGS depend on how selection is coupled across loci. In the liability threshold model, strong synergistic epistasis generates a global compensation mechanism—driven by tiny shifts in the mean phenotype—that propagates BGS effects to strongly selected variants otherwise immune to linked selection. This coupling reduces genetic variance across almost the entire effect-size distribution by an amount determined by a nonlinear average of local effective population size reductions across the genome. Conversely, under stabilizing selection, BGS can counterintuitively increase genetic variance. This occurs because BGS shifts strongly selected sites into the weakly selected underdominant regime where they persist at intermediate frequencies longer than in the equivalent directional selection model. Our results inform both longstanding evolutionary conversations regarding synergistic epistasis and efforts to model the impact of background selection on individual variants in recombining genomes.
Pushing the limits of fluorescence imaging with a restoration neural network aggregating large-view statistics
Retinol saturase in the mitochondria antagonizes IDH2 and GLUD1 acetylation to mediate heart repair
Facilitating endogenous cardiomyocyte proliferation has emerged as an important strategy for cardiac repair. Conserved retinol saturase (Retsat) functions in producing all-trans 13,14-dihydroretinol in the endoplasmic reticulum (ER). However, Retsat’s role and mechanism in heart regeneration remain unclear. Here, we uncover that Retsat is upregulated in cardiomyocytes during cardiac regeneration in mice. Cardiomyocyte-specific Retsat knockin promotes cardiac regeneration and improves cardiac function after injury. Conversely, cardiomyocyte-specific knockout of Retsat inhibits heart regeneration in neonatal mice. Surprisingly, Retsat drives cardiomyocyte proliferation independently of its classical retinol saturase activity in the ER. Retsat also localizes in cardiomyocyte mitochondria, and mitochondrial-specific overexpression of Retsat can stimulate cardiomyocyte proliferation and heart repair after injury. Mechanistically, Retsat in the mitochondria acts as an antagonist of Idh2 and Glud1 acetylation, reducing their acetylation levels and enhancing their activities. Furthermore, Retsat enters mitochondria by interacting with Tom70 and Tim23 proteins. These data suggest that targeting Retsat is a promising strategy for promoting cardiac regeneration after heart injury.
Enhancing hydrogen permeation barrier performance of ErCo2 magnetic refrigeration material via surface oxide layer formation
Abstract The ErCo 2 intermetallic compound exhibits a significant magnetocaloric effect at approximately 32 K and has potential applications as a magnetic refrigeration material for hydrogen liquefaction. However, exposure to a hydrogen atmosphere may lead to hydride formation, which weakens the magnetocaloric effect. Thus, preventing hydrogen permeation into ErCo 2 is crucial. Herein, we enhance the hydrogen permeation barrier (HPB) performance of ErCo 2 particles by using electroless Cu plating followed by oxidation treatment to form a CuO layer with a thickness of a few micrometers. In experiments, ErCo 2 particles, with a 1.5- to 5-µm-thick CuO surface layer, exhibited a large magnetic entropy change of 24 J kg⁻¹ K⁻¹ even after exposure to a H 2 atmosphere at 1.27 MPa and 296 K for 7 d. Experimental analyses and first-principles calculations revealed the potential of CuO as an HPB material for magnetic refrigeration.
Single-molecule dissection of CFTR folding defects and pharmacological rescue
Cystic fibrosis is a lethal genetic disorder caused by misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, most commonly due to the ΔF508 mutation. Despite extensive study, CFTR’s folding process has remained inaccessible to direct observation. Here, we apply single-molecule magnetic tweezers to resolve the complete folding trajectories of wild-type and ΔF508 CFTR with near–amino acid resolution. We find that CFTR follows a hierarchical, template-guided folding pathway in which N-terminal domains scaffold downstream folding. This mechanism tightly couples the free energy states of intermediates, allowing ΔF508-induced instability to propagate across the folding pathway. Pharmacological correctors, in synergy with ATP, reshape the entire folding energy landscape by catalyzing transitions rather than simply stabilizing end states. These long-range, allosteric effects reveal a folding-embedded regulatory network. Our work provides a quantitative framework for mapping multidomain protein folding and therapeutic rescue, offering a broadly applicable strategy for interrogating rare mutations and accelerating structure-based drug discovery.
Lactate metabolism reprogramming through orthogonal tandem catalysis to reverse intervertebral disc degeneration
Metabolic trajectories in developing human neocortical neurons
The shift from glycolysis to oxidative phosphorylation is a key step in neural differentiation. Yet, the timing of metabolic rewiring in the development from progenitors to neurons remains elusive, especially in human corticogenesis. To bridge this gap, here we adopted a unique cell platform based on neocortex-derived human neuroepithelial stem cells, modeling their physiological transition into functional neurons in a 4-mo longitudinal study and until the acquisition of electrophysiological competence. Using quantitative proteomics, combined with NAD(P)H fluorescence lifetime imaging and metabolomics, we investigated the entire differentiation process and describe how metabolic pathways drive cortical neuron maturation. The prevalent metabolic adaptations were then confirmed in a human neocortical specimen. This study provides a spatiotemporal map of neocortical metabolism during development and offers a framework to investigate human neurometabolic disorders.
Alpibectir–Ethionamide combination (AlpE) for the treatment of tuberculosis
Abstract Ethionamide (Eto) and prothionamide (Pto) are second-line antibiotics used for tuberculosis (TB) treatment. Both are prodrugs whose antibacterial activity depends on bioactivation by oxidases in Mycobacterium tuberculosis , including the Baeyer-Villiger monooxygenase MymA. Through biophysical, genetic, and cellular assays, we show that the clinical candidate alpibectir (Alp, BVL-GSK098) binds the transcriptional regulator VirS, increasing MymA expression and potentiating Eto and Pto activity. Alpibectir also boosts the activity of the corresponding host-derived sulfoxide metabolites. We additionally show that alpibectir exhibits intrinsic antibacterial activity via overexpression of the mymA operon. The alpibectir/Eto (AlpE) combination is rapidly bactericidal in vitro and in mice, lowers the frequency of spontaneous resistance of Eto, and remains active on Eto- and isoniazid-resistant strains, including isolates with inhA promoter mutations. Alpibectir was safe in a Phase 1 human clinical trial. Together with the potentiation data presented here, these findings highlight its potential to optimize TB chemotherapy by reducing Eto/Pto doses, which can minimize dose-related side effects, enhancing adherence.