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Sublingual NMN administration increases early circulating terminal catabolites 2PY and 4PY compared with oral administration in healthy adult men
Abstract Sublingual administration of nicotinamide mononucleotide (NMN) is hypothesized to enhance systemic bioavailability by bypassing hepatic first-pass metabolism, a significant limitation of oral intake. However, direct comparative evidence in humans has been lacking. This study aimed to compare the acute pharmacokinetics of NMN following single-dose oral and sublingual administration in a randomized, two-period crossover trial involving 14 healthy adult males. Participants received NMN via both routes, separated by an 8-day washout period. Blood samples were collected for 60 min post-administration to measure NMN and its metabolites, including nicotinamide (NAM), nicotinamide adenine dinucleotide (NAD⁺), and the terminal catabolites N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY). The incremental area under the curve (iAUC) was significantly higher for the terminal metabolites 2PY and 4PY following sublingual administration compared to the oral route. In contrast, no significant differences were found for the blood concentrations of NMN, NAM, or NAD⁺ between methods. Both administration routes were well-tolerated, with no adverse events reported. These findings provide the first direct evidence in humans that sublingual administration leads to a more rapid increase in the terminal metabolites (2PY and 4PY) over 0–60 min, although the metabolic origin of these increases could not be distinguished in the present study.
Modeling audio dynamics using hierarchical assisted K-means model for structured speaker profiling in TED talks
Heterotypic intercellular adhesion tunes efficiency of cell-on-cell migration
Cell migration across epithelial barriers occurs in diverse developmental, immunological, and pathological contexts. Here, we investigate the contribution of heterotypic adhesion between migrating cells and epithelial “substrate” cells to transepithelial migration. Using an in silico model inspired by the migration of primordial germ cells across the midgut epithelium in the Drosophila embryo, we show that heterotypic adhesion modulates migration efficiency in a nonmonotonic manner, revealing the existence of an optimal adhesion regime. Consistent with this prediction, in vivo overexpression of E-cadherin in germ cells accelerated their exit from the midgut relative to controls. Beyond providing experimentally testable predictions, our model integrates and explains previous observations on the role of heterotypic adhesion in cell-on-cell migration, offering a framework for understanding transepithelial migration across biological contexts.
An AI-driven framework for evaluating local and state authorities’ permitting processes
Abstract The demand for new energy infrastructure is increasing across the United States, but heterogenous permitting processes and embedded requirements across different local jurisdictions can cause project delays, increase “soft costs,” and hinder developer expansion. This study analyzes the variability in local permitting requirements across the U.S. and develops a quantitative approach to describe their clarity and effectiveness in enabling infrastructure project development. By using an Energy Language Model (ELM), a large language model (LLM) for energy technologies, we systematically gathered permitting information from nearly 300 state-, county-, and city-level documents, creating a structured dataset of requirements and procedures on an unprecedented scale and speed. Our analysis revealed that local (city and county) permitting requirement documents are underrepresented compared to state-level guidance documents, which can impede timely and cost-effective installation of new electric infrastructure. Our validation process showed that the final database has an accuracy of approximately 95%. We, further, created a new quantitative method to score permitting requirements for clarity and efficiency, with electric vehicle supply equipment as an initial use case. The average local permitting document scored a 1.8 out of 5, which we interpret as meaning that half of the requirements developers face when installing electric infrastructure are ambiguous, increasing both cost and time. We also created a “Generalized Permit Process”, highlighting common procedural steps and identifying specific opportunities for municipalities to improve their documentation. This research establishes a systematic and scalable framework for evaluating the complexities of local infrastructure permitting processes by combining LLM-powered data collection and quantitative scoring. The framework enables policymakers and developers to identify and mitigate procedural bottlenecks, with the expectation that these improvements can accelerate application review and approval, reduce project costs, and expedite connection to utility distribution grids. As a foundational approach for streamlining local project development processes, this study’s methods are intended to be extended to a wide range of energy applications.
Correction for Ajourlou et al., Upper mantle temperatures illuminate the Iceland hotspot track and understanding of ice–Earth interactions in Greenland
Systemic testosterone induces structural, immunological, and sex steroid receptor changes in human XX skin
Abstract Skin-resident cells express multiple sex steroid receptors, making the cutaneous microenvironment sensitive to hormonal fluctuations. Transgender individuals assigned female at birth receiving gender-affirming hormone treatment (GAHT) with systemic testosterone often undergo several surgical procedures, underscoring the importance of understanding how GAHT influences skin biology and wound-healing capacity. This study aimed to characterize how XX (genotype) skin responds to systemic testosterone exposure. Discarded skin samples from plastic surgeries were collected from XX patients with and without testosterone treatment and analyzed for sex steroid receptor expression, immune cell markers, and structural integrity components. In testosterone-treated skin, we observed, in dermis, a 2.77-fold increase in androgen receptor-positive cells, elevated estrogen receptor α- and progesterone receptor-positive cell counts, a 43% reduction in CD45 positive immune cells, and a 2.93-fold increase in collagen density compared with untreated controls. In the epidermis, testosterone treatment resulted in reduced progesterone receptor-positive cell numbers and increased fibronectin expression. Collectively, testosterone-treated XX skin exhibited features resembling a male skin phenotype, potentially driven by altered sex steroid receptor expression, shifts in immune cell infiltration, and changes to structural organization. These findings highlight the need for further studies to elucidate the mechanisms underlying testosterone-induced skin remodeling and its implications for surgical outcomes.
LARP1 integrates MYC and mTOR signaling to enable anabolic growth during tumor initiation
Tumor initiation requires the integration of oncogenic signals with environmental cues to enable anabolic growth. MYC is central to tumorigenesis, with its deregulation observed in over 60% of human cancers. Oncogenic MYC profoundly rewires transcription, enabling cells to bypass cell cycle checkpoints and reset metabolism. A cornerstone of this rewiring is the upregulation of biomass-producing pathways, particularly ribosome biogenesis. How and when MYC’s oncogenic program is translationally executed—either immediately or until a favorable metabolic context emerges—remains a central unanswered question in tumor initiation, limiting our understanding of tumor latency and early intervention. Here, we identify LARP1 as a critical effector of MYC-driven transformation, connecting MYC oncogenic activity with mTOR signaling. Mechanistically, MYC represses miR-26a/b, relieving posttranscriptional repression of LARP1 and leading to its upregulation. LARP1 associates with the translational machinery, loading it with the anabolic translatome induced by MYC in a translationally poised state. Upon permissive mTOR signaling, and dependent on the phosphorylation of LARP1 at serines 689 and 697, this program is rapidly translated, fueling the biosynthetic processes essential for tumor development. Importantly, genetic deletion of LARP1 or pharmacological mTOR inhibition completely abrogates tumor initiation in a genetically engineered colorectal organoid model of MYC-driven tumorigenesis. This underscores the physiological relevance of this two-step mechanism in which LARP1 bridges the anabolic translatome primed by MYC with its metabolic execution controlled by mTOR. By temporally uncoupling transformation from metabolic permissiveness, this mechanism defines a critical checkpoint in early tumorigenesis, revealing a potential vulnerability for intercepting MYC-driven cancer before biomass expansion.
Solvent-free synthesis of coumarin derivatives for improved anti-corrosion and mechanical performance of primer coatings
Abstract In the current study, an environmentally friendly and energy-efficient synthesis of two coumarin derivatives was achieved using a solvent-free grinding technique. This green protocol offers several advantages over conventional methods, including shorter reaction times, the absence of hazardous solvents, mild conditions, straightforward workup, low cost, and high product yields. The chemical structures of the synthesized derivatives were confirmed by IR, $$\:1\text{H}$$ NMR, $$\:13\text{C}$$ NMR, and mass spectrometry. The coumarin-based corrosion inhibitors (compounds 3 and 6) were incorporated into a commercial solvent-based primer to enhance its protective properties against corrosion. Dynamic Mechanical Analysis (DMA) revealed an increase in storage modulus (E′) and thermal resistance, particularly in the formulation modified with the pyrazole-containing compound 6, which retained stiffness at elevated temperatures. Complementary thermogravimetric analysis (TGA) confirmed improved thermal stability, as shown by higher degradation onset temperatures and greater char yields in the modified coatings. The inclusion of these compounds significantly improved the mechanical performance of the coated films. Notably, the formulation containing compound 6 exhibited superior hardness, impact resistance, and adhesion, attributed to strong interfacial interactions with the primer matrix. The anticorrosive performance of the modified primers was further evaluated using salt spray testing. Both compounds significantly enhanced corrosion resistance compared to the unmodified primer, with compound 6 providing superior protection. These findings were supported by quantum chemical calculations, which showed that compound 6 exhibited a lower energy gap (ΔE = 1.915 eV), indicating higher reactivity and stronger interaction with the metal surface. Overall, the study demonstrates the dual function of coumarin-based corrosion inhibitors in enhancing both the mechanical integrity and corrosion resistance of commercial primer coatings.
Conceptual priorities shape individual gaze patterns during naturalistic visual attention
Our visual landscape consists of not only people, places, and objects (e.g., “soldier,” “stadium,” “flag”) but also the conceptual relationships that unite them (e.g., “patriotism”). Because conceptual knowledge varies across individuals, this level of structure may support individualized patterns of attentional selection during naturalistic scene viewing. Here, we ask whether individuals’ gaze patterns reflect, in part, latent attentional priorities organized in conceptual space. Participants (N = 61) freely explored a diverse set of immersive real-world scenes (N = 100) in head-mounted VR while their gaze position was continuously recorded. We modeled gaze behavior using spatial, visual, and conceptual feature spaces, leveraging embeddings from large vision and language models, to uncover the latent priorities guiding individuals’ unique patterns of selective attention across environments. Individuals exhibited stable and idiosyncratic gaze patterns across scenes and test–retest sessions, consistent with trait-like individual differences in attention. Spatial, visual, and conceptual feature spaces each explained unique variance in individual gaze patterns, with conceptual features contributing variance beyond that explained by spatial and visual features alone. Notably, language-model–based predictions were particularly effective at capturing these individualized patterns. Together, these findings indicate that naturalistic visual attention is structured at multiple levels—including a conceptual level—revealing stable individual differences in how people sample and prioritize information across complex visual environments.
How do researchers choose what to work on?
Trajectories of quality of life in pancreatic cancer survivors during the first year after surgery: a longitudinal study
Abstract Although quality of life (QOL) improves over time for most pancreatic cancer patients after surgery, some patients may show different patterns of QOL. Beyond determining distinct QOL trajectories, identifying characteristics of patients who have different trajectories can help identify pancreatic cancer patients who may benefit from intervention. We aimed to identify trajectories of QOL in pancreatic cancer patients for one year after the surgery, to determine the factors influencing these changes. This longitudinal study recruited 120 pancreatic cancer patients, and their QOL, anxiety, depression, social support, self‑efficacy, and sleep quality were assessed. Data were collected at 1 month (T1), 3month (T2), 6month (T3), and 12month (T4) after surgery. Group-Based Multivariate Trajectory Modeling (GBMTM) was used to identify distinct subgroups of patients with similar patterns of QOL change after surgery. A univariate analysis was used to determine which variables were associated with trajectory membership. A multinomial logistic regression was performed to identify factors associated with trajectory group membership. 104 patients were analyzed and identified with three trajectory groups, the low, moderate and high QOL group. All of three groups exhibited a sustained upward trend in functional domain scores, followed by a slight decline at 12 months. Correspondingly, symptom domain scores showed a consistent downward trajectory across all groups, with a slight increase observed at 12 months. Compared with the high QOL group, the odds of the low QOL group were 1.139 times higher in the SDS (OR = 1.139, 95% CI: 1.037–1.252, P = 0.007), and the odds of the low QOL group were 1.762 times higher than the high QOL group in the PSQI (OR = 1.762, 95% CI: 1.161–2.674, P = 0.008). Compared to the high QOL group, the odds of the moderate QOL group were 1.127 times higher in the SDS (OR = 1.127, 95% CI: 1.037–1.226, P = 0.005), and the odds of the moderate QOL group were 1.535 times higher in the PSQI (OR = 1.535, 95% CI: 1.055–2.235, P = 0.025). Conversely, occupation, BMI, SAS scores, and GSES scores showed no statistically significant effect on trajectory group ( P > 0.05). Identifying high‑risk groups for reduced QOL after surgery is necessary. Moreover, psychosocial interventions and sleep methodologies should be provided to alleviate psychological symptoms and improve sleep quality to enhance patients’ QOL.
Transformations of the spatial activity manifold convey aversive information in CA3
Hippocampal circuits form cognitive maps that represent spatial position and integrate contextual information, including affective cues, into episodic memory representations. We investigated how spatial and affective information are combined in the population activity of CA3 axons by analyzing the activity of intermediate-to-dorsal and dorsal-to-dorsal axons in mice navigating a linear track before, during, and after exposure to an aversive air puff stimulus. Both axonal populations maintained a robust, time-invariant activity manifold that encoded spatial information independent of affective context. Deformations of this common manifold encoded the presence of the aversive stimulus without disrupting the spatial representation. Despite differences in spatial coding, both axonal populations encoded affective information with similar efficacy. This population-level encoding was distributed similarly across place and nonplace cells. Our findings demonstrate that hippocampal CA3 axons integrate spatial and affective information within a common representational geometry while maintaining the separability of each information type.
A multi-dimensional approach combining HPLC, ion mobility and high resolution mass spectrometry for investigating transition metal complexes
Abstract Organometallic complexes play a central role in catalysis and medicinal chemistry, yet their analytical characterization via mass spectrometry remains challenging due to their reactivity, susceptibility to fragmentation and the resulting overlapping isotopologue patterns, especially in complex reaction mixtures. Herein, we present a high-performance liquid chromatography ion mobility mass spectrometry workflow for the separation and analysis of group-six metal complexes. Chromatographic separation was combined with variation of electrospray ionization source conditions, allowing fragmentation behavior to be tuned according to specific analytical requirements. Ion mobility spectrometry provided an additional separation dimension that enabled the determination of collision cross sections as molecular descriptors for all investigated complexes. Analysis of the ion mobility data revealed systematic, metal-dependent trends consistent with expected structural differences. These correlations facilitated the assignment of the central metal even for species of low abundance or those lacking characteristic isotopologue patterns. Overall, this work demonstrates that the combination of chromatographic separation and ion mobility-based trend analysis provides a versatile platform for the characterization of organometallic species.
A protective role for APP in nuclear waste clearance via lysosomal exocytosis
Amyloid precursor protein (APP) is widely known for its role in Alzheimer’s disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological functions remain incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear waste material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.
Daily briefing: How many elementary particles are there?
Evaluation of metal-oxide semiconductors for the photocatalytic degradation of chloroquine phosphate in real-world water matrices
Abstract The persistence of pharmaceuticals in aquatic environments poses an increasing threat to aquatic ecosystems and human health, as conventional wastewater treatment plants often fail to remove contaminants of emerging concern (CECs) effectively. This work offers a systematic comparative assessment of the photocatalytic activity of TiO₂, ZnO, CeO₂, Bi₂O₃, and WO₃ nanoparticles for degrading chloroquine phosphate (CLQ), a widely used antiviral and anti-inflammatory drug, under ultraviolet irradiation in ultrapure water, drinking water, and synthetic seawater. The semiconductors were thoroughly characterised for morphology, crystalline structure, optical bandgap, and surface charge. Reactive oxygen species (ROS) generation, including hydroxyl radicals ( · OH) and singlet oxygen (¹O₂), was measured to clarify degradation efficiency in each matrix. TiO₂ demonstrated the highest photocatalytic efficiency, achieving up to 83% CLQ degradation in drinking water, consistent with its superior ROS production. ZnO and CeO₂ showed moderate activity, with performance significantly influenced by pH and ionic composition, while Bi₂O₃ and WO₃ remained suppressed, especially in complex water matrices. Overall, this study emphasises the importance of assessing photocatalysts under realistic environmental conditions and identifies TiO₂ as the most robust and adaptable semiconductor for removing CLQ, even in complex water matrices.
Subcellular metallomic networks orchestrate physiological outcomes: Single-cell mapping via an integrated SEM-FIB-TOF-SIMS platform
The spatial organization of essential, nonessential, and toxic metal(loid) elements (MEs) within plant cells underpins physiological function. Yet, comprehensive subcellular imaging of the full ME spectrum remains challenging due to trade-offs among spatial resolution, elemental coverage, and structural correlation. Here, we present an integrated scanning electron microscopy–focused ion beam–time-of-flight-secondary ion mass spectrometry platform that overcomes these limitations by achieving nanoscale coregistration of ultrastructure with ME distribution. Applying this high-fidelity workflow to Arabidopsis , soybean, and wheat, we constructed single-cell metallome maps revealing an evolutionarily conserved subcellular architecture: chloroplasts enrich essential MEs (e.g., magnesium, iron, copper), whereas vacuoles compartmentalize nonessential [e.g., lanthanum (La)] and toxic MEs [e.g., cadmium (Cd), lead, arsenic]. We demonstrate that while this architecture remains stable under homeostasis, it undergoes dynamic, stimulus-specific, and dose-dependent remodeling under stress. Low-dose La(III) enhances pairwise and higher-order colocalizations of essential MEs within chloroplasts, correlating with improved photosynthetic efficiency and growth. High-dose La(III) induces nonphysiological La-ME associations and, critically, drives aberrant Cd(II) accumulation in chloroplasts—revealing a cross-toxicity mechanism wherein La(III) disrupts native sequestration barriers. In contrast, although high-dose Cd(II) is largely excluded from chloroplasts, it triggers a widespread redistribution of essential MEs, progressively eroding spatial organization. Thus, while both ions inhibit growth, they perturb metallomic networks via distinct mechanisms: La(III)-mediated disruption of sequestration vs. Cd(II)-induced systemic compartmental collapse. Our findings establish that subcellular ME networks are dynamically regulated and orchestrate physiological outcomes.
Selenium-induced metabolic reprogramming in soybean activates nucleotide transport pathways and suppresses primary carbon metabolism
Abstract Selenium biofortification in soybean is one approach to addressing widespread selenium deficiency in human populations, yet the temporal dynamics of gene expression and antioxidant responses following selenium enrichment remain poorly characterized. Here, we examined the physiological and transcriptional responses of the HK88 soybean variety to selenium-enriched nutrient solution treatment, with seedlings sampled at 1, 24, and 48 h post-treatment. Total tissue selenium rose from 0.01 mg/kg at 1 h to 0.33 mg/kg at 48 h, with parallel increases in both inorganic and organic fractions, consistent with active biotransformation, though this interpretation remains to be confirmed experimentally. Antioxidant responses followed a distinct temporal pattern: superoxide dismutase (SOD) and peroxidase (POD) activities were initially lower in treated plants at 1 h relative to controls but were elevated at 24 and 48 h, while catalase (CAT) activity remained comparatively low across all time points. Malondialdehyde (MDA) levels were lower in selenium-treated plants at 1 h, suggesting early membrane stabilization, though this difference was no longer apparent by 48 h. RNA sequencing of 18 libraries identified 6,793 differentially expressed genes (DEGs) at 1 h, peaking at 13,196 (approximately 18% of the 72,513 annotated genes) at 24 h, then declining to 8,996 at 48 h. A Venn diagram analysis identified 565 DEGs shared across all three time points, comprising 196 consistently up-regulated and 369 consistently down-regulated genes. Up-regulated genes were enriched for nucleotide transmembrane transport functions, including ATP, ADP, and purine transport, with associated ABC transporter activity. Down-regulated genes were predominantly associated with primary carbon metabolism, including monosaccharide biosynthesis, gluconeogenesis, and the Calvin cycle. Gene Set Variation Analysis (GSVA) indicated positive enrichment scores for nucleotide transport pathways at 24 and 48 h in treated plants, contrasting with negative scores in controls. Mantel tests revealed significant associations between gene set activity profiles and measured physiological traits, particularly for gene sets related to molecular function and selenium accumulation. These findings suggest that selenium biofortification in HK88 is associated with a coordinated metabolic shift, in which primary carbon fixation is reduced while nucleotide transport capacity is enhanced, supporting antioxidant defense during selenium assimilation.
Glycosylation-independent functions for distinct glypican core proteins drive cell-specific responses in corticogenesis
The extracellular matrix plays critical roles in orchestrating cell communication and behaviors in response to various extracellular signals. It is a complex network composed of proteins and polysaccharides, whose individual and synergistic roles in cellular signaling, structural integrity, and tissue homeostasis remain active areas of investigation. Here, we find that in the developing cerebral cortex, distinct glypicans, which are heparan sulfate proteoglycans, present very precise and complementary expression patterns. More precisely, GPC4, which is expressed in cortical progenitors, promotes their proliferation and the generation of intermediate progenitors, whereas neuronal GPC2 acts as a brake on radial neuronal migration. The diverse biological functions of these proteoglycans are widely regarded as being intrinsically tied to their glycosaminoglycan (GAG) chains. Strikingly, we found that these effects are mediated only through glypican core proteins, rather than their heparan sulfate glycosylations. We found that the only difference between them is in their C-terminal disordered regions, which have a high density of charged residues. GPC2 is strongly basic, whereas GPC4 is acidic. Together, our findings highlight how specific proteoglycan protein cores are required to drive sequential cellular responses during cortical development in a glycosylation independent manner.