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p38β-mediated BiP phosphorylation drives stemness and chemoresistance by suppressing UPR activation in hepatocellular carcinoma
Abstract Tumor-initiating cells (TICs) promote tumor initiation and therapy resistance, yet the kinase regulators that sustain TICs remain incompletely defined. Here, we identify the stress kinase p38β (MAPK11) supports TIC maintenance and drug resistance in hepatocellular carcinoma (HCC). Integrated analysis of chemotherapy-enriched HCC spheroids, and DepMap data prioritized p38β as a kinase linked to stemness and chemoresistance. High p38β expression correlates with poor prognosis and aggressive clinicopathological features in HCC patients. Mechanistically, p38β phosphorylates the endoplasmic reticulum (ER) chaperone BiP at threonine 648, enhancing its association with the unfolded protein response (UPR) sensors PERK and IRE1-α. This modification suppresses UPR activation and reduces unfolded protein accumulation, thereby preserving ER proteostasis under chemotherapeutic stress. Functionally, p38β-driven BiP phosphorylation sustains TIC phenotypes and cisplatin resistance in vitro and in vivo. BiP inhibition with HA15 restores UPR signaling and sensitizes patient-derived xenograft and organoid models to cisplatin, revealing a targetable p38β–BiP axis in HCC.
Mitochondrial electron transport chain is essential for acute inflammatory stress responses in mouse fibroblasts
Abstract Fibroblasts are linked to stress responses in a broad number of diseases. Here, we used immortalized mouse embryonic fibroblasts (iMEFs) to elucidate their signaling behavior in response to proinflammatory lipopolysaccharides (LPS) and angiotensin II (Ang-II). To test for the role of the mitochondrial electron transport chain (ETC), iMEFs were cultured in glucose- and galactose-containing media promoting glycolysis and mitochondrial oxidative phosphorylation, respectively. In addition, we used alternative oxidase (AOX), a ubiquinol oxidoreductase that serves as a naturally evolved rescue mechanism in case of ETC disruption. We found that within 24 h of treatment, LPS upregulated a number of proinflammatory genes, namely Tlr4 , Il6 , Tgfb1 , Nlrp3 , Casp1 , and Il1b ; largely, the effect was more pronounced in galactose-containing media and attenuated by AOX. The increase in transcripts resulted partly in elevated cytokine secretion. Twenty-four hours of Ang-II treatment also induced these genes, albeit to a lesser degree and less sensitive to AOX. Cellular oxygen consumption rates (OCRs) were higher in galactose media but remained unaffected by either stimulus. Our results suggest that fibroblasts undergo a similar proinflammatory phenotypic shift in response to different stressors. This response is shaped by ETC activity, which, surprisingly, is not reflected in altered OCRs.
Extensive binding of poorly characterized human transcription factors to genomic dark matter
Abstract The functional impact of a large portion of the human genome known as “dark matter DNA”, which is composed mainly of repeat sequences, remains unknown. The genome also encodes many putative and poorly characterized transcription factors. Here, we determine genomic binding locations of 166 poorly characterized human transcription factors in living cells. Nearly half of them associate strongly with known regulatory regions such as promoters and enhancers, frequently co-localizing with each other at conserved motif matches. The other half often associate with genomic dark matter, however, at largely non-overlapping (i.e., unique) sites, via intrinsic sequence recognition. Fifty-four of the latter half, which we term dark transcription factors , mainly bind within regions of closed chromatin, with each recognizing a unique set of repeat sequences. The dark transcription factors include many KZNFs, which are known to bind and silence transposable elements, and other transcription factors with apparent repressive functions. Others may be pioneer transcription factors. For example, we find that induction of TPRX1, a known regulator of zygotic preimplantation, leads to chromatin opening at many of its binding sites in the dark matter genome.
Effect of fractionated therapeutic radiotherapy on surface microhardness and roughness of giomer- and ormocer-based restorative composites: an in vitro study
Abstract The influence of therapeutic radiation on the surface properties of contemporary restorative materials remains an important area of investigation. This study aimed to assess the effect of therapeutic radiation on the microhardness and surface roughness of two restorative materials, as these properties are associated with restoration durability. Ninety-six discs were fabricated from Giomer and Ormocer resin composites (n = 48 per material). Specimens were randomly allocated to two subgroups: surface microhardness ( MH ) and roughness ( Ra ), based on the tests performed (n = 24). For each test, specimens were further subdivided into two subgroups (n = 12). IR0: control, no irradiation; IR1: irradiated, exposed to a total of 70 Gy over 35 days (2 Gy/day, 5 days/week) using a linear accelerator (10 MV photons, 2 Gy/fraction). MH was measured using a 100 g load for 15 s, and Ra was evaluated using a non-contact digital microscopy method and analyzed with WSxM software. Data were analyzed using two-way ANOVA, with significance set at p < 0.05. No significant differences were detected between control and irradiated specimens in either microhardness or surface roughness ( p > 0.05). Both restorative materials demonstrated stable surface microhardness and roughness, following exposure to a clinically relevant radiotherapy protocol.
Linearly dispersing carriers in atomically thin NdTe3
Expanding the supply of human leukocytes for research by harvesting cell concentrates from Trima Accel tubing sets
Abstract Leukoreduction system (LRS) chambers from the Trima Accel apheresis platform are widely used as a convenient source of human peripheral blood mononuclear cells (PBMCs) for immunological research. However, increasing demand has prompted the search for alternative sources. Here, we investigated whether residual cell concentrates recovered from Trima Accel tubing sets, typically discarded after platelet apheresis, could serve as a substitute for concentrates obtained from LRS chambers. Paired samples from 20 healthy platelet donors were analyzed for recovered volume, cellular composition and yield, leukocyte subset distribution, and functional responsiveness. Tubing sets contained significantly greater volumes (23.04 ± 14.1 ml vs. 8.14 ± 0.97 ml) but lower leukocyte concentrations (35.19 ± 16.99 × 10³/µl vs. 147.60 ± 59.63 × 10³/µl) than LRS chambers. Absolute leukocyte numbers were slightly higher in LRS chambers. However, cell frequencies in tubing sets showed a minor enrichment of monocytes and a modest lymphocyte depletion. Detailed flow cytometry characterization further revealed comparable distributions of major leukocyte populations and T cell subsets, including naïve and memory compartments, without biologically meaningful differences in activation or differentiation markers. Importantly, PBMCs from both sources exhibited comparable functional responses following phytohemagglutinin (PHA) stimulation, including similar changes in activation marker expression and cytokine production. Short-term storage of tubing set samples for 24 h at 4 °C did not compromise cell viability. Overall, tubing sets represent a functionally equivalent and practical alternative leukocyte source for research applications.
Structural basis for the contribution of latent TGFβ binding protein to TGFβ latency and activation
Abstract Transforming growth factor-β (TGFβ) is a potent cytokine that controls all aspects of cellular behavior. TGFβ is secreted in complex with its prodomain and latent TGFβ-binding protein-1 (LTBP1), forming the large latent complex (LLC), which through interaction with the extracellular matrix enables integrin-mediated activation. Although TGFβ structures are known, the influence of LTBP1 on the structure and activity of TGFβ is unknown. Here, we report the LLC cryo-EM structure comprising the LTBP1 eight-cysteine domain covalently bound to TGFβ, revealing a hydrophobic interface between TGFβ and LTBP1. Structure-guided mutagenesis shows that the interface is important for complex formation and TGFβ activity. Our structure supports a contralateral domain swapped architecture in the LLC, and simulations show that this architecture requires increased force to overcome barriers for integrin-mediated activation, while the covalent attachment of TGFβ to LTBP1 redistributes force to reduce unfolding barriers. These insights will be important for therapeutic strategies targeting TGFβ.
PelvisNet: sex-specific skeletal age estimation framework using X-ray radiographs
Abstract Accurate skeletal age estimation is essential in medicolegal investigations, particularly when identification records are unavailable or suspected of tampering. Unlike other joints, the pelvis remains informative throughout adolescence and early adulthood, exhibiting strong sexual dimorphism. However, traditional age-estimation techniques based on the pelvis rely heavily on experts and are highly subjective, prone to inter-observer differences. Furthermore, low contrast, high inter-variability between foreground and background, variability in sex-specific age patterns, and anatomical overlap in pelvis X-rays make it difficult to extract automatic features. To overcome these limitations, this paper presents PelvisNet, a new sex-specific deep learning framework for estimating skeletal age from pelvis radiographs. The proposed framework consists of Contrast Limited Adaptive Histogram Equalization (CLAHE) for low-contrast image enhancement, Region-Based Symbolic Segmentation (RSSeg) for accurate extraction of high inter-variability in the foreground and background of the pelvis region, and an EfficientNetB5-based network for hierarchical feature learning, effectively extracting anatomical overlap features. Additionally, the sex-specific age pattern aids sex classification, and probabilistic information is then combined with deep features to estimate age groups. The framework was evaluated on a database of 1,837 pelvis radiographs obtained from primary and secondary sources across age categories relevant to medicolegal practice. The accuracy of sex-based age group estimation reached 91.67%. The proposed framework offers a reliable, clinically interpretable decision-support tool for medicolegal age estimation, where accuracy and reliability are important, particularly across overlapping adolescent age groups.
Global trade-offs between consumption, carbon prices and equity
Nonlinear reduced order probabilistic emulation for high-dimensional thermospheric density using SINDYc
Abstract This work demonstrates the first successful application of SINDYc, a framework for dynamics identification with control, to model thermospheric density. It also marks the first use of SINDYc on such a high-dimensional system, significantly exceeding the complexity of prior applications in the literature, thus highlighting its operational and scientific value. Here we develop and study the components of a probabilistic emulator of the thermosphere using the output of TIE-GCM, a physics-based model used to describe the thermosphere-ionosphere system. The analysis covers altitudes ranging from 100 to 450 km. The thermospheric density state is represented by a tensor $$\rho (t) \in \mathbb {R}^{24 \times 20 \times 16} \sim \mathbb {R}^{7680}$$ . From this, we obtain the latent space representation using PCA and do SINDYc-based nonlinear modeling. Building upon previous Dynamic Mode Decomposition with control (DMDc) approaches with nonlinear inputs, we show that the relative MAPE improvement of SINDYc models over DMDc reaches a peak of $$\sim 70\%$$ during the recovery phase of geomagnetic storms. Moreover, the SINDYc model accurately tracks the dynamical evolution of the density state, matching or exceeding the fidelity of the NRL-MSIS model along the CHAMP satellite trajectory during the storm. The framework’s seamless transition between discrete and continuous formulations further underscores its versatility, making this advancement significant for both scientific exploration and operational applications.
Vitamin B5 supports anti-PD1 response in HER2-positive gastric cancer and enhances interaction between naïve B cells and T cells
Comprehensive NMR metabolomic profiling reveals a pro-atherogenic signature in psoriasis
Abstract Psoriasis (PS) is a chronic inflammatory skin disease associated with cardiometabolic comorbidity. While systemic inflammation is recognized as a major driver of this risk, metabolomic signatures linking PS to cardiometabolic dysfunction remain incompletely defined. The aim of this study was to characterize the serum metabolomic profile of PS and identify metabolic alterations that may contribute to cardiometabolic risk. Fasting serum samples from 455 individuals with PS and 591 matched controls were measured using proton NMR spectroscopy. A total of 325 biomarkers including lipoproteins, fatty acids, amino acids, apolipoproteins, inflammation-related metabolites and their ratios were quantified. PS demonstrated an atherogenic metabolic signature characterized by increased LDL, ApoB, triglyceride-rich VLDL, and small HDL/LDL subclasses. Elevations in saturated, monounsaturated, and omega-6 fatty acids–including linoleic acid were observed, alongside increases in histidine and valine and decreases in glycine and phenylalanine. Differential correlation and interaction analyzes revealed extensive remodeling of the metabolic network architecture in psoriasis. It can be concluded that PS is associated with coordinated disturbances across lipid, fatty-acid, and amino-acid pathways, reflecting a systemic pro-atherogenic and pro-inflammatory environment. These metabolomic alterations provide mechanistic insight into heightened cardiometabolic risk and highlight potential biomarkers for disease stratification and future interventional studies.
Genome shuffling enables quantitative trait locus mapping in Bacillus subtilis
Abstract Genetic mapping is a powerful tool for eukaryotic genetics that has only been applied to bacteria in limited circumstances. Quantitative trait locus (QTL) mapping generally relies on sexual recombination to break linkages between genes, yet bacteria rarely undergo sufficient homologous recombination to generate suitable mapping populations. In this work, we used iterative biparental genome shuffling by protoplast fusion in Bacillus subtilis to generate a population of bacteria with substantial random recombination throughout their genomes. Individual shuffled progeny were arrayed in well plates, resequenced, and characterized for a range of complex phenotypes, including spore germination and swarming motility. Genetic mapping of the resulting phenotypes identified high-confidence QTLs of moderate size (~15 kb), and these associations were validated through targeted genetic swaps. This B. subtilis QTL population can easily be used to map additional phenotypes and the general approach for QTL mapping is applicable to a wide range of Gram-positive and Gram-negative bacteria using diverse methods for genome-wide recombination.
The role of adult romantic attachment in long-term childhood cancer survivors’ social relationships and help-seeking
Abstract Childhood cancer survivors (CCS) are at risk for health-related and social challenges that can extend far into adulthood. However, CCS’ trajectories are heterogeneous. As a potential influencing factor, the present work investigated adult romantic attachment in conjunction with their relationship perceptions and experiences and help-seeking behavior. CCS (N = 633, aged 24–49 years) were recruited in cooperation with the nationwide German Childhood Cancer Registry (GCCR). Participants underwent a comprehensive medical examination at the study centre. Validated self-report questionnaires (including the ECR-RD8, PHQ-9, F-SozU K6, UCLA 3-item loneliness scale) and further items regarding help-seeking behavior were applied. Adult romantic attachment orientations were substantially related to CCS’ relationships in adulthood: Both more attachment anxiety and avoidance were linked to higher loneliness (r = 0.471, p < .001; r = 0.320, p < .001) and lower perceived social support (r = −0.349, p < .001; r = -0.300, p < .001). While 20.2% of CCS reported a need for psychosocial support, only 7.3% reported currently using a professional support offer. Lastly, attachment orientations also played a role in whether CCS voiced such a need when experiencing distress: Attachment anxiety moderated the relationship between suicidal ideation and the expression of a need for support, diminishing help-seeking. The findings emphasize the importance of integrating attachment-informed approaches in the long-term care of CCS. Tailored interventions addressing the interpersonal and emotional needs shaped by attachment styles could enhance resilience and mitigate barriers to seeking psychosocial support.
Phase separation of ecDNA condensates establishes in-trans contact domains that boost selective MYC regulatory interactions
Integrated One-Health analysis of antimicrobial resistance, biofilm formation, and genetic relatedness of Enterococcus spp. at the human-food interface
Abstract Enterococcus species are opportunistic pathogens and reservoirs of antimicrobial resistance (AMR) that can be transmitted through food chain. This study investigated Enterococcus faecalis and Enterococcus faecium isolated from retail meat, workers and consumers within a One Health framework. A total of 250 samples yielded 50 (20%) isolates, which were analyzed for antimicrobial resistance, virulence genes, biofilm formation, and RAPD-PCR genotyping. This study provides an integrated One Health assessment linking food contamination, occupational exposure, and human colonization. Beef meat showed the highest isolation rate, and E. faecium predominated among consumers. High resistance rates were observed for rifampin (94%, 47/50), erythromycin, and tetracycline (88%, 44/50, each), while vancomycin resistance was low (8%, 4/50). Multidrug resistance was observed in 88% of isolates, and MAR index ranged from 0.07 to 0.86 (average = 0.43). Biofilm formation occurred in 68% (34/50) of isolates, with moderate strength predominated. Resistance genes were widely distributed, particularly tet L (88%, 44/50), while esp (84%, 42/50) and gel E (68%, 34/50) were the most prevalent virulence genes. RAPD-PCR revealed five clusters with moderate discriminatory power (D = 0.729), demonstrating genetic relatedness across sources. Importantly, the co-occurrence of resistance, virulence, and biofilm traits across genetically related isolates highlights the possibility of the food chain as a potential transmission interface. These findings highlight the role of Enterococcus species in AMR dissemination within a One-Health framework.
Structural Characterization of Native RNA Polymerase II Transcription Complexes and Nucleosomes in Drosophila melanogaster
Abstract Structural studies of eukaryotic RNA polymerase II (Pol II) transcription often rely on in vitro assembly, which may not fully represent native conditions. To investigate Pol II transcription in metazoan cells, we developed a method to isolate native transcription complexes from Drosophila melanogaster embryos using FLAG-tag affinity purification and Micrococcal Nuclease treatment. Cryo-EM and proteomics studies revealed diverse transcription complexes and nucleosomes, including a metazoan Rpb4/Rpb7 stalk-less Pol II elongation complex and a hexameric nucleosome lacking an H2A/H2B dimer. Notably, nucleosome is found only downstream of the nucleosome elongation complex, underscoring it as a major energy barrier and a time-consuming step during Pol II progression through chromatin. Proteomics identified co-purified factors involved in transcription initiation, elongation, and RNA modification. This study provides a framework for investigations of transcription in cells, paving the way for future studies of transient and minor complexes.