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Metabolic control of glycosylation forms for establishing glycan-dependent protein interaction networks

Protein–protein interactions (PPIs) are crucial for comprehending the molecular mechanisms and signaling pathways underlying diverse biological processes and disease progression. However, investigating PPIs involving membrane proteins is challenging due to the complexity and heterogeneity of glycosylation. To tackle this challenge, we developed an approach termed glycan-dependent affinity purification coupled with mass spectrometry (GAP–MS), specifically designed to characterize changes in glycoprotein PPIs under varying glycosylation conditions. GAP–MS integrates metabolic control of glycan profiles in cultured cells using small molecules referred to as glycan modifiers with affinity purification followed by mass spectrometry analysis (AP–MS). Here, GAP–MS was applied to characterize and compare the interaction networks under five different glycosylation states for four bait glycoproteins: BSG, CD44, EGFR, and SLC3A2. This analysis identified a network comprising 156 interactions, of which 131 were determined to be glycan dependent. Notably, the GAP–MS analysis of BSG provided distinct information regarding glycosylation-influenced interactions compared to the commonly used glycosylation site mutagenesis approach combined with AP–MS, emphasizing the unique advantages of GAP–MS. Collectively, GAP–MS presents distinct insights over existing methods in elucidating how specific glycosylation forms impact glycoprotein interactions. Additionally, the glycan-dependent interaction networks generated for these four glycoproteins serve as a valuable resource for guiding future functional investigations and therapeutic developments targeting the glycoproteins discussed in this study.

Author Correction: EZH2 regulates oncomiR-200c and EMT markers in esophageal squamous cell carcinomas

Telescopes team up to probe distant worlds

Author Correction: Detection of cotton crops diseases using customized deep learning model

Reciprocal interaction between cortical SST and PV interneurons in top–down regulation of retinothalamic refinement

Refinement of thalamic circuits is crucial for the proper maturation of sensory circuits. In the visual system, this process is regulated by corticothalamic feedback during the experience-dependent phase of development. Yet the cortical circuits modulating this feedback remain elusive. Here, we demonstrate opposing roles for cortical somatostatin (SST) and parvalbumin (PV) interneurons in shaping retinogeniculate connectivity during the thalamic sensitive period (P20-30). Early in the refinement process, SST interneurons promote the strengthening and pruning of retinal inputs in the thalamus, as evidenced by disrupted synaptic refinement following their ablation. In contrast, PV interneurons, which mature later, act as a brake on this refinement, with their ablation leading to enhanced pruning of retinogeniculate connections. Notably, manipulating the relative balance between these inhibitory circuits can regulate sensory deprivation-induced retinogeniculate remodeling. Taken together, our findings show that cortical SST and PV interneuron circuits drive experience-dependent reciprocal antagonism that gates cortical feedback regulation of feedforward thalamic refinement.

Homoploid hybridization adds clarity to the origins of octoploid strawberries

The evolutionary histories of many polyploid plant species are difficult to resolve due to a complex interplay of hybridization, incomplete lineage sorting, and missing diploid progenitors. In the case of octoploid strawberry with four subgenomes designated ABCD, the identities of the diploid progenitors for subgenomes C and D have been subject to much debate. By integrating new sequencing data from North American diploids with reticulate phylogeny and admixture analyses, we uncovered introgression from an extinct or unsampled species in the clade of Fragaria viridis , Fragaria nipponica , and Fragaria nilgerrensis into the donor of subgenome A of octoploid Fragaria prior to its divergence from F. vesca subsp . bracteata . We also detected an introgression event from F. iinumae into an ancestor of F. nipponica and F. nilgerrensis. Using an LTR-age-distribution-based approach, we estimate that the octoploid and its intermediate hexaploid and tetraploid ancestors emerged approximately 0.8, 2, and 3 million years ago, respectively. These results provide an explanation for previous reports of F. viridis and F. nipponica as donors of the C and D subgenomes and suggest a greater role than previously thought for homoploid hybridization in the diploid progenitors of octoploid strawberry. The integrated set of approaches used here can help advance polyploid genome analysis in other species where hybridization and incomplete lineage sorting obscure evolutionary relationships.

Tumor-promoting UBR4 coordinates impaired mitophagy–associated senescence and lung adenocarcinoma pathogenesis

Cellular senescence, an irreversible cell cycle arrest, plays a pivotal role in development, aging, and tumor suppression. However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear. Here, we describe the tumorigenic involvement of ubiquitin protein ligase E3 component n-recognin 4 (UBR4), an E3 ubiquitin ligase of the N-degron pathway, in lung adenocarcinoma (LUAD). Public genome databases revealed high UBR4 expression in LUAD patients, associated with a dysregulated cell cycle and impaired mitochondrial homeostasis. UBR4 knockout (ΔUBR4) in A549 lung cancer cells induced cellular senescence with defective mitochondria. Restoration of UBR4 or antioxidant treatment reversed the ΔUBR4 phenotypes caused by impaired mitophagy. Mitochondrial stress exacerbated mitochondrial dysfunction in ΔUBR4 cells, contributing to diverse cellular phenotypes. Additionally, ΔUBR4 cells exhibited substantially slow tumor growth in mouse xenograft models. In LUAD patients, UBR4 levels correlated with tumor stage, mitophagy markers, and poor survival. These findings suggest a tumor-promoting function of UBR4 in LUAD by regulating mitochondrial quality control. Further research into the pharmacological inhibition of UBR4 could open promising avenues for developing effective antitumor therapies targeting LUAD.

Reactivation of an embryonic cardiac neural crest transcriptional profile during zebrafish heart regeneration

During vertebrate development, the heart primarily arises from mesoderm, with crucial contributions from cardiac neural crest (CdNC) cells that migrate to the heart and form a variety of cardiovascular derivatives. Here, by integrating bulk and single cell RNA-seq with ATAC-seq, we identify a gene regulatory subcircuit specific to migratory cardiac crest cells composed of key transcription factors egr1, sox9a, tfap2a, and ets1. Notably, we show that cells expressing the canonical neural crest gene sox10 are essential for proper cardiac regeneration in adult zebrafish. Furthermore, expression of all transcription factors from the migratory cardiac crest gene subcircuit are reactivated after injury at the wound edge. Together, our results uncover a developmental gene regulatory network that is important for CdNC fate determination, with key factors of the program reexpressed during regeneration.

Conserving the beauty of the world’s reef fish assemblages

On shallow rocky and coral reefs, cultural and recreational values, like aesthetics, are critical aspects of Nature’s Contributions to People (NCP) that support human well-being and provide billions of dollars in tourism revenue. Quantifying the aesthetic value of reef ecosystems and uncovering the conditions that enhance it could support NCP-based management. Here, we combine a global dataset of reef fish surveys, species-level aesthetic values, and causal modeling to assess the global status and drivers of reef fish assemblage aesthetic value. We find that aesthetic value is inherently linked to species richness, displaying a latitudinal gradient with peaks in the tropics, but varies strongly with the presence of exceptionally beautiful or less-beautiful species. Sea surface temperature, primary productivity, human gravity, and protection status are the strongest drivers of assemblage-level aesthetic value. Protection against human impacts consistently enhances aesthetic value by boosting taxonomic and phylogenetic diversity, and this effect is greatest in species-rich, tropical ecoregions. Economic development has little influence, indicating that low-income countries are not constrained from maintaining beautiful fish assemblages. Our results therefore suggest that marine protected areas (MPAs) can support multiple NCPs simultaneously, particularly in developing tropical countries. While we highlight the effectiveness of MPAs, given the low level of marine protection globally and the sensitivity of aesthetic value to environmental conditions, the beauty of the world’s reefs appears severely threatened. Aesthetic value should be immediately integrated into reef conservation and management plans.

Estimating the extent and sources of model uncertainty in political science

Assessing model uncertainty is crucial to quantitative political science. Yet, most available sensitivity analyses focus only on a few modeling choices, most notably the covariate space, while neglecting to jointly consider several equally important modeling choices simultaneously. In this article, we combine the exhaustive and systematic method of the Extreme Bounds Analysis with the more multidimensional logic underpinning the multiverse approach to develop an approach to sensitivity analyses. This allows us to systematically assess the degree and sources of model uncertainty across multiple dimensions, including the control set, fixed effect structures, SE types, sample selection, and dependent variable operationalization. We then apply this method to four prominent topics in political science: democratization, institutional trust, public good provision, and welfare state generosity. Results from over 3.6 bn estimates reveal widespread model uncertainty, not just in terms of the statistical significance of the effects, but also their direction, with most independent variables yielding a substantive share of statistically significant positive and negative coefficients depending on model specification. We compare the strengths and weaknesses of three distinct approaches to estimating the relative importance of different model specification choices: nearest 1-neighbor; logistic; and deep learning. All three approaches reveal that the impact of the covariate space is relatively modest compared to the impact of sample selection and dependent variable operationalization. We conclude that model uncertainty stems more from sampling and measurement than conditioning and discuss the methodological implications for how to assess model uncertainty in the social sciences.

Enigmatic carbon isotopic variability in the oceanic upper mantle

Unraveling the origin(s) of carbon on Earth has remained challenging, not only because of the multiple isotopic fractionation episodes that may have occurred during planet formation processes but also because the end point of these processes, the current isotopic value of Earth’s deep carbon reservoirs remains poorly constrained. Here, we present carbon isotopic measurements on rare undegassed mid-ocean ridge basalts from the Pacific, Atlantic, and Arctic Oceans that have preserved the isotopic signature of their mantle source. We find that Earth’s present-day convecting upper mantle has variable δ 13 C value from ~−10 to −4‰, significantly different from the δ 13 C value of peridotitic diamonds and with the highest values being restricted to the Atlantic. Evidence for significant mantle heterogeneity contrasts with previous assumptions and its origin remains puzzling being uncorrelated with geochemical markers associated with either subduction and surficial recycling processes or lower mantle contributions. The data do not preclude other causes such as primordial mantle heterogeneity. We suggest that the δ 13 C value of the bulk silicate Earth may need to be revised.

Mixing and Matching of Hybrid Megasynthases is a Hub for the Evolution of Metabolic Diversity in Cyanobacteria

Abstract Modular megasynthases, such as polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs), are molecular assembly lines that biosynthesize many pharmaceutically and ecologically important natural products. Understanding how these compounds evolve could inspire the artificial evolution of compound diversity by metabolic engineering. Over the past two decades, a number of seminal studies have significantly contributed to our understanding of natural product evolution. However, the evolution of NRPS and PKS assembly lines remains poorly understood, especially for NRPS/PKS hybrids. Here, we provide substantial evidence for a remarkable cluster‐mixing event involving three cyanobacterial biosynthetic gene clusters (BGCs), resulting in the emergence of novel peptide‐polyketide hybrids that were named minutumamides. By combining retro‐evolutionary analysis with structure‐guided genome mining, we could discover a potential evolutionary ancestor that links nostopeptolide and minutumamide biosynthesis. In addition, we were able to trace nostopeptolide‐related module and domain blocks in various other biosynthetic pathways, indicating a surprisingly vivid mixing and matching of biosynthesis genes in the evolution of NRPS and cis ‐acyltransferase PKS/NRPS pathways, which was previously regarded as a unique feature of trans ‐acyltransferase ( trans ‐AT) PKS. These remarkable insights into the evolutionary plasticity of NRPS‐PKS assembly lines provide valuable guidance for pathway engineers looking for productive combinations that yield “nonnatural” hybrid natural products.

Mark C. Lipke

An ancient origin of the naked grains of maize

Adaptation to novel environments requires genetic variation, but whether adaptation typically acts upon preexisting genetic variation or must wait for new mutations remains a fundamental question in evolutionary biology. Selection during domestication has been long used as a model to understand evolutionary processes, providing information not only on the phenotypes selected but also, in many cases, an understanding of the causal loci. For each of the causal loci that have been identified in maize, the selected allele can be found segregating in natural populations, consistent with their origin as standing genetic variation. The sole exception to this pattern is the well-characterized domestication locus tga1 ( teosinte glume architecture1 ), which has long been thought to be an example of selection on a de novo mutation. Here, we use a large dataset of maize and teosinte genomes to reconstruct the origin and evolutionary history of tga1 . We first estimated the age of tga1-maize using a genealogy-based method, finding that the allele arose approximately 42,000 to 49,000 y ago, predating the beginning of maize domestication. We also identify tga1-maize in teosinte populations, indicating that the allele can survive in the wild. Finally, we compare observed patterns of haplotype structure and mutational age distributions near tga1 with simulations, finding that patterns near tga1 in maize better resemble those generated under simulated selective sweeps on standing variation. These multiple lines of evidence suggest that maize domestication likely drew upon standing genetic variation at tga1 and cement the importance of standing variation in driving adaptation during domestication.

Light‐Induced Disruption of 1D Wire‐Like Arrays of Monoatomic Ag(I) Ions: Single‐Crystal Reaction with Crystal Softening

Abstract The exploitation of noncovalent bonding in the solid state is attractive to generate one‐dimensional (1D) wire‐like assemblies of metals and uncover dynamic and physical properties of such intriguing structures. Herein, we describe a metal‐organic crystal based on Ag(I) ions that assemble to be organized into 1D wire‐like assemblies maintained by argentophilic interactions. UV‐light irradiation of the crystal composed of the 1D structures results in a single‐crystal‐to‐single‐crystal (SCSC) photodimerization that transforms the 1D periodic metal arrays to isolated metal dimers. The structural reconfiguration creates small voids in the crystal and the resulting solids exhibit a substantial increase in softness up to 60%.

Sp140L functions as a herpesvirus restriction factor suppressing viral transcription and activating interferon-stimulated genes

Herpesviruses, including Epstein–Barr virus (EBV) – a human oncogenic virus and essential trigger of multiple sclerosis – must bypass host DNA-sensing mechanisms to establish lifelong, latent infection. Therefore, herpesviruses encode viral proteins to disrupt key host factors involved in DNA sensing and viral restriction. The first viral latency protein expressed, EBNA-LP, is essential for transformation of naïve B cells and establishment of viral gene expression, yet its role in evading host defenses remains unclear. Using single-cell RNA sequencing of EBNA-LP Knockout (LPKO)-infected B cells, we reveal an antiviral response landscape implicating the “speckled proteins” as key cellular restriction factors countered by EBNA-LP. Specifically, loss of Sp100 or the primate-specific Sp140L reverses the restriction of LPKO, suppresses a subset of canonically interferon-stimulated genes, and restores transcription of essential latent viral genes and cellular proliferation. Notably, we also identify Sp140L as a restriction target of the herpesvirus saimiri ORF3 protein, implying a role for Sp140L in immunity to other diverse DNA viruses. This study reveals Sp140L as a restriction factor that we propose links sensing and transcriptional suppression of viral DNA to an Interferon-independent innate immune response, likely relevant to all nuclear DNA viruses.

Linking pregnancy- and birth-related risk factors to a multivariate fusion of child cortical structure

Pregnancy- and birth-related factors affect offspring brain development, emphasizing the importance of early life exposures. While most previous studies have focused on a few variables in isolation, here we investigated associations between a broad range of pregnancy- and birth-related variables and multivariate cortical brain MRI features. Our sample consisted of 8,396 children aged 8.9 to 11.1 y from the Adolescent Brain Cognitive Development Study. Through multiple correspondence analysis and factor analysis of mixed data, we distilled numerous pregnancy and birth variables into four overarching dimensions; maternal pregnancy complications, maternal substance use, low birth weight and prematurity, and newborn birth complications. Vertex-wise measures of cortical thickness (CT), surface area (SA), and curvature were fused using linked independent component analysis. Linear mixed-effects models showed that maternal pregnancy complications and low birth weight and prematurity were associated with smaller global SA. Additionally, low birth weight and prematurity was associated with complex regional cortical patterns reflecting bidirectional variations in both SA and CT. Newborn birth complications showed multivariate patterns reflecting smaller occipital- and larger temporal area, bidirectional frontal area variations, and reduced CT across the cortex. Maternal substance use showed no associations with child cortical structure. By employing a multifactorial and multivariate morphometric fusion approach, we connected complications during pregnancy and fetal size and prematurity to global SA and specific regional signatures across child cortical MRI features.

Ordered Co‐Assembly of Soft‐in‐Hard Hetero‐Structured Pulse Guidance Ion‐Accelerator for Dendrite‐Free Aqueous Zinc‐Ion Battery Anodes

Abstract Constructing a solid electrolyte interface (SEI) layer to suppress dendrite growth is an effective approach in Zn‐based aqueous batteries. Traditional SEI layers are limited by their simple structure and composition, enabling only one functionality of either providing nucleation sites or facilitating desolvation. In this study, a pulse guidance ion‐accelerator is constructed by kinetics‐controlled co‐assembly of zincophilic micelles and zincophobic metal‐organic framework (MOF). The closely packed soft micelles, in conjunction with the hard MOF host particles, form a multi‐tiered soft‐in‐hard hetero‐structure that accelerates adsorption, pre‐desolvation, and subsequent desolvation processes, facilitating the (002) crystal plane dendrite‐free deposition. As a result, stable cycling over 1900 h (31 mV polarization) in symmetric cell and 5200 cycles in the Zn//Cu battery (99.8% coulombic efficiency) can be achieved. These findings will effectively promote the development of stable and long‐cycling aqueous zinc‐ion batteries.

The brain computes dynamic facial movements for emotion categorization using a third pathway

Emerging theories in cognitive neuroscience propose a third brain pathway dedicated to processing biological motion, alongside the established ventral and dorsal pathways. However, its role in computing dynamic social signals for behavior remains uncharted. Here, participants (N = 10) actively categorized dynamic facial expressions synthesized by a generative model and displayed on different face identities—as “happy,” “surprise,” “fear,” “anger,” “disgust,” “sad”—while we recorded their MEG responses. Using representational interaction measures that link facial features with MEG activity and categorization behavior, we identified within each participant a functional social pathway extending from the occipital cortex to the superior temporal gyrus. This pathway selectively represents, communicates, and integrates facial movements that are essential for the behavioral categorization of emotion, while task-irrelevant identity features are filtered out in the occipital cortex. Our findings uncover how the third pathway selectively computes complex dynamic social signals for emotion categorization in individual participants, offering computational insights into the dynamics of neural activity.

ATF6 enables pathogen infection in ticks by inducing <i>stomatin</i> and altering cholesterol dynamics

How tick-borne pathogens interact with their hosts has been primarily studied in vertebrates where disease is observed. Comparatively less is known about pathogen interactions within the tick. Here, we report that Ixodes scapularis ticks infected with either Anaplasma phagocytophilum (causative agent of anaplasmosis) or Borrelia burgdorferi (causative agent of Lyme disease) show activation of the ATF6 branch of the unfolded protein response (UPR). Disabling ATF6 functionally restricts pathogen survival in ticks. When stimulated, ATF6 functions as a transcription factor, but is the least understood out of the three UPR pathways. To interrogate the Ixodes ATF6 transcriptional network, we developed a custom R script to query tick promoter sequences. This revealed stomatin as a potential gene target, which has roles in lipid homeostasis and vesical transport. Ixodes stomatin was experimentally validated as a bona fide ATF6-regulated gene through luciferase reporter assays, pharmacological activators, RNA interference transcriptional repression, and immunofluorescence microscopy. Silencing stomatin decreased A. phagocytophilum colonization in Ixodes and disrupted cholesterol dynamics in tick cells. Furthermore, blocking stomatin restricted cholesterol availability to the bacterium, thereby inhibiting growth and survival. Taken together, we have identified the Ixodes ATF6 pathway as a contributor to vector competence through Stomatin-regulated cholesterol homeostasis. Moreover, our custom, web-based transcription factor binding site search tool “ArthroQuest” revealed that the ATF6-regulated nature of stomatin is unique to blood-feeding arthropods. Collectively, these findings highlight the importance of studying fundamental processes in nonmodel organisms.