Browse Articles

Spacetime perspective of gravitational lensing in perturbed cosmologies

The FGFR inhibitor pemigatinib overcomes cancer drug resistance to KRAS G12C inhibitors in mesenchymal lung cancer

KRAS mutations are high prevalence oncogenic drivers for multiple cancers. With the advent of new classes of KRAS inhibitors that are showing meaningful clinical activity, research is now turning to questions of optimal combinations of therapies for specific indications, as many patients with KRAS G12C mutations do not respond and/or develop resistance to single-agent treatment. Here, we investigate combination therapies that may overcome resistance to KRAS G12C inhibitors. We found that pemigatinib, a potent and selective FGFR1–3 inhibitor, had a significantly high Bliss synergy score in combination with KRAS G12C inhibitors, and FGFR1 activity was shown to decrease KRAS G12C-dependency conferring inherent resistance in mesenchymal-like cell lines. Knockdown experiments verified the importance of FGFR1, but not FGFR2-4, for the synergistic effect with KRAS G12C inhibitors. Additionally, human lung cancer xenograft and patient-derived xenograft models with a mesenchymal phenotype and high FGFR1 expression were sensitive to the combination of G12C inhibitors and pemigatinib. In short, we demonstrate that pemigatinib and KRAS G12C inhibitors are promising agents for combination therapy in non-small cell lung cancer with a mesenchymal-like phenotype harboring high FGFR1 expression and KRAS G12C mutations to broaden patient response.

Theta-phase locking of single neurons during human spatial memory

Abstract Memory processes may rely on complex interactions between single-neuron activity and local field potentials. To better understand such spike–field relationships in humans, we examined human theta-phase locking—neuronal firing at similar theta phases over time—using single-neuron recordings in epilepsy patients performing a spatial memory task. Applying frequency-adaptive theta-phase estimation in a broad 1–10 Hz frequency range, we found that theta-phase locking was widespread in the human medial temporal lobe during memory encoding and retrieval. Time-resolved spectral parameterization and cycle-by-cycle analysis demonstrated stronger theta-phase locking during steep aperiodic slopes and prominent theta oscillations. Phase-locking strength was similar across successful and unsuccessful memory trials, with most neurons spiking at similar theta phases during encoding and retrieval. Some neurons shifted their preferred phase, supporting theories that encoding and retrieval are separated within the theta cycle. These results show how local field potential properties and memory states influence human theta-phase locking.

In-cell NMR reveals the first direct observation of endogenous interaction between HIV Tat protein and Tat RNA aptamer in human cells

Abstract RNA–protein interactions lie at the basis of numerous regulatory and functional cellular biological processes, including transcriptional control, RNA processing, nuclear export, and viral replication. Despite their fundamental biological significance, direct structural investigation of RNA–protein complexes in live human cells remains an unresolved problem due to resolution limits in spatial information, delivery of molecules, and real-time monitoring under native conditions. Existing studies rely on pre-existing in vitro complexes added to cells and therefore overlook important aspects of endogenous binding and localization. Here, we report the first in-cell nuclear magnetic resonance (NMR) study of the de novo formation of an RNA–protein complex in living human cells. By using a model system involving the HIV-1 Tat protein and its high-affinity RNA aptamer, we expressed Tat endogenously in HeLa cells and introduced the aptamer by electroporation. Direct observation was made of native complex formation within the intracellular milieu. In-cell NMR spectra exhibited characteristic chemical shift perturbations and nuclear Overhauser effect (NOE) signatures indicative of specific RNA–protein binding under physiological conditions. Comparison directly with in vitro spectra confirmed structural integrity and binding specificity in the intracellular environment. Remarkably, we obtained a partial NOE-based assignment of the RNA upon complexation with Tat in living cells—an unprecedented step towards cellular structural biology. Complementary confocal microscopy validated nuclear co-localization, enabling functionally relevant interaction. This work shows the first direct, real-time evidence for native RNA–protein complex assembly in human cells. It provides a new paradigm for probing RNA-mediated regulatory events in vivo and expands the horizon of therapeutic RNA design.

Measuring individual semantic networks: A simulation study

Accurately capturing individual differences in semantic networks is fundamental to advancing our mechanistic understanding of semantic memory. Past empirical attempts to construct individual-level semantic networks from behavioral paradigms may be limited by data constraints. To assess these limitations and propose improved designs for the measurement of individual semantic networks, we conducted a recovery simulation investigating the psychometric properties underlying estimates of individual semantic networks obtained from two different behavioral paradigms: free associations and relatedness judgment tasks. Our results show that successful inference of semantic networks is achievable, but they also highlight critical challenges. Estimates of absolute network characteristics are severely biased, such that comparisons between behavioral paradigms and different design configurations are often not meaningful. However, comparisons within a given paradigm and design configuration can be accurate and generalizable when based on designs with moderate numbers of cues, moderate numbers of responses, and cue sets including diverse words. Ultimately, our results provide insights that help evaluate past findings on the structure of semantic networks and design new studies capable of more reliably revealing individual differences in semantic networks.

Space-confined synthesis of sinter-resistant high-entropy nanoparticle library

Abstract The tailorable confinement of high-entropy nanoparticles (HE-NPs) within molecular sieves (HE-NPs@MSs), synergizing merits of cocktail effects and geometric polymorphs, holds potential for advancing heterogeneous catalysis. However, effective and universal synthesis affording size homogeneity and production scalability remains elusive. In this contribution, we present a versatile strategy for encapsulating ultrafine HE-NPs within diverse mesoporous/microporous MSs to enable the rational construction of HE-NPs@MS library. By utilizing the approach of quenching space-confined liquid metal droplets, the resulting HE-NPs@MSs comprise anti-sintered HE-NPs (1 to 5 nm in diameter) with narrow size distributions. As a proof-of-concept demonstration, a HE-NPs@MS prototype catalyst containing trace amounts of Pt is employed in the propane dehydrogenation reaction, achieving a propylene formation rate of up to 44.2 mol gPt⁻¹ h⁻¹, which is 31.6 times greater than that of the monometallic Pt@MS counterpart. Our strategy facilitates high-throughput synthesis and large-scale production, opening tantalizing opportunities in the utilization of high-entropy nanomaterials for various applications.

‌Rockburst intensity grading prediction based on the LOF-ENN-KNN model‌

Correction: The impact of vocabulary assessments on quality of life: Insights from professionals on their application with students with disabilities

Revisiting the role of oxidation in stable and high-performance lead-free perovskite-IGZO junction field-effect transistors

Abstract Mitigating the oxidation susceptibility of Sn remains a critical issue for improving the environmental stability of lead-free perovskites. Herein, we show that the oxidized surface layer of Sn-based perovskites can be utilized to improve transistor performance, rather than being entirely suppressed. We report perovskite-IGZO junction field-effect transistors that use this oxidized layer to suppress gate current to below 10−10 A, enabling enhancement-mode operation. We refer to these as barriered junction field-effect transistors. The combination of the gate leakage suppression and high polarizability of the perovskite layer results in a field-effect mobility of 29.4 cm2V−1s−1, subthreshold swing of 67.1 mV dec−1, and on/off current ratio exceeding 105 under ≤1 V operation. These devices maintain stable operation in ambient conditions. Furthermore, we demonstrate their applicability by constructing logic gates such as NOT, NOR and NAND. These findings highlight the potential of exploiting Sn-based perovskite oxidation to advance electronic devices.

Permeability of the composite coal in the grouting section around the CBM drainage borehole in the coal mine

Down-regulation of MIR-378A-3P expression associated with inflammation: The effects of restoring its levels

Epigenetics has emerged as a modulator of inflammation-related diseases and changes in miRNA expression have been associated with regional location, inflamed mucosa and disease activity in Crohn´s disease (CD). We analyse here the differential ileal miRNA expression in fibrotic tissue from patients with complicated CD and its relevance in inflammation and fibrosis. A miRNA sequencing analysis has been performed in ileal surgical resections from both patients with complicated CD and control subjects. The correlation analysis of data with an mRNA seq study performed in the same samples pointed to hsa-miR-378a-3p as an epigenetic regulator of inflammatory and fibrotic genes. Results demonstrate a significant diminution in the expression of miR-378a-3p in three different inflammatory conditions: ileum from complicated CD patients, intestine from DSS (Dextran Sulfate Sodium)-treated mice and macrophages polarized towards an M1 phenotype. Treatment with miR-378a-3p mimics failed to prevent inflammation and fibrosis in DSS-treated mice while it increased the expression of several cytokines and chemokines in both murine intestine and M1 macrophages. In conclusion, our study shows the downregulation of miR-378a-3p expression in human and murine intestinal inflammation and demonstrates that restoring the intestinal miR-378a-3p levels did not prevent inflammation and fibrosis in murine chronic colitis while intensified the expression of inflammatory and fibrotic markers.

Structural insights into Type II-D Cas9 and its robust cleavage activity

Automatic detection of persistent physiological changes after COVID infection via wearable devices with potential for long COVID management

Evaluation of acute ocular toxicity after definitive-intent radiation therapy in canine sinonasal tumors

Acute toxicity and survival were documented in dogs undergoing radiotherapy for sinonasal tumors. However, few studies specifically investigated ocular toxicity, resulting in limited data on radiation tolerance thresholds. This study aimed to quantify acute ocular toxicity, compare toxicity levels using three different scoring systems, and establish practical preliminary dose-response limits. Dogs with sinonasal tumors treated with a definitive-intent 10-fraction radiotherapy protocol were included if they underwent prospective ophthalmic examinations, both prior to radiotherapy and at least once within three months following treatment. Ocular toxicity was assessed using three scoring systems: 1) Modified McDonald-Shadduck (evaluated by ophthalmologists), 2) Veterinary Radiation Therapy Oncology Group (VRTOG) 1.0 (evaluated by radiation oncologists), and 3) VRTOG2.0 (evaluated retrospectively). Radiation doses to each eye, retina, cornea, lacrimal, and accessory lacrimal gland were documented, and adherence to the new institutional ocular dose constraints was analyzed. Seventy client-owned dogs (140 eyes) were enrolled between 2016 and 2024, yielding 241 ophthalmic examinations. Clinically relevant ocular toxicity was identified in 28 eyes (20%) according to the modified McDonald-Shadduck system, 14 eyes (10%) using the VRTOG1.0 system (grade ≥2), and in 15 eyes (11%) using VRTOG2.0 toxicity (grade ≥3). Adherence to our institutional constraints resulted in low rates of clinically relevant toxicity: only 0.7% of eyes according to VRTOG 1.0 and 1.4% according to VRTOG2.0. TD5% and TD50% risk thresholds were established to facilitate optimized planning and reduced ocular risks. In conclusion, all dogs showed rather mild and only rarely clinically relevant ocular toxicity. Clinically relevant results of the very detailed modified McDonald-Shadduck scoring system seem to be accurately reflected by the VRTOG2.0 scoring system, which is more practical for daily clinical assessments. Detailed ocular evaluations are recommended primarily for dogs with clinically relevant VRTOG2.0 toxicity. Adherence to institutional ocular dose constraints significantly minimizes the risk of clinically relevant ocular toxicity.

Addendum: Global mean nitrogen recovery efficiency in croplands can be enhanced by optimal nutrient, crop and soil management practices

Nanoantennas and metasurfaces tailored by electron beam lithography and substrate conductivity

Perceived social support according to the type and number of addictions

Background Addiction is very closely related to social determinants. It can be an outcome of the excessive consumption pushed by society and be protected against by society’s many positive dimensions. The main objectives of the present paper are to examine whether perceived social support (PSS) – the perceived availability of others to provide us assistance when needed – varies (a) according to different types of addiction (i.e., gambling, gaming, alcohol, cannabis, and nicotine), and (b) according to the presence of multiple addictions. Methods A sample of 5654 male emerging adults (mean age = 21.34 years old) completed a questionnaire that included a scale for measuring PSS and several screening tools used to identify addictive behaviors like gambling, gaming, and the consumption of alcohol, cannabis, or nicotine. Results Compared to a non-addicted control group and to peers with alcohol, cannabis or nicotine disorder, male emerging adults with gambling or gaming addiction reported the lowest levels of PSS. Moreover, these findings showed that PSS decreased among male emerging adults with multiple addictions. Conclusion Our results suggest that young men with gambling and gaming disorders may be at a greater risk of social isolation and loneliness and, thus, of experiencing deteriorations in their physical and mental health.

Adipocyte RNA-binding protein CELF1 promotes beiging of white fat through stabilizing Dio2 mRNA

Optimizing water-efficient agriculture: evaluating the sustainability of soil management and irrigation synergies using fuzzy extent analysis

Abstract Sustainable agriculture demands the integration of optimized irrigation and soil tillage practices. Poor selection or mismatched combinations of these practices can lead to inefficient resource use, declining soil health, and reduced crop productivity. Despite extensive research on individual tillage and irrigation methods, limited studies explored their combined effects on multiple agricultural sustainability parameters. This gap underscores the need for a comprehensive assessment framework that can guide farmers and stakeholders in identifying optimal combinations for diverse agricultural objectives. This study employs a compounded fuzzy extent analysis to evaluate the cumulative impact of various soil tillage and irrigation methods on key agricultural parameters, including affordability, maximum yield, climate resilience, water usage, soil disruption, disease resistance, ease of operation, nutrient utilization, and crop diversification. The analysis compares individual practices and their combinations using comparative matrices to identify the most suitable options across all parameters. The fuzzy logic approach addresses data uncertainty by converting linguistic variables into triangular fuzzy numbers, enabling more accurate decision-making. The results indicate that Zero Tillage is the most effective tillage practice (score of 0.176), while Deficit Irrigation emerges as the most efficient irrigation method, scoring 0.144. The research suggests that integrating Zero-Tillage (ZT) with Deficit Irrigation (DI) is the most cost-effective agricultural practice. Additionally, combining No-Tillage (NT) with Surface Irrigation and Mulching (SIM) results in higher yields and improved water use efficiency. Furthermore, the synergy of No-Tillage (NT) and Drip Irrigation (DI) enhances crop resilience to climate change. These findings provide valuable insights for developing sustainable agricultural strategies that balance productivity, resource conservation, and environmental protection.

EIM: An effective solution for improving multi-modal large language models

Enabling large language models (LLMs) to have multi-modal capabilities, such as vision-language learning, has become a current research hotspot and the next milestone in LLM development with the advent of models like GPT4. The basic structure of current multi-modal LLMs usually includes three parts: the image encoder for extracting visual features, the semantic space transformation network ST for aligning the multi-modal semantic spaces, and LLM for generating text. Current works on multi-modal LLMs primarily focus on enhancing performance by utilizing larger image encoders and LLMs, and designing more complex fine-tuning methods and STs, which results in an escalation of model parameters. In this paper, we propose EIM, a novel effective solution for improving the performance of multi-modal large language models from the perspective of training process which reduces the need to introduce new parameters and modify the model structure, and is ignored and less explored in current research. EIM includes corresponding improvement measures in the image encoder, ST, and LLM. To validate EIM, we first apply it to ClipCap and conduct experiments on the COCO Caption dataset. Secondly, we extend EIM to the multi-modal LLMs, such as LLaMA-Adapter and LaVIN, and evaluate them on the ScienceQA dataset. Finally, we also conduct multi-modal chatbot experiments with the EIM enhanced LaVIN and evaluate it on the MME benchmark. The COCO Caption dataset experimental results of ClipCapeim, which is a model that applies EIM on the ClipCapsmall, show the 1.75% performance improvement when compared to those of ClipCaplarge, which has 3.13 times the number of parameters of ClipCapeim. The experimental results on the ScienceQA dataset and MME benchmark show that EIM can achieve competitive performance with 7B model parameters when compared to the 13B multi-modal LLMs, which confirms the effective performance improvement of EIM for multi-modal LLMs.