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Functional integrity of the SEL1L–HRD1 complex is critical for endoplasmic reticulum–associated degradation and organismal viability
The SEL1L–HRD1 complex is the most conserved branch of endoplasmic reticulum–associated degradation (ERAD), yet whether SEL1L is strictly required for HRD1 function in mammals has remained unclear. Here, we show, using complementary in vivo and in vitro approaches, that direct SEL1L–HRD1 binding is essential for ERAD activity and neonatal survival. Three knock-in mouse models targeting this interface reveal a clear genotype–phenotype relationship: the L709P variant, which abolishes SEL1L–HRD1 association, causes complete neonatal lethality; the partially disruptive S658P variant results in partial lethality; and the P699T mutation preserves the interaction and yields normal viability. Mechanistically, our data show that the SEL1L–HRD1 interface is essential for ERAD complex formation and activity, enabling both substrate handoff and E2 enzyme recruitment, and that the L709P mutation effectively uncouples these core steps of the mammalian ERAD pathway. These findings establish SEL1L–HRD1 coupling as a core requirement for mammalian ERAD function and early postnatal viability.
Analytical and clinical validation of CancerMaster, an automated targeted NGS panel, for tumor-only precision oncology
Intense solar radiation constrains plant species richness in global grasslands
The search for predictors of plant diversity has challenged scientists for decades. Here we identify intense photosynthetically active radiation (PAR) as a major factor constraining plant species richness in global grasslands. We show that the strength of the negative relationship between species richness and PAR increases with increasing elevation and that species richness is more strongly correlated with intense PAR than with UV-B radiation, climate variables, and atmospheric nitrogen deposition. In addition to species richness, plant biomass was also negatively correlated with PAR at higher elevations, indicating that intense PAR also constrains plant biomass in montane grasslands. Furthermore, we show that the decrease in plant species richness with increasing PAR is mainly caused by a decrease in species richness of forbs, sedges, and rushes. In contrast, species richness of grasses was only negatively correlated with PAR at high elevations, and species richness of legumes was not significantly correlated with PAR. Our results suggest that PAR constrains plant species richness in global grasslands and limits the extent to which plant species of specific functional groups can migrate uphill in response to climate warming.
Airway mucus plugs in COPD clinical phenotypes and prognosis across stable and exacerbation states
Predictive free energy simulations through hierarchical distillation of quantum Hamiltonians
Obtaining the free energies of condensed phase chemical reactions remains computationally prohibitive for high-level quantum mechanical methods. We introduce a hierarchical machine learning framework that bridges this gap by distilling knowledge from a small number of high-fidelity quantum calculations into increasingly coarse-grained, machine-learned quantum Hamiltonians. By retaining explicit electronic degrees of freedom, our approach further enables a faithful embedding of quantum and classical degrees of freedom that captures long-range electrostatics and the quantum response to a classical environment to infinite order. As validation, we compute the proton dissociation constants of weak acids and the kinetic rate of an enzymatic reaction entirely from first principles, reproducing experimental measurements within chemical accuracy or their uncertainties. Our work demonstrates a path to condensed phase simulations of reaction free energies at the highest levels of accuracy with converged statistics.
Turbulence and particle dynamics in volcanic clouds in humid atmospheres
Mitochondrial transfer in the HSC–HCC–macrophage network shapes hepatocellular carcinoma progression
Mitochondrial crosstalk between tumor cells and components of the tumor microenvironment (TME) is a critical yet underexplored mechanism driving hepatocellular carcinoma (HCC) progression. Here, we demonstrate that in HCC, mitochondria can be transferred from hepatic stellate cells to cancer cells via tunneling nanotubes (TNTs), supplying essential energy for tumor growth. Simultaneously, cancer cells offload damaged mitochondria to macrophages through extracellular vesicles (EVs), facilitating their clearance and promoting tumor development. To disrupt this mitochondrial exchange, we developed a responsive liposomal nanocarrier (L&G@Lipo PPV ) coencapsulating L-778123 and GW4869 to simultaneously inhibit TNT-mediated and vesicle-mediated mitochondrial transfer. This work provides the first comprehensive evidence of mitochondrial transfer dynamics in the TME, with tumor cells as the central hub, and highlights L&G@Lipo PPV as an innovative and effective strategy to block mitochondrial crosstalk. Our findings address critical challenges of drug solubility and delivery, offering a rational approach to reprogram the TME and suppress liver cancer progression.
Research on improved models for facial expression recognition in mice with abnormal glucose metabolism
Evaluation of targeted and immune combination therapies in a rat model of hormone receptor–positive breast cancer
Estrogen receptor (ER) positive breast cancer is the most prevalent subtype, commonly responsive to endocrine therapies. Immune checkpoint inhibitors (ICIs) have limited efficacy in ER-positive disease, highlighting the need for the development of combination immunotherapies for these patients. We previously established that nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats mimic immune evasive mechanisms and the heterogeneity of ICI response observed in patients. We identified a “luminal growing” gene signature in ER-positive tumors, which correlated with tumor growth and immune-related differences. Here, we evaluated targeting candidates from this signature KMT5B/C and IKBKE using inhibitors A-196 and IKBKEi respectively, alongside anti-estrogen (fulvestrant) and a TGFβ blocking antibody (NIS793), both individually and in combination with αPD-L1, within this rat model. Fulvestrant emerged as the most effective treatment, inducing regression of most existing tumors and reducing on-treatment tumor burden when combined with αPD-L1. A-196, while ineffective as a monotherapy, demonstrated enhanced response when combined with αPD-L1. Comprehensive tumor profiling through polychromatic flow cytometry and single-cell RNA sequencing revealed that A-196 induced a luminal-to-basal shift in tumor epithelial cells, enhancing antigen presentation, whereas epithelial-to-mesenchymal transition was linked to fulvestrant resistance. Our findings underscore the value of the rat mammary tumor model for preclinical studies in ER-positive breast cancer and advocate for the further validation and potential clinical development of KMT5B/C inhibitors to enhance the efficacy and broaden the applicability of ICI therapy in cancer patients.
Degradation of pharmaceutical contaminants in sewage wastewater using biosynthesised nanoparticle produced by halophilic bacterial strain and phytotoxicity
Dopaminergic mechanisms supporting hippocampal postencoding dynamics in humans
Deficits in dopamine function cause alterations in episodic memory. Converging evidence implicates dopamine in postencoding hippocampal mechanisms inferred to support long-term memory, though there is a lack of direct evidence in humans. We address this gap using pharmacological functional MRI (fMRI) and positron emission tomography (PET). Using a motivated reward encoding task on and off oral methylphenidate, we tested whether individual differences in baseline dopamine ([ 11 C]raclopride PET D2/3 receptor density) relate to drug-induced changes in hippocampal postencoding processes. Our study focused on healthy older adults, who are among those most vulnerable to memory decline and may benefit from pharmacologically enhancing dopamine. We found that methylphenidate administration was associated with improved memory performance relative to placebo for both high and low reward conditions. Older adults with high receptor density showed greater persistence of hippocampal multivoxel patterns into postencoding rest and stronger hippocampus-midbrain resting-state connectivity following encoding while on methylphenidate. These findings support the view that enhanced dopaminergic tone, verified through PET, directly modulates hippocampal postencoding dynamics in humans. Substantial variation in neurobiological effects was associated with individual differences in baseline dopamine function as older adults with high dopamine receptor density profiles showed preferential benefit of drug on hippocampal function, though these insights are qualified by null associations between memory performance and postencoding hippocampal activity. Individuals with lower dopamine receptor profiles showed preferential benefit of reward incentives suggesting altered sensitivity to extrinsic motivational factors depending on endogenous dopamine function.
Plasma screening in mid-charged ions observed by K-shell line emission
Abstract Dense plasma environment affects the electronic structure of ions via variations of the microscopic electrical fields, also known as plasma screening . This effect can be either estimated by simplified analytical models, or by computationally expensive and to date unverified numerical calculations. We have experimentally quantified plasma screening from the energy shifts of the bound-bound transitions in matter driven by the x-ray free electron laser (XFEL). This was enabled by identification of detailed electronic configurations of the observed K $$\upalpha$$ α , K $$\upbeta$$ β and K $$\upgamma$$ γ lines. This work paves the way for improving plasma screening models including connected effects like ionization potential depression and continuum lowering, which will advance the understanding of atomic physics in the Warm Dense Matter regime.
Environmental conditions shape the global distribution of ant societies
Sociality has evolved several times and is a key strategy for overcoming environmental challenges and promoting ecological success. Yet, it remains unclear how environmental conditions shape global variation in social traits of animals. With their diverse societies and global distribution, ants are ideal to test whether environmental conditions influence the distribution of animal social traits worldwide. Here, we used trait data for a total of 3,299 ant species to explore how three key social traits (reproductive structure, colony size, and worker polymorphism) vary with environmental conditions globally. We show that trait compositions are strongly structured by biomes, indicating that habitat types, as well as environmental factors like temperature and seasonality, influence sociality. Our findings highlight the crucial role of the environment in shaping the global distribution of sociality in ants, contributing to a better understanding of how complex animal societies evolved.
HLA-DPA1 as a diagnostic biomarker differentiating early- and late-onset preeclampsia
Clathrin-mediated endocytosis of ERECTA family receptors is essential for proper stomatal development in <i>Arabidopsis</i>
Stomata, specialized structures of plant epidermis, are crucial for gas (e.g., CO 2 , O 2 , and H 2 O) exchange between plants and the environment. Stomatal density and pattern are governed by ERECTA family (ERf) receptor-like kinases-controlled signaling. Clathrin-mediated endocytosis (CME) is a new mechanism for the internalization of receptors to activate the downstream signaling in animals. Here, we found that mutation of CME components resulted in formation of stomatal clusters and thus increased stomatal index. The adaptor protein 2σ (AP2σ) subunit of CME interacted with ERf. ERf receptor internalization required CME. Furthermore, the ERf receptor motifs were identified to be recognized by AP2σ. Genetic analysis showed that CME components CHC2, CLC2, and CLC3 acted downstream of EPIDERMAL PATTERNING FACTOR 1/2 while upstream of YODA and worked together with ERf to regulate stomatal development. Consistently, EPF2-induced MAPK activation was significantly reduced in chc2-2 clc2 clc3 and ap2μ clc2 clc3 mutants or when the ERf endocytic motifs were mutated, leading to stabilized SPEECHLESS protein and misregulated stomatal lineage progression. Overall, our findings demonstrate that activation of the ERf receptors via internalization is essential for stomatal development, establishing a mechanism of CME-mediated receptor internalization activation in plants.
Green synthesis of Ag/ZnO nanocomposites from Phyllanthus emblica seed for multifunctional wound healing applications
T cell receptors for antigen on intraepithelial cytolytic T lymphocytes in celiac disease engage enterocyte HLA-E and HLA-B
We compared duodenal biopsies showing active celiac disease (CeD) to normal controls using single-cell RNA sequencing, cyclic immunofluorescence, RNAScope, and proximity ligation assays. There is increased infiltration of villous but not crypt epithelium T cells bearing either αβ or γδ T cell receptors (TCRs) in CeD. Both T cell subsets are activated cytotoxic T lymphocytes (CTLs) and are the predominant mucosal source of IFNγ. In response to this IFNγ, villous but not crypt enterocytes show an IFNγ signature, including nuclear phospho-STAT1 protein, class II HLA molecules and IFNγ-inducible chemokines known to recruit CTLs (e.g., CCL3, CCL4, CXCL10, and CXCL11) and receptors for these chemokines are expressed on the infiltrating CTLs. Villous enterocytes also display increased HLA-E and HLA-B mRNAs and proteins. Bioinformatic analyses (NICHES) and proximity ligation assays show frequent binding of both αβ and γδ TCRs with enterocyte HLA-E or HLA-B , but not HLA-DR . In contrast, NKG2C, proposed as an alternative trigger of CTL activation, is infrequently expressed and shows few interactions with HLA-E. Our data suggest that activated intraepithelial CTLs produce IFNγ which recruits additional CTLs and increases antigen-dependent killing of villous epithelium using either conventional or HLA-E antigen presentation.