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High-throughput screening for class I peptide MHC binding via yeast surface display

T cells rely on short peptides presented by highly polymorphic major histocompatibility complexes (MHCs) to selectively initiate adaptive immune responses. Despite its importance, few techniques can systematically evaluate stable peptide presentation across diverse MHC alleles. Here, we describe a yeast display pipeline that can be deployed to rapidly screen peptides to identify class I pMHC binders across many alleles. Through this, we isolate unique biological phenomena such as alteration of the peptide presentation of HLA-B57 via interaction with the antiviral small molecule abacavir. We apply this approach to multiple pathogen proteomes ( Mycobacterium tuberculosis Type VII secretion substrates, SARS-CoV-2, Dengue, and Zika) to create a comprehensive list of potential T cell antigens. Altogether, this platform acts as a flexible tool to generate large unbiased datasets for class I peptide binding at a speed and scale competitive with the biological systems they represent.

Impact of a community-based antiretroviral therapy delivery model for people living with HIV in Cambodia

Protective role of fucoidan against cognitive deficits and redox imbalance in a scopolamine-induced Alzheimer’s disease model in rats

Saffron sporopollenin modified with graphene oxide for efficient extraction of acetaminophen from serum using deep eutectic solvent prior to HPLC

Body mass index distinctly modulates the associations between Alistipes and CRP/IL-6 in metabolic and lupus inflammatory features

Several investigations have documented relationships between body mass index (BMI) and gut microbiota composition in the context of inflammation. However, the precise interaction between BMI and gut microbiota influencing inflammatory markers is still unclear, presenting a challenge for personalized interventions. This study aimed to analyze anthropometric, biochemical and inflammatory variables of participants with systemic lupus erythematosus (SLE) compared to those with low-grade metabolic inflammation (MI), as well as to elucidate the impact of gut microbiota composition, particularly Alistipes , in relation to adiposity, as assessed by BMI, on inflammatory markers within the METAINFLAMATION cohort. A total of 127 adults diagnosed with both diseases, categorized according to the WHO definition of obesity (BMI ≥ 30 kg/m 2 ) and phenotypically analyzed by 16S sequencing of fecal samples. The results showed that patients with low-grade MI had higher anthropometric values, glycosylated hemoglobin and triglyceride levels. On the other hand, patients with SLE and high BMI showed elevated insulin, CRP, and fibrinogen levels, alongside significant changes in Alistipes abundance. Notably, CRP levels were influenced by both BMI and Alistipes, particularly in lupus individuals with higher BMI, and elevated IL-6 was associated with higher CRP in this subgroup. CRP levels are influenced by BMI and Alistipes shahii abundance, especially in lupus individuals with higher BMI. In addition, elevated IL-6 concentrations are significantly associated with more elevated CRP levels in SLE individuals with higher BMI. These findings showed that CRP levels are influenced by BMI and Alistipes, particularly in lupus individuals with higher BMI and highlight the need for personalized approaches based on body composition, inflammatory markers and gut microbiota in patients with lupus and obesity for improving clinical management and outcomes.

Ribonuclease RNase Z is an evolutionarily conserved deAMPylase

Protein AMPylation is a highly conserved posttranslational modification in which adenosine monophosphate (AMP) is covalently attached to protein substrates. Our studies revealed that the mitochondrial AMPylase, Selenoprotein O (SelO), regulates cellular metabolism and oxidative stress response through AMPylation of key metabolic enzymes. Remarkably, SelO-mediated AMPylation is conserved in bacteria and humans, yet the enzyme that removes the AMP from modified proteins remains unknown. We show that the ribonuclease, RNase Z, is both necessary and sufficient to catalyze deAMPylation of AMPylated substrates. These results establish RNase Z as a moonlighting enzyme with previously unrecognized functional roles beyond tRNA processing, expanding our understanding of its biological significance. Furthermore, identification of an evolutionarily conserved deAMPylase highlights the importance of reversible AMPylation as a biological regulatory mechanism, akin to well-studied post translational modifications such as protein phosphorylation.

State-selective small molecule degraders that preferentially remove aggregates and oligomers

Abstract TRIM21 is a unique E3 ligase that uses a clustering-based activation mechanism to degrade complex multimeric substrates. This activity underpins the targeted protein degradation technology Trim-Away and genetically encoded degraders that selectively target aggregated tau protein and prevent tauopathy. Here we describe small molecules that mimic TRIM21’s natural epitope and function as either effective inhibitors or potent and selective degraders called TRIMTACs. TRIMTACs mediate degradation as rapidly as PROTACs but can also selectively degrade specific protein pools depending on assembly state. We demonstrate the utility of this state-specific degradation by selectively removing the pro-inflammatory signalling protein Myd88 when assembled into the Myddosome and the cell-death protein RIPK3 when polymerised into the Necrosome. We further show that TRIMTACs can inhibit seeded tau aggregation under conditions where a PROTAC is ineffective. These results highlight that TRIM21’s clustering-based activation can be exploited by small molecule degraders to carry out state-selective degradation of therapeutic targets.

NIRS chemometrics for rapid nutritional profiling of vegetable pea (Pisum sativum L.) germplasm

KAL suppresses cholangiocarcinoma growth via downregulating miR-21 and modulating the PTEN/AKT signaling pathway

CEO greed and corporate technological innovation: Analyst coverage as an external governance mechanism in China’s A-share market

As the Fourth Industrial Revolution advances, technological innovation has emerged as a key driver for firms to shape core competitiveness. The corporate governance literature recognizes CEO personality traits as key determinants of a firm’s technological innovation. Drawing on Upper Echelons Theory and Behavioral Agency Theory, this study investigates the effect of CEO greed on corporate technological innovation using a sample of China’s A-share companies listed on the Shanghai and Shenzhen stock exchanges from 2011 to 2023. We find that: (1) CEO greed significantly fosters corporate technological innovation. (2) Analyst coverage strengthens the positive relationship between CEO greed and corporate technological innovation. (3) This effect varies significantly across different firms and industries. (4) CEO greed significantly promotes exploitative (shorter-cycle) innovation, but has no significant effect on exploratory (longer-cycle) innovation.

The potential existential threat of large language models to online survey research

The advancement of large language models poses a severe, potentially existential threat to online survey research, a fundamental tool for data collection across the sciences. This work demonstrates that the foundational assumption of survey research—that a coherent response is a human response—is no longer tenable. I designed and tested an autonomous synthetic respondent capable of producing survey data that possesses the coherence and plausibility of human responses. This agent successfully evades a comprehensive suite of data quality checks, including instruction-following tasks, logic puzzles, and “reverse shibboleth” questions designed to detect nonhuman actors, achieving a 99.8% pass rate on 6,000 trials of standard attention checks. The synthetic respondent generates internally consistent responses by maintaining a coherent demographic persona and a memory of its prior answers, producing plausible data on psychometric scales, vignette comprehension tasks, and complex socioeconomic trade-offs. Furthermore, its open-ended text responses are linguistically sophisticated and stylistically calibrated to the level of education of its assigned persona. Critically, the agent can be instructed to maliciously alter polling outcomes, demonstrating an overt vector for information warfare. More subtly, it can also infer a researcher’s latent hypotheses and produce data that artificially confirms them. These findings reveal a critical vulnerability in our data infrastructure, rendering most current detection methods obsolete and posing a potential existential threat to unsupervised online research. The scientific community must urgently develop new data validation standards and reconsider its reliance on nonprobability, low-barrier online data collection methods.

Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice

Fast computation model for superconducting pinning Maglev mechanical system

AI-driven classification and precision cutting algorithms using machine vision in a customer-operated fish processing system

On the performance of active RIS-enhanced NOMA systems with spectrum sharing mechanisms

This paper presents a comprehensive performance analysis of a downlink non-orthogonal multiple access (NOMA) network assisted by an active reconfigurable intelligent surface (ARIS) in a cognitive spectrum-sharing scenario. Unlike conventional passive RIS (PRIS), the ARIS can both adjust phase shifts and amplify incident signals, thereby mitigating inter-user interference and overcoming multiplicative fading. We consider a two-user secondary network coexisting with a primary user, where the base station communicates with the secondary users via the ARIS. Closed-form expressions for the outage probability (OP), throughput, energy efficiency (EE), and an approximation for the ergodic data rate (EDR) are derived under Nakagami- m fading, along with asymptotic OP analysis to reveal the achievable diversity order. We also formulate and solve an optimization problem for the NOMA power allocation coefficient to minimize OP. The main contributions are: (i) proposing an ARIS-assisted NOMA architecture for spectrum-sharing networks and comparing it with PRIS and orthogonal multiple access (OMA) schemes; (ii) deriving exact OP, throughput, and EE expressions, and an approximate EDR expression, validated by Monte Carlo simulations; (iii) providing asymptotic OP analysis to characterize the diversity order; and (iv) optimizing NOMA power allocation to minimize OP. Numerical results confirm that ARIS significantly outperforms PRIS and OMA in terms of OP, throughput, EC, and EE, demonstrating its potential to enhance spectral efficiency, reliability, and coverage in next-generation spectrum-sharing NOMA networks.

Engineering a spatiotemporal macrophage circuit via STING phase separation to override immune suppression in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its highly immunosuppressive tumor microenvironment (TME), which fuels metastasis and resistance to immunotherapy. Through comprehensive analysis of single-cell RNA sequencing datasets, we identified multiple heterogeneous tumor-associated macrophage (TAMs) subpopulations as key regulators of PDAC progression, which coexpress MRC1 and exert their effects by actively suppressing antitumor immune responses. To overcome this barrier, we developed a spatiotemporal macrophage reprogramming platform that leverages STING phase separation to reprogram TAM plasticity and reshape the immune landscape. This system, MRC1-targeting peptide–M@BLZ945 (PMMB), integrates a colony-stimulating factor 1 receptor (CSF-1R) inhibitor and a STING agonist within a macrophage-mimetic nanostructure, enabling sequential, controlled reprogramming of TAMs. By leveraging STING phase separation, PMMB stabilizes TAMs in an antitumor CD80 + phenotype while preventing excessive inflammation, achieving durable immune activation. In preclinical models, PMMB not only suppresses both primary and metastatic PDAC but also enhances CD8 + T cell infiltration, reinvigorates anti-PD-1 therapy responses, and mitigates immune exhaustion. These findings establish spatiotemporal macrophage circuit engineering via STING phase separation as a cross-scale strategy to override PDAC’s immune barriers and drive next-generation macrophage-targeted immunotherapy. This study paves the way for rationally designed, precision macrophage modulation strategies in solid tumors.

Ancient gene clusters govern the initiation of monoterpenoid indole alkaloid biosynthesis and C3 stereochemistry inversion

Occurrence and characterisation of Toxoplasma gondii infection in free-living Eurasian beavers, Castor fiber, from southern England

Abstract Toxoplasma gondii is a globally distributed apicomplexan protozoan of zoonotic importance. Domestic cats ( Felis catus ) and related felids constitute its sole definitive hosts, while numerous warm-blooded species serve as intermediate hosts . Infection outcomes for intermediate hosts range from latent toxoplasmosis to behaviour alteration and fatal systemic disease. Oocysts, the lifecycle environmental stage, are often washed into watercourses, making river-dwelling species like Eurasian beavers ( Castor fiber ) particularly at risk. To investigate the presence and impact of T. gondii on beavers in the United Kingdom, archived brain, heart, and liver from 23 beavers necropsied between 2021 and 2023 were screened for T. gondii DNA by nested- and quantitative PCR. Positive samples were genotyped using a panel of six published PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) assays and amplicon sequencing. Sequences were aligned with those reported previously from UK and other wildlife species to assess the occurrence of shared genotypes. Toxoplasma gondii DNA was detected in 19/23 (83%) Eurasian beavers; all consistent with PCR-RFLP ToxoDB#3 with limited genetic diversity, concurring with findings from previous surveillance of UK wildlife species. Following histopathological screening non-suppurative toxoplasmosis was characterised in 3/6 tissues selected from two animals. These results demonstrate a high occurrence of T. gondii infection in UK beavers

Overburden movement laws in thin bedrock workfaces under thick backfilled loose bodies

Abstract A detailed investigation was conducted on the geological conditions of thin bedrock workfaces under thick backfilled loose bodies in the first panel of the 22-upper coal seam at Shigetai Coal Mine. Utilizing both physical similarity modeling and numerical simulation techniques, the study comprehensively examined the overburden movement patterns and failure characteristics under these conditions. The physical simulation results indicate that as the working face approaches the open-pit slope area, the height of overburden failure gradually increases. When the thin bedrock becomes unstable due to rotation, unconsolidated materials at the slope base flow into the goaf. Subsequently, roof-cutting pressure on the thin bedrock causes simultaneous movement of backfilled loose bodies at different heights, resulting in minor surface settlement. As mining progresses, fracturing alternates periodically between roof-cutting and relief phases, ultimately expanding the surface subsidence zone. The maximum subsidence of the thin bedrock remains less than the mining height of the coal seam. Numerical simulations reveal that when the working face leaves the open-pit slope, the overburden failure height rises rapidly. Upon entering the thin bedrock workface area, advanced fractures develop, and the thin bedrock undergoes full-thickness fracturing in small cycles with intervals of approximately 10 m. The advanced stress fluctuates around the original rock stress, and the movement of backfilled loose bodies quickly reaches the surface. When re-entering the open-pit slope, the development of advanced fractures ceases, and the overburden failure height increases again. The advanced stress gradually rises and stabilizes in the waste dump area. Subsidence in the thin bedrock workface area consistently exceeds that in the open-pit slope area. Maximum subsidence values at different measurement heights are observed within the thin bedrock zone and shift toward the slope base as height increases. When exiting the slope, subsidence in the open-pit area is greater than when entering it. This research elucidates the dynamic fracturing mechanisms and movement patterns of overburden in thin bedrock workfaces beneath thick backfilled loose bodies, providing a theoretical foundation for safe mining in similar geological settings.

Prediction method for the reaction force of vehicle door sealing systems

The accuracy of calculating the reaction force in vehicle sealing systems using moment equilibrium equations from statics is highly dependent on the degree of simplification in the mathematical model. This study demonstrates that employing the Finite Element (FE) method allows for a comprehensive consideration of the coupling effects between the door and the flexible seal, thereby eliminating errors inherent to model simplification and single-boundary variables. Consequently, this approach improves the prediction accuracy of the sealing system’s reaction force. In this work, a multi-boundary coupling simulation method for a vehicle door sealing system was established using the Finite Element (FE) method, which accounts for the interaction between the seal and the complex door structure. The results, based on data from three distinct vehicle models (with three doors tested per model), show a mean absolute percentage error (MAPE) of 7% between the simulated and experimentally measured static closing forces. This close agreement verifies the reliability of the proposed method. This study provides a comprehensive strategy for predicting and optimizing the reaction force in vehicle sealing systems. It was found that a 75% increase in the compression load deflection (CLD) of the lock-side seal yields a 22% increase in the total sealing system reaction force.