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REV-ERB-alpha and -beta coordinately regulate astrocyte reactivity and proteostatic function

The molecular circadian clock is a ubiquitous transcriptional–translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α ( Nr1d1 ) and REV-ERB-β ( Nr1d2 ) are components of the core circadian clock which regulate metabolism, neuroinflammatory responses, synaptic pruning, and protein aggregation, though the cell type–specific effects and relative compensatory effects of REV-ERB-α AND -β in the brain are unknown. To study the CNS functions of REV-ERBs, we developed mouse lines with global or astrocyte-specific, conditional knockout of both REV-ERB-α and -β. We demonstrate that inducible postnatal global deletion of both REV-ERB-α and -β unmasks extensive transcriptional changes in the brain in disease-relevant pathways such as protein catabolism, complement, and oxidative stress which are not observed with REV-ERB-α deletion alone, and drives spontaneous astrocyte reactivity. Astrocyte-specific deletion of REV-ERB-α/-β recapitulates this spontaneous astrocyte reactivity phenotype, indicating that REV-ERBs regulate astrocyte activation in a cell-autonomous manner downstream of the core circadian clock. Upstream transcription factor analysis revealed that REV-ERB-α/-β repress transcription of Stat3 , and astrocytic deletion of REV-ERBs induced astrocytic STAT3 expression and downstream STAT3-mediated gene expression, providing a mechanistic link to the astrocyte reactivity shift. Dual REV-ERB deletion enhanced astrocyte alpha-synuclein uptake and protein degradation in vitro and mitigated alpha-synuclein spreading pathology in an in vivo model of Parkinson’s Disease. This study reveals REV-ERBs as regulators of astrocyte function and implicates astrocyte REV-ERBs as potential therapeutic targets to prevent synucleinopathies and other neurodegenerative pathologies.

RNA sequencing reveals differential expression of circular RNAs in human small cell lung cancer

Stepwise differentiation from precursor intermediates and distinct Th1 checkpoints promote CD4 Th1 cell differentiation during chronic viral infection

CD4 + helper T cells are essential for controlling viral infections. During chronic LCMV infection, CD4 + T cells differentiate into heterogeneous populations, including a TCF-1 hi progenitor subset that serves as a reservoir to continuously replenish type 1 helper (Th1) and follicular helper (Tfh) T cells. The gradual loss of CD4 + Th1 cell responses impairs the immune system’s ability to control viral replication and contributes to the development of CD8 + T cell exhaustion. However, the mechanisms directing Th1 differentiation and the factors underlying their progressive decline during chronic infection remain poorly understood. In this study, we delineate the stepwise differentiation trajectory of Th1 cells, tracing their progression from TCF-1 hi progenitors through an intermediate state to fully differentiated Th1 cells. We identify an intermediate CD4 + T cell subset that serves as a precursor to Th1 cells, demonstrate that PD-1/PD-L1 signaling suppresses the transition from the progenitor to intermediate state, whereas the chromatin-remodeling complex PBAF restricts the terminal differentiation of CD4 + T cells into the Th1 subset. Notably, the combined blockade of PD-1/PD-L1 and genetic ablation of PBAF component (ARID2) additively enhanced Th1 differentiation and maintenance, leading to effective viral control. Thus, targeting these mechanisms driving CD4 Th1 cell differentiation and maintenance could enhance therapeutic strategies to restore Th1 function and control chronic infection.

Problematic mobile phone and social media use among adolescents and its relationship with cyberbullying, cybervictimisation and social anxiety

Evolutionary pathways in epistatic mechanical networks

An elastic spring network is an example of evolvable matter. It can be pruned to couple separated pairs of nodes so that when a strain is applied to one of them, the other responds either in-phase or out-of-phase. This produces two pruned networks, with incompatible functions, that are nearly identical but differ from each other by a set of “mutations” each of which removes or adds a single bond in the network. We generate ensembles of network pairs that differ by a fixed number, M , of discrete mutations and evaluate all M ! mutational paths between the in- and out-of-phase behaviors up to M = 14. With a threshold response for the network to be considered sufficiently fit for either function, so that nonfunctional networks are disallowed, only some mutational pathways are viable. We find that there is a surprisingly high critical response threshold above which no evolutionarily viable path exists between the two networks. The few remaining pathways at this critical value dictate much of the behavior along the evolutionary trajectory. The effect of multiple mutations is epistatic, that is, the impact of a mutation is not invariant but depends on what other mutations have already occurred. In most cases, the mutations break up into two distinct classes based on epistasis. The analysis clarifies how the number of mutations and the position of a mutation along the pathway affect the evolutionary outcome.

Multi-responsive, room-temperature self-healing salep-based nanocomposite hydrogels with enhanced mechanical performance as smart biomaterial

Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response

The general control nonderepressible 2 (GCN2) is a conserved stress-responsive protein that plays a critical role in restoring cellular homeostasis in the integrated stress response (ISR). In response to amino acid starvation or ribosome stalling and collisions, GCN2 phosphorylates the translation initiation factor eIF2α, conferring translational control to alleviate stress. GCN2 is a multidomain protein, containing a tandem kinase domain (KD) and a catalytically inactive pseudokinase domain (ψKD). Stress-induced activation of the kinase domain requires allosteric regulation and dimerization mediated by its regulatory domains. While the pseudokinase domain is essential for GCN2 function in yeast, its mechanistic role remains unclear and underexplored in other organisms. Here, we present the first crystal structure of the human GCN2 ψKD, revealing its distinct structural features. The structure visualizes an insertion N-terminal to helix αC unique to the GCN2 ψKD that interacts with the pseudoactivation loop, stabilizing an inactive conformation. Further structural analysis shows that the ψKD forms a dimer in the crystal lattice via a network of hydrophobic and electrostatic interactions spanning both the N- and C-lobes. Mutations that disrupt the dimer interface reduced downstream ATF4 expression that is important for stress adaptation, underscoring the functional significance of the GCN2 ψKD dimer in regulating GCN2 activity. Complementary AI-guided structure predictions indicate that the dimeric GCN2 ψKD architecture is conserved across evolution. These results support the role of ψKD dimerization as a regulatory feature in GCN2-mediated ISR signaling.

Changes in circulating small non-coding RNAs after castration in a cohort of prostate cancer patients

Fe metal–organic framework–derived heterojunction for metabolic diagnosis of thymic epithelial tumor

Thymic epithelial tumors (TETs), rare yet clinically significant malignancies, face diagnostic challenges due to their occult presentation and lack of noninvasive risk-stratification tools, leading to systemic overtreatment and poor prognoses for high-risk subtypes. To address this unmet need, we developed a Fe 3 O 4 @Fe metal–organic framework heterojunction-enhanced laser desorption ionization mass spectrometry (LDI MS) platform for the efficient analysis of serum metabolic fingerprints (SMFs). Engineered through gradient pyrolysis, this nanomaterial synergizes ultraviolet absorption and photothermal conversion from its two constituent components with enhanced charge separation, achieving 1,000-fold improvement in sensitivity and thus enabling direct SMF acquisition from 1 μL of serum. Coupled with machine learning, the platform demonstrates robust diagnostic performance, yielding area under the curve (AUC) of 0.960 for distinguishing TETs from benign control and AUC of 0.856 for hierarchical risk stratification, outperforming clinical workflows. Beyond advancing material design for LDI MS, this work establishes a clinically translatable framework for rapid, large-scale screening, addressing critical gaps in TET management through metabolic-driven stratification.

Therapeutic effects of vitamin D and intermittent fasting on metabolic associated steatotic liver disease in rats

Conformationally gated multisite proton-coupled electron transfer in the ribonucleotide reductase <i>β</i> subunit

Ribonucleotide reductase (RNR) is an essential enzyme that converts ribonucleotides into deoxyribonucleotides, enabling DNA synthesis and repair in all living organisms. Central to class Ia RNR activity is a long-range radical transport pathway spanning ∼ 32 Å across the α and β subunits by a series of proton-coupled electron transfer (PCET) reactions. Although the collinear PCET reactions in the α subunit have been extensively studied, the multisite, orthogonal PCET reactions in the β subunit are less well understood. This work focuses on orthogonal PCET between the redox-active tryptophan, W48, and interfacial tyrosine, Y356, in the β subunit. Multiscale modeling strategies are employed to explore this PCET reaction. The simulations show that radical transfer from W48 to Y356 is thermodynamically favorable and is likely to occur by electron transfer from Y356 to the W48 cationic radical in conjunction with proton transfer from Y356 to a glutamate, E52, which forms a hydrogen-bonding interaction with Y356 following oxidation of W48. The conformational gating motion of Y356 is shown to be critical for allowing this residue to participate in PCET with W48 in the β subunit and with a tyrosine in the α subunit. Application of vibronically nonadiabatic PCET theory highlights the significance of hydrogen tunneling and conformational motions that shorten the distance between Y356 and E52. This work demonstrates how conformational gating, hydrogen-bonding networks, and hydration at the α / β interface modulate PCET in RNR. These fundamental insights are also applicable to other biomolecular systems and may guide therapeutic and protein engineering applications.

Analysis of the effect of pressure force on the microstructure properties of pressure measuring films

Abstract Pressure measuring films make it possible to determine pressure in the contact zone. The solution is now successfully used in various scientific and industrial sectors, e.g., for research in medicine (orthopaedic template design), mechanical engineering or geology. Among the available types of pressure measuring system, mono-sheet or two-sheet films type can be found. This article focuses on the study of transfer sheets included in the set of two-sheet type films, within the framework of the described research work, qualitative and quantitative analyses of the transfer sheet microstructure were carried out with the aim of determining the changes in the microstructural properties of this sheet that occur as a result of force loading. There is a lack of description of the phenomena occurring during the use of pressure measurement films in the available literature. All research done to date was focused on practical use of this method in measurement of contact area or pressure distribution. The presented experimental results, together with a detailed description, will allow the reader to better understand the principle of operation and the mechanisms of phenomena that occur during pressure measurements using pressure measuring films. In addition, an analysis of the chemical composition of both sheets was carried out. The knowledge of the distribution of the microcapsules (size and number of pre-damaged ones) can be used in numerical simulation with the pressure measurement films. Also the manufacturers range of measurement accuracy (± 15%) was clarified by measuring the number of the pre-damaged microcapsules and non-uniform distribution of microcapsules.

Quantum benchmarking of high-fidelity noise-biased operations on a detuned Kerr-cat qubit

Ubiquitous noise sources in quantum systems remain a key obstacle to building quantum computers, necessitating the use of quantum error correction codes. Recently, error-correcting codes tailored for noise-biased systems have been shown to offer high fault-tolerance thresholds and reduced hardware overhead, positioning noise-biased qubits as promising candidates for building universal quantum computers. However, quantum operations on these platforms remain challenging, and their noise structures have not yet been rigorously benchmarked to the same extent as those of conventional quantum hardware. In this work, we develop a comprehensive quantum control toolbox for a scalable noise-biased qubit, detuned Kerr-cat qubit, including initialization, universal single-qubit gates, and quantum nondemolition readout. We systematically characterize the noise structure of these operations using gate set tomography and dihedral randomized benchmarking, achieving high local gate fidelities, with F [ Z ( π / 2 ) ] = ( 99.18 ± 0.066 ) % and F [ X ( π / 2 ) ] = ( 92.5 ± 0.23 ) % . Notably, the noise bias of the detuned Kerr-cat qubit approaches 250 with a phase-flip time of 4   μ s , which outperforms its resonant-Kerr-cat qubit counterparts as reported previously, representing a state-of-the-art performance benchmark for Kerr-cat qubits. Moreover, our results reveal a critical overestimation of operational noise bias inferred from bit-flip and phase-flip times alone, highlighting the necessity of a precise and direct benchmarking for noise-biased qubit operations. Our work thus establishes a framework for systematically characterizing and validating the performance of quantum operations in structured-noise architectures, which lays the groundwork for implementing efficient quantum error correction in next-generation architectures.

Influence of laser beam intensity profile on deep bone ablation in laser osteotomy

Intronic polyadenylation–derived long noncoding RNA modulates nucleolar integrity and function

RNAs transcribed from protein-coding gene loci are widely assumed to be translated into proteins. However, intronic polyadenylation (IPA) occurring near the transcription start site or within early introns can generate noncoding RNAs derived from protein-coding loci. Despite their abundance, the functional roles of such RNAs remain largely unexplored. In this study, we investigated one such noncoding RNA, CUL1-IPA , transcribed from the CUL1 gene locus. Our study revealed that CUL1-IPA is an RNA polymerase II–dependent IPA isoform that is polyadenylated, stable, and translocates to the nucleolus. Functional characterization demonstrated CUL1-IPA to play a critical role in maintaining nucleolar integrity. RNA-protein interaction assay identified GPATCH4 and NOP58, nucleolar proteins involved in ribosomal RNA (rRNA) processing, as binding partners of CUL1-IPA . Consistent with its localization and interactions, loss of CUL1-IPA led to the reduction in rRNA levels and consequent decrease in overall protein synthesis. This effect on rRNA levels could be reversed by reintroducing CUL1-IPA , confirming its functional importance. Furthermore, as nucleolar stress is known to affect cell cycle progression, we found that CUL1-IPA loss resulted in G2/M cell cycle phase arrest. Moreover, reduced CUL1-IPA expression was associated with improved survival outcomes in cancer patients. Together, our findings demonstrate that CUL1-IPA , an IPA-derived long noncoding RNA (lncRNA), forms an RNA-protein complex in the nucleolus to support nucleolar structure and function. This study provides an insight into the biological function of a lncRNA originating from a protein-coding gene and highlights the broader significance of IPA-derived noncoding RNAs as regulatory molecules.

Enhanced accumulation of anticancer compounds in C. roseus hairy root cultures through elicitation and precursor feeding

Abstract Catharanthus roseus is a medicinal plant known for producing numerous indole terpenoid alkaloids. This study investigated the effects of methyl jasmonate, yeast extract, tryptophan, and tryptamine on the accumulation of four key alkaloids—ajmalicine, catharanthine, vincristine, and vinblastine—in hairy root cultures of C. roseus . Additionally, the expression levels of two biosynthetic genes, tryptophan decarboxylase (TDC) and strictosidine synthase (STR) were analyzed to explore potential transcriptional responses to elicitation. All concentrations of methyl jasmonate (MeJA) increased the levels of ajmalicine and catharanthine, while MeJA (10 and 250 µM) increased the levels of vinblastine. In contrast, yeast extract (YE) generally suppressed all indole alkaloid production. Tryptophan (TRPh) (50 mg/l) enhanced the production of catharanthine and vinblastine, while tryptamine (TRM) (100 mg/l) enhanced the production of vinblastine. Gene expression analysis revealed that methyl jasmonate (10 and 100 µM), tryptophan (50 and 250 mg/l), and tryptamine (100 mg/l) upregulated TDC and STR expression, whereas yeast extract downregulated these genes. These findings demonstrate that elicitor and precursor treatments can modulate both metabolic output and transcriptional activity in C. roseus hairy roots, providing useful insights for optimizing the in vitro production of anticancer compounds.

A framework integrating multiscale in silico modeling and experimental data predicts CAR-NK cell cytotoxicity across target cell types

Natural killer (NK) cells may be engineered with chimeric antigen receptors (CARs) to recognize tumor-associated antigens which bolsters their antitumor activity. More so than CAR-T cells, CAR-NK cell responses result from an integration of signals from a wider range of innate activating cytotoxic receptors, inhibitory receptors, and adhesion receptors in addition to the engineered CAR, making computational modeling of CAR-NK cell cytotoxicity more difficult than CAR-T cells. Uncovering mechanisms and predicting tumor cell responses to CAR-NK cytotoxicity is essential for improving therapeutic efficacy. The complexity of these effector–target interactions and the donor-to-donor variations in NK cell receptor (NKR) repertoire preclude the use of predictive models based on a single receptor, requiring function to be determined experimentally for each donor, CAR, and target combination. Computational modeling generates frameworks that allow the relationships of these factors to biologic outcomes to be explored without resource-consuming experiments. Here, we developed a computational mechanistic multiscale model which considers heterogenous expression of CARs, NKRs, adhesion receptors, and their cognate ligands, signal transduction, and NK cell-target cell population kinetics. The model is trained with quantitative flow cytometry and in-vitro cytotoxicity data and accurately predicts the short-term, long-term, and in-vivo cytotoxicity of CAR-NK cells. Furthermore, using Pareto optimization we explored the effect of CAR proportion and NK cell signaling on the differential cytotoxicity of CD33CAR-NK cells to cancer and healthy cells. This model can be extended to predict CAR-NK cytotoxicity across many antigens and tumor targets and serves as a tool to mechanistically explore CAR-NK signaling and biology.

The association between nausea and vomiting of pregnancy and postpartum depression symptoms: a longitudinal study

The socioeconomic returns to citizenship: A randomized controlled trial

Based on observational studies, conventional wisdom suggests that citizenship carries economic benefits. We leverage a randomized experiment from New York where low-income registrants with permanent residency who wanted to become citizens entered a lottery to receive fee vouchers to naturalize. Voucher recipients were about 36 p.p. more likely to naturalize. Yet, we find no discernible effects of access to citizenship on multiple economic outcomes, including income, credit scores, access to credit, financial distress, and employment. Leveraging a multidimensional immigrant integration index, we similarly find no measurable effects on noneconomic integration. However, we do find that citizenship reduces fears of deportation. Explaining divergence from past studies, our results also reveal evidence of positive selection into citizenship, suggesting that observational studies are susceptible to selection bias.

Spatial paradox between urban center expansion and vitality loss in Guangzhou, China