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Dosage compensation and meiotic sex chromosome inactivation are maintained under relaxed selection
Dosage compensation and meiotic sex chromosome inactivation (MSCI) are key mechanisms regulating gene expression from the X chromosome in male-heterogametic species. While the convergent evolution of these mechanisms is well documented, their evolutionary fate under relaxed selection remains poorly understood. Here, we test whether dosage compensation and MSCI persist following three independent transitions to parthenogenesis in stick insects, where selection on male phenotypes is relaxed. Using rare males occasionally produced by parthenogenetic females, chromosome-level genome assemblies, RNA-seq from multiple tissues, and immunocytochemistry, we find that dosage compensation is fully conserved across all seven studied somatic tissues. This is even the case in the oldest, approximately 1.5 My old all-female lineage and for tissue-specific genes for which dosage variation is not expected to be very deleterious. Meiotic X inactivation in the germline is also conserved. Surprisingly, however, expression data and cytological markers indicate that MSCI signatures are even stronger in parthenogenetic males, a pattern likely driven by prolonged autosomal transcription during meiosis. These results indicate that X-targeting dosage compensation and MSCI are highly stable over evolutionary time and may be maintained in all-female lineages by a combination of evolutionary constraint, pleiotropy, or very weak selection, whereas autosomal expression during meiosis shifts rapidly under relaxed selection.
Personalized content generation in family education based on deep learning
Tumor-derived cytokine enhances bitter sensing through remote control of bitter taste neurons via the Upd3/Spz5/Toll-6 axis in <i>Drosophila</i>
The sense of taste is essential as it governs appetite and the feeding process. However, it is largely unknown whether and how tumors in a host communicate with peripheral taste sensing. Using the well-established yki S168A tumor models in Drosophila melanogaster , we found that flies carrying brain or gut tumors exhibit enhanced avoidance of bitter compounds such as caffeine but showed no avoidance of sucrose, and the degree of the avoidance was correlated with severity of the tumor phenotype. Through RNAi screening of upregulated cytokines secreted by malignant tumors, we identified Upd3 as a key factor in this process. Tumor-derived Upd3 promotes systematic increase of Spz5 expression, a fly neurotrophin, which in turn activates the Toll-6 receptor in peripheral bitter sensing neurons, leading to upregulation of the bitter-sensing receptor Gr66a. In vivo Ca 2+ imaging demonstrated heightened responses to caffeine by Gr66a + neurons in tumor-bearing flies. Interestingly, a similar phenomenon was observed in murine tumor models, where tumors also caused behavioral hypersensitivity to bitter tastants. Our findings reveal how tumors affect animals’ feeding behavior as well as the underlying mechanism. Our findings also suggest that such tumor-induced behavioral alterations are likely conserved across species.
Spatial inequalities in out-of-hospital cardiac arrest in Lombardy, Italy are associated with ageing, population density and low income
Bursa of Fabricius–independent B cells establish an IgA-mediated intestinal barrier that safeguards gut–liver homeostasis
The bursa of Fabricius (BF), a specialized lymphoid structure in birds, regulates avian B-cell development. However, the BF starts to regress posthatching, suggesting that as-yet-unidentified structures assume this function during maturation. This study reveals that BF-independent B-cell genesis involving the gut cecal tonsils (CTs) predominates over the BF-dependent pathway posthatching. Although B-cell progenitors originating from the bone marrow (BM) typically migrate to the BF, we identified a population that instead migrates to the CTs through CXCL12/CXCR4-mediated chemotaxis. These BF-independent CXCR4 + pre-B cells acquired surface IgM expression within the CT follicular region (FR) and differentiated into immunoglobulin A (IgA)-producing plasma cells. Inhibition of CXCR4 + cell influx from the BM impaired formation of the FR, altered the responsiveness of intestinal IgA to commensal bacteria, promoted gut dysbiosis, allowed translocation of pathogenic bacteria (e.g., Streptococcus alactolyticus ) to the liver, and ultimately caused hepatic inflammation and metabolic dysfunction. These abnormalities were reversed by administering an IgA-enriched fecal preparation derived from healthy chickens. Collectively, these results reveal the existence of a population of BF-independent B cells that function in CTs. These cells represent a promising target for maintaining and improving the immunological and microbiological environment of the avian intestinal tract, which is closely linked to hepatic homeostasis.
Impaired left ventricular transmural strain gradient linked to septal flash in complete left bundle branch block
Targeted α-synuclein mRNA degradation by PMO-based RNA-degrading chimeras
α-Synucleinopathies are devastating neurodegenerative diseases characterized by pathological accumulation of a neuronal protein, α-synuclein (αSyn). Lowering soluble αSyn levels is a promising therapeutic strategy to limit aggregation and neurotoxicity, but directly targeting this protein is hindered by its intrinsically disordered structure and other factors, such as its conformational heterogeneity and intracellular drug delivery barriers. Consequently, increasing attention has been directed toward targeting the SNCA transcript, which encodes αSyn. Here, we developed phosphorodiamidate morpholino oligonucleotide (PMO)-based RNA-degrading chimeras (RDCs) that selectively bind the 5′ untranslated region of SNCA messenger RNA (mRNA) and recruit RNase L for targeted RNA degradation. Through the systematic evaluation of nine RDCs, we identified and optimized 4-D1, which effectively reduced SNCA mRNA and αSyn protein expression in HEK293T cells in an RNase L-dependent manner. 4-D1 lowered SNCA transcript and αSyn protein levels in both primary cortical neurons from humanized SNCA mice and in human induced pluripotent stem cell–derived cortical neurons. This reduction prevented prion-like seeding induced by patient-derived αSyn fibrils and protected neurons from fibril-induced cytotoxicity. Finally, in vivo studies confirmed the efficacy of 4-D1 in reducing αSyn mRNA expression in humanized SNCA mice. These findings indicate that PMO-based RDCs may represent a promising therapeutic modality for α-synucleinopathies.
Nano Eco-Scale: A scoring system for the assessment of the greenness and safety of manufactured nanomaterials for analytical and environmental applications
Abstract Manufactured nanomaterials (MNMs) have transformed analytical and environmental applications by improving efficiency and reducing resource use. However, the "nano-paradox" has raised concerns about the use and development of nanotechnology, complicating regulatory agencies’ ability to monitor MNM’s environmental impact. In this work, a novel metric tool, the Nano Eco-Scale, is proposed to assess the greenness and environmental safety of nanomaterials used in analytical and environmental applications. The framework is based on the principles of green analytical chemistry and is aligned with REACH regulations for nanomaterials, while incorporating recommendations from the Organization for Economic Co-operation and Development for standardized characterization and safety evaluation. The tool assigns penalty points to deviations from the ideal nanomaterial across four main domains: synthesis conditions, nanomaterial toxicity, exposure during use, and waste generation and disposal. The overall score is calculated as 100 minus the total penalty points. The Nano Eco-Scale score supports the evaluation and comparison of environmental impacts associated with MNM-based analytical applications such as sensing, environmental monitoring, and water treatment. This approach encourages detailed characterization, highlights potential ecotoxicity risks, and promotes safer-by-design strategies. As a screening tool, it enables rapid comparisons and helps guide the selection of safer and more sustainable options. Additionally, it facilitates systematic data collection that could support future classification approaches. The developed tool supports regulatory efforts and advances the responsible use of nanotechnology in analytical and environmental fields.
Cryogenic silicification enables nongenetic functional continuity across mammalian cell generations
Mammalian cells are intrinsically soft, with Young’s moduli typically ranging from 0.1 to 10.0 kPa depending on the organization of the F-actin cytoskeleton, rendering them highly susceptible to mechanical and environmental stresses. This inherent fragility severely constrains their manipulation and functional deployment under nonphysiological conditions. Here, we report a cryogenic dormancy–enabled silicification strategy that achieves deep integration of inorganic silica reinforcement within living mammalian cells while preserving cell viability and proliferative capacity. Transient membrane permeability during cryogenic dormancy allows intracellular accumulation of silicic acid, which subsequently undergoes protein-mediated condensation to form a conformal amorphous silica network spanning both extracellular and intracellular compartments. The resulting silica–cell hybrids, termed Silicacytes , exhibit substantially enhanced mechanical robustness and resistance to a broad range of environmental stresses. Notably, this materials-mediated reinforcement is neither permanent nor genetic in nature: silica structures are progressively partitioned during cell division, conferring a pseudoheritable enhancement that persists for two to three generations before gradually dissipating. By enabling a reversible and temporally bounded extension of cellular robustness without altering genetic identity, cryosilicification establishes a nongenetic mode of functional continuity across cell generations. This work expands the conceptual framework of material–cell interactions and provides a general strategy for transient cellular reinforcement, with implications for cell engineering, immune cell manipulation, and the development of adaptive biohybrid systems.
Comparison of atmospheric cold plasma and pulsed electric fields for bioactive compound extraction and color preservation in Rosa foetida Herrm
Fly navigational responses exploit plume-specific odor motion and gradient cues
Odor cues guide animals to food and mates. Different environmental conditions can create differently patterned odor plumes, making navigation more challenging. Prior work has shown that animals turn upwind when they detect odor and cast crosswind when they lose it. Animals with bilateral olfactory sensors can also detect directional odor cues, such as odor gradient and odor motion. It remains unknown how animals use these two directional odor cues to guide crosswind navigation in odor plumes with distinct statistics. We investigated this problem theoretically and experimentally. Here, we show that these directional odor cues provide complementary information for navigation in different plume environments. We numerically analyzed experimentally generated plumes to show that odor gradient cues are more informative about crosswind directions in a smooth odor plume, while odor motion cues are more informative in a complex plume. Neural networks trained to optimize crosswind turning converged to distinctive network structures that are tuned to odor gradient cues in a smooth plume and to odor motion cues in a complex one. These trained networks improved the performance of artificial agents navigating plume environments that match the training environment. Last, we recorded Drosophila fruit flies as they navigated these odor plume environments. In the smooth plume, the gradient cue was the significant predictor of fly crosswind turning; in the complex plume, the motion cue was the significant predictor. Overall, these results demonstrate that these directional odor cues are complementary across environments and that animals exploit this relationship to navigate plumes with different statistics.
Combining residual U-Net and data augmentation for dense temporal segmentation of spike wave discharges in single-channel EEG
Abstract Manual annotation of spike-wave discharges (SWDs), the electrographic hallmark of absence seizures, is labor-intensive for long-term electroencephalography (EEG) monitoring studies. While machine learning approaches show promise for automated detection, they often struggle with cross-subject generalization due to high inter-individual variability in seizure morphology and signal characteristics. In this study we compare the performance of 16 machine learning classifiers on our own manually annotated dataset of 961 hours of EEG recordings from C3H/HeJ mice, including 22,637 labeled SWDs, and find that a 1D U-Net performs best. We then improve its performance by employing residual connections and data augmentation strategies combining amplitude scaling, Gaussian noise injection, and signal inversion to enhance cross-subject generalization. Our proposed model, AugUNet1D, achieves an average F1-score of 0.90 with balanced precision (0.91) and recall (0.90), representing a 29% relative improvement over the “Twin Peaks” algorithmic baseline and exceptional cross-subject performance. AugUNet1D, pretrained on our manually annotated data, along with the dataset itself, is made public for other users.
Dielectric levitation optical tweezers for powerful mesoscale biomanipulation
Optical tweezers (OT), a cornerstone of micromanipulation, are fundamentally constrained by substrate-induced adhesion and friction, limiting their application to mesoscale objects and fragile biological specimens where overcoming these resistive forces requires physiologically damaging laser powers. Here, we overcome this long-standing challenge by introducing dielectric levitation optical tweezers (DL-OT), a multiphysics platform that seamlessly integrates alternating-current dielectric levitation with optical traps. By using negative dielectrophoresis (n-DEP) to actively neutralize the normal force, DL-OT eliminates solid – solid contact and near-wall viscous drag. Crucially, we demonstrate the fundamental superiority of this active physical levitation over traditional passive antiadhesion coatings. This physical decoupling enables the smooth translation of large biological samples using low, biologically safe optical powers (~15 mW) rather than nonviable levels (>150 mW). The creation of this frictionless environment not only boosts the maximum manipulation speed of standard microtargets by 40% but also enables the stable optical transport of previously intractable mesoscale objects (100 to 260 μm), including microgears and shrimp eggs. By preventing photothermal damage and mechanical deformation, DL-OT demonstrates very good biocompatibility, significantly enhancing cell viability postmanipulation. Building upon these advantages, we demonstrate advanced on-chip biofabrication protocols through the targeted, high-precision assembly of multicellular spheroids and the safe transport of patient-derived organoids, followed by their success in situ culture. By transforming OT from a microscale tool into a mesoscale assembly platform, DL-OT paves the way for breakthroughs in tissue engineering, regenerative medicine, and the bottom – up assembly of living systems.
Semantic neighborhood-aware fuzzy clustering for balanced text categorization
Social evolution and diminished olfactory function in larval honey bees
Social evolution made larval honey bees dependent on adult colony members for feeding; they are confined to cells in waxen honeycombs and visited about 100 times per day by adult “nurse” bees. Based on organismal resource conservation theory, we predicted larvae have diminished olfactory capabilities at both the molecular and behavioral levels. Consistent with theory, larvae expressed very low levels of Orco , an essential gene for olfactory receptor (OR) function. By contrast, they showed higher expression of Ir25a, essential for other forms of sensory perception including gustation. Also consistent with theory, behavioral assays demonstrated that larvae cannot find food via olfaction, suggesting they use taste for feeding. By contrast, it is known that adult honey bees use OR-based olfaction extensively for a variety of behavioral functions, and the honey bee genome contains many OR-encoding genes. Comparative transcriptomic analyses of social and nonsocial insects suggest that this developmentally regulated suppression of olfactory function is related to social evolution, especially systems of offspring care.
Optimal control of a heat flow system via novel enhanced quadratic interpolation optimization tuned 2DOF-PID controller
Abstract This study addresses the optimal temperature regulation problem of a laboratory-scale heat flow system using a two-degree-of-freedom proportional–integral–derivative (2DOF-PID) controller tuned by a newly developed enhanced quadratic interpolation optimization (eQIO) algorithm. The main contribution lies in improving the original quadratic interpolation optimization (QIO) framework by integrating two lightweight enhancement mechanisms: a periodic parabolic local search to strengthen local exploitation and a stagnation-aware diversity recovery strategy to prevent premature convergence. The enhanced formulation preserves the deterministic interpolation-based structure of QIO while increasing convergence reliability and robustness without introducing additional algorithmic complexity. The effectiveness of eQIO is first evaluated on ten benchmark functions from the CEC-2019 test suite and compared with QIO, mountain gazelle optimization, tuned moss growth optimization, whale optimization algorithm, and superb fairy-wren optimization algorithm. Statistical results obtained from 500 independent runs indicate that eQIO consistently improves average solution quality and reduces standard deviation relative to QIO, while achieving competitive performance against population-based metaheuristic algorithms. Subsequently, eQIO is employed to tune the parameters of the 2DOF-PID controller for real-time temperature regulation experiments under step, square, and sinusoidal reference signals. The experimental results demonstrate reduced overshoot, lower steady-state error, improved tracking accuracy, and smoother control effort compared with alternative optimizer-based tuning approaches. Quantitatively, the proposed eQIO-based 2DOF-PID controller reduces the total mean absolute error (MAE) by 14.8% under step–square reference signals and by 45.8% under step–sinusoidal reference signals compared with the original QIO-based controller, while also providing smoother control action and improved tracking robustness. Overall, the proposed eQIO-driven 2DOF-PID framework establishes a computationally efficient and experimentally validated methodology for reliable thermal system control.
Revealing ancient macroH2A features through in vivo analysis in the cricket <i>Gryllus bimaculatus</i>
macroH2A is one of the most atypical histone variants, being three times larger than canonical H2A due to its unique extranucleosomal macrodomain. Once thought to be vertebrate-specific, macroH2A is in fact an evolutionary ancient histone, encoded by two genes in vertebrates and a single gene in other eukaryotes. However, the absence of macroH2A in Drosophila and Caenorhabditis elegans have precluded its functional characterization beyond vertebrates. Here, we report the functional characterization of macroH2A in an invertebrate, enabled through genome editing in the cricket Gryllus bimaculatus . Endogenous tagging of the cricket macroH2A gene revealed a highly dynamic distribution of macroH2A during gametogenesis and a general association with heterochromatin. In embryos, macroH2A shows a remarkable enrichment in differentiating cells, particularly in the nervous system and muscles. Interestingly, complete gene deletion reveals that macroH2A is dispensable for viability but critical for survival after irradiation. We further show that embryos lacking the linker and macrodomain of macroH2A are equally hypersensitive to DNA damage, demonstrating that this nonhistone region safeguards genome integrity beyond vertebrates. Finally, removing the extranucleosomal domain of macroH2A unexpectedly disturbs its chromatin incorporation in a cell-type-specific manner. This study thus reveals deeply conserved features of macroH2A, shared between insects and vertebrates, but also provides insights about the regulation of its chromatin incorporation.
Experimental evaluation of the thermal performance of a parallel microchannel cooling system for thermal management of multicore processors under low computational loads
Distinct cell type–specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation
Persistent activation of the integrated stress response (ISR) is a central driver of cognitive decline in both neurodevelopmental and neurodegenerative disorders. However, the cell type–specific mechanisms underlying these deficits remain poorly understood. By integrating single-cell RNA-seq and single-cell assay for transposase-accessible chromatin sequencing, we generated a brain ISR atlas using Ppp1r15b R658C mice, a clinically relevant model of intellectual disability characterized by selective and persistent ISR activation. We find that distinct brain cell types differentially engage transcriptional and chromatin remodeling programs. Notably, selective deletion of the major ISR downstream effector ATF4 in GABAergic neurons, but not in glutamatergic neurons, exacerbates ISR-mediated cognitive decline in Ppp1r15b R658C mice, demonstrating that different neuronal subtypes rely on distinct ISR effectors. We define a molecular single-cell signature of persistent ISR activation that serves as a metric of ISR-mediated cellular vulnerability and as a biomarker for cognitive dysfunction across human cognitive disorders. These findings demonstrate that cell type–specific responses drive cognitive dysfunction during persistent ISR activation.