Browse Articles

Study design and the sampling of deleterious rare variants in biobank-scale datasets

One key component of study design in population genetics is the “geographic breadth” of a sample (i.e., how broad a region across which individuals are sampled). How the geographic breadth of a sample impacts observations of rare, deleterious variants is unclear, even though such variants are of particular interest for biomedical and evolutionary applications. Here, in order to gain insight into the effects of sample design on ascertained genetic variants, we formulate a stochastic model of dispersal, genetic drift, selection, mutation, and geographically concentrated sampling. We use this model to understand the effects of the geographic breadth of sampling effort on the discovery of negatively selected variants. We find that samples which are more geographically broad will discover a greater number of variants as compared to geographically narrow samples (an effect we label “discovery”); though the variants will be detected at lower average frequency than in narrow samples (e.g., as singletons, an effect we label “dilution”). Importantly, these effects are amplified for larger sample sizes and fitness effects. We validate these results using both population genetic simulations and empirical analyses in the UK Biobank. Our results are particularly important in two contexts: the association of large-effect rare variants with particular phenotypes and the inference of negative selection from allele frequency data. Overall, our findings emphasize the importance of considering geographic breadth when designing and carrying out genetic studies, especially at biobank scale.

Population sequencing for phylogenetic diversity and transmission analyses

Genomic diversity in pathogen populations is foundational for evolution and adaptation. Understanding population-level diversity is also essential for tracking sources and revealing detailed pathways of transmission and spread. For bacteria, culturing, isolating, and sequencing the large number of individual colonies required to adequately sample diversity can be prohibitively time-consuming and expensive. While sequencing directly from a mixed population will show variants among reads, they cannot be linked to reveal allele combinations associated with phylogenetic inheritance patterns. Here, we describe the theory and method for using population sequencing directly from a mixed sample, along with a minimal number of individually sequenced colonies, to describe the phylogenetic diversity of a population without haplotype reconstruction. To demonstrate the utility of population sequencing in capturing phylogenetic diversity, we compared isogenic clones to population sequences of Burkholderia pseudomallei from sputum of a single patient. Our results point to the pathogen population being highly structured, suggesting that for some pathogens, sputum sampling may preserve structuring in the lungs and thus present a noninvasive alternative to understanding colonization, movement, and pathogen/host interactions. We also analyzed population sequences of Staphylococcus aureus derived from different people and different body sites to reveal directionality of transmission between hosts and across body sites, demonstrating the power and utility for characterizing the spread of disease and identification of reservoirs at the finest levels. We anticipate that population sequencing and analysis can be broadly applied to accelerate research in a wide range of fields reliant on a foundational understanding of population phylogenetic diversity.

An Enzymatic Platform for Aniline Synthesis Through Oxidative Amination

Abstract Aniline motifs are commonly found in natural products and synthetic molecules. While chemists have developed numerous methods for constructing C(sp 2 )─N bonds, their biocatalytic counterparts in nature are primarily limited to P450‐based protein machineries. To address this limitation, we developed a biocatalytic platform for aniline synthesis based on oxidative amination of cyclohexanones. Through directed evolution of a flavin‐dependent enzyme Pt OYE, we identified several protein catalysts (e.g., OYE_G3 and OYE_M3) that exhibited activity across a broad array of substrates, enabling the preparation of 40 different secondary and tertiary anilines with various substitution patterns in up to 91% GC conversion. Mechanistic investigations revealed the improved kinetic performance of the evolved variants on the desaturation of imines. Additionally, mutations introduced through protein engineering further reduced the propensity for phenol formation. This enzymatic platform represents a highly promising application of flavin‐dependent enzymes, showcasing their great potential in organic synthesis and drug development.

Deciphering decomposition pathways of high explosives with cryogenic X-ray Raman spectroscopy

We employed cryogenic X-ray Raman spectroscopy to investigate the early-stage decomposition of the high explosive molecule hexanitrohexaazaisowurtzitane (CL-20). By systematically varying the radiation dose under cryogenic conditions, we induced the decomposition of the molecule using ionizing radiation and observed the evolution of spectral features at the carbon, nitrogen, and oxygen K edges. Through extensive first-principles calculations, we identified key intermediates in the early stages of the decomposition process, resulting from C–C and C–N bond cleavage which leads to the opening of the internal cage structure. A detailed analysis of spectral trends and fingerprints provided evidence supporting N–NO 2 homolytic cleavage as the primary initial decomposition pathway. The combination of advanced core-level spectroscopy methods and state-of-the-art theoretical calculations enabled a comprehensive characterization of the molecular changes induced by controlled radiation dose exposures. Our findings establish a benchmark for understanding the decomposition chemistry of high-explosive materials, offering important insights into their stability and reactivity under extreme conditions.

<i>CACNA1D</i> is a circadian gene and causes familial advanced sleep phase

Familial advanced sleep phase (FASP) is a heritable human sleep trait characterized by early sleep onset and offset times. We have identified five variants in five different families in the human voltage-gated calcium channel subunit alpha1 D ( CACNA1D ) that cosegregate with FASP. The variants in CACNA1D lead to altered channel dynamics in vitro. A mouse model of the E427K variant has a normal circadian period under constant darkness but displays altered phase shifts in response to light in the subjective night at circadian time (CT) 16 and CT22. Overall, these experiments establish CACNA1D as an FASP gene with altered entrainment, highlighting the ability of human genetics to uncover novel aspects of human circadian regulation.

BRCA2 reversion mutation–independent resistance to PARP inhibition through impaired DNA prereplication complex function

Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2 Δ/Δ prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably, we recovered multiple independent single guide RNAs (sgRNAs) targeting three different members ( Cdt1, Cdc6, and Dbf4 ) of the DNA prereplication complex (pre-RC), each of which independently conferred resistance to olaparib and the next-generation PARP-1 selective inhibitor AZD5305. Moreover, sensitivity to PARP inhibition was restored in Brca2 Δ/Δ , Cdc6-depleted prostate cells by knockdown of geminin, a negative regulator of Cdt1, further implicating the critical role of a functional pre-RC complex in PARPi sensitivity. Furthermore, ~50% of CRPC tumors have copy number loss of pre-RC complex genes, particularly CDT1 . Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition.

Disrupted diencephalon development and neuropeptidergic pathways in zebrafish with autism-risk mutations

Hundreds of human mutations are linked to autism and related disorders, yet the functions of many of these mutated genes during vertebrate neurodevelopment are unclear. We generated 27 zebrafish mutants with presumptive protein-truncating mutations or specific missense variants corresponding to autism-risk alleles in 17 human genes. We observed baseline and stimulus-driven behavioral changes at larval stages, as well as social behavior differences in lines tested as juveniles. Imaging whole-brain activity revealed a near identical activity map for mutations in the unrelated genes kmt5b and hdlbpa , defined by increased activity mainly in the thalamus and mesencephalon. Mutating 7 of the 17 risk genes resulted in substantial brain size differences, localized to the diencephalon in three cases and more widespread in others. Using RNA sequencing, we further defined molecular drivers of the observed phenotypes for three mutants, identifying targetable disruptions in neuropeptide signaling, neuronal maturation, and cell proliferation. This multimodal screen nominated brain regions, cell types, and molecular pathways that may contribute to autism susceptibility.

Reciprocal projections between the globus pallidus externa and cortex span motor and nonmotor regions

The globus pallidus externa (GPe) is a heterogeneous nucleus of the basal ganglia, with intricate connections to other basal ganglia nuclei, as well as direct connections to the cortex. The anatomic, molecular, and electrophysiologic properties of cortex-projecting pallidocortical neurons are not well characterized. Here, we show that pallidocortical neurons project to diverse motor and nonmotor cortical regions, are organized topographically in the GPe, and segregate into at least two distinct electrophysiological and molecular phenotypes. In addition, we find that the GPe receives direct synaptic input from deep layers of diverse motor and nonmotor cortical regions, some of which form reciprocal connections onto pallidocortical neurons. These results demonstrate the existence of a fast, bidirectional circuit between the GPe and the cortex that is ideally positioned to integrate information about behavioral goals, internal states, and environmental cues to rapidly modulate behavior.

Square Planar Ru( <i> ⁱ </i> Pr ₂ PCH ₂ CH ₂ NH) ₂ and its Role in Fast and Selective Catalytic Amine–Borane Dehydropolymerization to Form High Molecular Weight Polyaminoboranes

Abstract Addition of t BuOK to orange RuCl 2 ( i Pr 2 PCH 2 CH 2 NH 2 ) 2 forms the pink, square planar, Ru(II) complex Ru( i Pr 2 PCH 2 CH 2 NH) 2 . This is an active catalyst (ToF 250 s −1 ) for the dehydropolymerization of H 3 B·NMeH 2 to give high molecular weight polyaminoborane, [H 2 BNMeH] n ( M n  = 138 700 g mol −1 ) at low loadings (0.03 mol%). An induction period observed is due to the initial formation of a hydroxy‐hydride species, Ru( i Pr 2 PCH 2 CH 2 NH 2 ) 2 (OH)(H), prior to fast turnover.

Single-cell resolution uncovers neighboring cell subtypes that share steroidogenic capacity during fetal testis development

Historically, endocrine cells were perceived to coordinate their output in a uniform manner. Recently however, single-cell technologies have uncovered heterogeneity within these populations, indicating that individual cells may operate as independently regulated units. Using high-resolution tools such as single-molecule fluorescent in situ hybridization (sm-FISH) and single-cell RNA sequencing (scRNA-seq), we investigated the contributions of individual and the collective of fetal Leydig cells to androgen production over time during mouse testis development. Temporal profiles of intratesticular androgens alongside the expression of steroidogenic pathway genes ( Star, Cyp11a1, Cyp17a1, and Hsd3b1 ) from prenatal to perinatal testes demonstrated that the peak in gene expression preceded the peak in androgen production. Spatially, steroidogenic cells were initially observed to be concentrated toward the anterior–posterior poles along the center of the dorsal–ventral axis of the fetal testis at embryonic day (E) 13 and then expanded to a uniform distribution by E16. Next, sm-FISH using probes for individual steroidogenic pathway genes exposed the following findings: gene transcription and processing of individual and combinations of steroidogenic pathway genes are not synchronized among fetal Leydig cells; and some fetal Leydig cells express incomplete sets of genes. Further, sm-FISH and scRNA-seq data corroborated the presence of fetal Leydig and other interstitial cell types harboring incomplete sets of steroidogenic pathway genes throughout developmental stages. Taken together, these findings highlight that fetal steroidogenic gene expression is tightly regulated and that transcript presence among interstitial cell types promotes the possibility that optimal androgen biosynthesis results from a cooperative effort among neighboring steroidogenic cells.

Enhancing Efficiency and Stability of Inverted Flexible Perovskite Solar Cells via Multi‐Functionalized Molecular Design

Abstract Inverted flexible perovskite solar cells (f‐PSCs) are promising candidates for mechanical photovoltaic applications due to their ease of preparation, lightweight, and portability. However, the weak interface connections, residual strain, and the nonradiative recombination loss among adjacent layers are critical challenges that restrict f‐PSCs development. To address these issues, a functionalized molecule with multiple hydrogen bond acceptors, 4‐Carboxyphenylboronic acid (4‐BBA), is designed in the perovskite precursor for modulating perovskite crystallization, which achieves uniform and stress‐relaxation perovskite film and forms a robust bridging structure anchored at the buried interface. Theoretical calculation and experimental results show that the C═O group passivates Pb 2+ with I − vacancy defect through Lewis acid‐base interactions, reducing trap‐assisted recombination. Furthermore, the designed 4‐BBA is preferentially deposited at the buried layer interface between the perovskite and substrate, forming hydrogen bonds with the self‐assembled monolayer via B─OH bonds, creating a mechanically stable bridge between the layers. As a result, the power conversion efficiency of the champion f‐PSC reached 25.30% (25.13% certified). And the f‐PSC open‐circuit voltage set a record of 1.21V. Importantly, the unencapsulated f‐PSC using 4‐BBA retains 95.3% of its original performance after 5000 cycles at a bending radius of 10mm, demonstrating extraordinary bending stability.

Increasing boreal fires reduce future global warming and sea ice loss

Biomass burning can affect climate via the emission of aerosols and their subsequent impact on radiation, cloud microphysics, and surface and atmospheric albedo. Biomass burning emissions (BBEs) over the boreal region have strongly increased during the last decade and are expected to continue increasing as the climate warms. Climate models simulate aerosol processes, yet historical and future Coupled Model Intercomparison Project (CMIP) simulations have no active fire component, and BBEs are prescribed as external forcings. Here, we show that CMIP6 used future boreal BBEs scenarios with unrealistic near-zero trends that have a large impact on climate trends. By running sensitivity experiments with ramped up boreal emissions based on observed trends, we find that increasing boreal BBEs reduces global warming by 12% and Arctic warming by 38%, reducing the loss of sea ice. Tropical precipitation shifts southward as a result of the hemispheric difference in boreal aerosol forcing and subsequent temperature response. These changes stem from the impact of aerosols on clouds, increasing cloud droplet number concentration, cloud optical depth, and low cloud cover, ultimately reducing surface shortwave flux over northern latitudes. Our results highlight the importance of realistic boreal BBEs in climate model simulations and the need for improved understanding of boreal emission trends and aerosol–climate interactions.

Data–Knowledge‐Dual‐Driven Electrolyte Design for Fast‐Charging Lithium Ion Batteries

Abstract Electric vehicles (EVs) starve for minutes‐level fast‐charging lithium‐ion batteries (LIBs), while the heat gathering at high‐rate charging and torridity conditions has detrimental effects on electrolytes, triggering rapid battery degradation and even safety hazards. However, the current research on high‐temperature fast‐charging (HTFC) electrolytes is very lacking. We revolutionized the conventional paradigm of developing HTFC electrolytes integrating with high‐throughput calculation, machine‐learning techniques, and experimental verifications to establish a data–knowledge‐dual‐driven approach. Ethyl trimethylacetate was efficiently screened out based on the approach and enabled batteries to work under high temperatures with distinctly restricted side reactions. A stable and highly safe fast‐charging (15‐min charging to 80% capacity) cycling without Li plating was achieved over 4100 cycles at 45 °C based on 181 Wh kg −1 pouch cells, demonstrating the state‐of‐the‐art in this field.

Multiple cortical systems influence a single vibrissa muscle

What is the neural substrate that enables the cerebral cortex to control a single mystacial vibrissa and orchestrate its movement? To answer this question, we injected rabies virus into the intrinsic muscle that protracts the rat C3 vibrissa and used retrograde transneuronal transport to identify the cortical neurons that influence the muscle. A surprisingly diverse set of cortical areas is the origin of disynaptic control over the motoneurons that influence the C3 protractor. More than two thirds of these layer 5 pyramidal neurons (L5PNs) are dispersed in frontal and parietal areas outside the primary motor cortex (vM1). This observation emphasizes the importance of descending motor commands from non-primary motor areas. More than a third of the L5PNs originate from somatosensory areas, such as the barrel field (vS1). The barrel field has been long considered a prototypic model system for studying sensory processing at the level of the cerebral cortex. Even so, we find that the number of L5PNs in vS1, and even their peak density, rivals the number and peak density of L5PNs in vM1. Thus, our results emphasize the importance of the barrel field in processing motor output. The distribution of L5PNs in vM1 and vS1 leads us to propose a model of vibrissa protraction in which vM1 output results in protraction, and vS1 output results in reciprocal inhibition (suppression) of protraction. This paired initiation and suppression of complementary movements may be a general feature of the descending output from the rodent M1 and S1.

Inside Back Cover: Cyclo‐P5 − Revisited: The Surprisingly Stable Uncoordinated Pentaphospholide Anion (Angew. Chem. Int. Ed. 24/2025)

Acridine‐Substituted‐Centronucleus Nonfullerene Acceptors Enables Organic Solar Cells with Over 20% Efficiency with Low Nonradiative Recombination Loss

Abstract In this work, we propose a novel strategy of introducing luminescent acridine units for central nuclear substitution in quinoxaline‐based acceptor molecules (named AQx‐ o ‐Ac and AQx‐ m ‐Ac) to enhance their photoluminescence quantum yields (PLQY), which can effectively improve the electroluminescent quantum efficiency (EQE EL ) of OSCs and thereby suppress Δ E nr . In addition, the substituted acridine unit accelerates molecular aggregation and optimizes molecular crystallization, effectively alleviating the static disorder of acceptor molecules and facilitating charge extraction and transport in OSCs. As a result, the PM6:AQx‐ m ‐Ac binary OSCs achieve an excellent PCE of 18.64% with an exceptionally low Δ E nr of 0.166 eV. To the best of our knowledge, a Δ E nr of 0.166 eV represents the lowest value reported for OSCs achieving PCEs over 18 %. Finally, the acceptor AQx‐ m ‐Ac is incorporated into PM6:eC9 blend as the third component, and the optimal ternary device produces a superior PCE of 20.28%. This work highlights the potential of promoting luminescence for suppressing nonradiative energy loss and charts a viable path for upcoming breakthrough in high‐efficiency organic photovoltaics.

Convergent expansions of keystone gene families drive metabolic innovation in Saccharomycotina yeasts

Many remarkable phenotypes have repeatedly occurred across vast evolutionary distances. When convergent traits emerge on the tree of life, they are sometimes driven by the same underlying gene families, while other times, many different gene families are involved. Conversely, a gene family may be repeatedly recruited for a single trait or many different traits. To understand the general rules governing convergence at both genomic and phenotypic levels, we systematically tested associations between 56 binary metabolic traits and gene count in 14,785 gene families from 993 Saccharomycotina yeasts. Using a recently developed phylogenetic approach that reduces spurious correlations, we found that gene family expansion and contraction were significantly linked to trait gain and loss in 45/56 (80%) traits. While 595/739 (81%) significant gene families were associated with only one trait, we also identified several “keystone” gene families that were significantly associated with up to 13/56 (23%) of all traits. Strikingly, most of these families are known to encode metabolic enzymes and transporters, including all members of the industrially relevant MAL tose fermentation loci in the baker’s yeast Saccharomyces cerevisiae . These results indicate that convergent evolution on the gene family level may be more widespread across deeper timescales than previously believed.

Revealing land control dynamics in emerging agricultural frontiers

The expansion of commodity agriculture into tropical and subtropical woodlands degrades ecosystem functionality, biodiversity, and the livelihood base of millions of people. Understanding where and how agricultural frontiers emerge is thus important. Yet, existing monitoring approaches typically focus on mapping deforestation and do not capture the shifts in land access and ownership that lay the ground for agricultural expansion, thereby missing early stages of frontier development. We develop an approach that captures these early dynamics and apply it to the entire 1,1 million km 2 of the Chaco, a global deforestation hotspot. Through the detection of linear features indicative of land claims and the analysis of their spatial–temporal dynamics, we reveal that the footprint of agricultural frontiers in the region extends far beyond that of deforestation. Most of the Chaco shows signs of land claiming, and although claiming activity is especially concentrated close to active deforestation, emergent claiming in remote parts of the Bolivian and Paraguayan Chaco indicates rapidly growing interest in land in these regions. Finally, the strong spatial correlation between land claiming and the disappearance of smallholder homesteads points to the social repercussions of early agricultural frontier expansion in the Chaco. By offering a transferable template to map land-control indicators at scale, our approach enables a better understanding of frontier processes and more accurate targeting of policy interventions in emerging agricultural frontiers globally.

Inside Front Cover: Optimizing the Selectivity of CH ₄ Electrosynthesis from CO ₂ over Cuprates through Cu─O Bond Length Descriptor (Angew. Chem. Int. Ed. 24/2025)

Fine ash from the Campanian Ignimbrite super-eruption, ~ 40 ka, southern Italy: implications for dispersal mechanisms and health hazard

Abstract Super-eruptions disperse volcanic ash over vast areas, impacting the environment and human health. Fine ash, particularly its respirable fraction (&lt; 4 µm), poses a significant health hazard by inhalation due to its high dispersal potential. Understanding the aerodynamic properties but also composition of ash particles is fundamental to constrain dispersal and deposition mechanisms in both proximal and distal environments. Current atmospheric dispersal models rely on empirical drag equations calibrated with geometric shape descriptors. However, these models often overlook the effects of the actual particle density, as a uniform componentry is typically assumed. In addition, particles have variable shapes but such data from super-eruptions remains limited and no standardized measurement methods exist. Here, we determine the terminal fall velocity (v t ) of fine ash from the Campanian Ignimbrite super-eruption (~ 40 ka, Campi Flegrei), by evaluating the components and particle shapes from proximal to ultra-distal locations. To verify the attribution of the proximal sample to the CI eruption, a 40Ar/39Ar dating was performed, allowing its correlation with the ultra-distal deposits. Results show that, due to the influence of shape and density, glass particles exhibit lower v t compared to mineral phases (v t, feldspar/v t, glass = 1.05 ± 0.03, v t, SiO2/v t, glass = 1.09 ± 0.02), enabling greater travel distances. Drag equations accounting for measured particle shapes differ significantly from spherical approximations. The spherical model overestimation of v t highlights the necessity of shape-specific models to produce more accurate dispersal predictions. Extremely low v t (&lt; 0.1 cm/s) for respirable ash fraction, which indicates prolonged atmospheric suspension and long-time resuspension potential, along with the presence of cristobalite, lead to important implications for health hazards. These findings further enhance our understanding of volcanic ash aerodynamic behaviour and the far-reaching impact of super-eruptions.