Browse Articles

The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma

Abstract Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation for rhabdomyosarcoma (RMS). Unfortunately, OT resistance has been reported in other cancers. Using preclinical mouse xenograft experiments, we show that OT effectively suppresses RMS growth, yet over half of RMS tumors develop resistance associated with transcriptomic changes that occur in the absence of recurrent genomic mutation. Importantly, most resistant RMS models upregulate the PIK3CA/AKT pathway, activating NRF2 phosphorylation and subsequent transcriptional expression of multidrug resistance ABC transporters. PIK3CA inhibitor alpelisib re-sensitizes resistant cells to OT by suppressing expression of ABC transporters. The combination of OT + alpelisib also kills RMS cells which are resistant to standard-of-care combination chemotherapy and was effective in preclinical xenograft mouse models at curbing tumor growth. Our work defines a common resistance pathway in RMS and has credentialled PIK3CA/AKT inhibition as a preclinical strategy to kill therapy resistant RMS.

Evaluation of antimicrobial and antibiofilm activities of peptide Impatiens balsamina-M1 and Zinc oxide nanoparticles against Helicobacter pylori

Increased inflammation and oxidative stress caused by accumulated metal particle exposure among metro station staff

Metro is a significant part of world transport, delivering over 58 billion passengers annually. Train operation processes generated PM rich in heavy metals in the station, but the natural ventilation underground is poor leading to a high PM exposure indoors. Though PM pollution in metro stations was reported widely, there is limited evidence of the adverse health effect of metro station PM. This study collected urinary samples from 74 metro station staff from three different metro stations in Tianjin for 8-OHdG, IL-6, MDA, GSH and T-AOC tests using commercial kits. PM samples were collected for metal composition tests using ICP-MS and oxidative potential test using DTT method. The average PM 2.5 concentration was 31.5 ± 12.4 μg/m 3 , meeting the Standard for indoor air quality in China. However, the indoor concentrations of Zn, Cu, Mn, and Fe were ten times higher than those in the ambient air, inferring a higher exposure level of metal particles. Urinary 8-OHdG, MDA, and IL-6 of senior employees (length of service in the metro station > 5 years) were significantly higher than new employees but not related to age, suggesting a significant influence on individual’s inflammation and oxidative stress led by PM exposure. Identified as characteristic elements in the metro stations, Mo and Ni, were also found significantly correlated with urinary IL-6 and GSH. The findings indicates that chronic metal PM exposure in the metro station may induce oxidative stress and inflammation. However, the accumulated PM 2.5 concentration showed a poor relation with biomarkers except for IL-6. Accumulated oxidative potential of PM was significantly correlated with urinary IL-6, 8-OHdG, GSH, and T-AOC. This result suggested the accumulated oxidative potential of PM as a better evaluation method of health influence led by PM rather than mass concentration.

Author Correction: Activating newborn neurons suppresses depression and anxiety-like behaviors

Development and performance evaluation of a PTO-based power assist system to improve traction force for electric tractors

Using participatory methods to develop a narrative intervention to alleviate distress in children hospitalised with TB in South Africa: The DIMPle project

Children who are hospitalised for tuberculosis (TB) experience challenges that put them at risk of developing emotional, behavioural, and social difficulties. In this methodological paper, we showcase the development of a narrative intervention toolkit with key components of the resulting version 1.0 tool. The study design was participatory and pragmatic, with researchers working with the routine staff of TB hospital wards, children admitted and their caregivers, to iteratively understand and improve children’s experiences of hospitalisation. The project included three phases: (1) a situational analysis to map children and healthcare providers’ perspectives on priorities and potential intervention components, (2) co-development of a beta-version of the intervention, and (3) piloting and incremental refinement toward a version 1.0 of the intervention. The intervention toolkit combined a series of activities alongside the story of ‘Courageous Curly’ to facilitate children’s engagement with their own experiences of hospitalisation, including psychosocial and treatment challenges, captured, and described throughout data collection. We found that dividing the story into short chapters facilitated children’s engagement with the section of story that is being told on a specific day. Each chapter of the story follows/mimics a different stage children can expect during their treatment journey while hospitalised for TB care. Implementation and evaluation of such interventions can mitigate the psychosocial impact of TB in children and inform policies to improve their overall TB care.

The bHLH transcription factor PIL1 orchestrates starch synthesis in key cereal crops

Carbon ion FLASH irradiation reduces acute skin toxicity compared with conventional dose rate irradiation

Abstract FLASH radiotherapy, defined by ultra-high dose rates exceeding 40 Gy/s, has shown potential for widening the therapeutic window due to its demonstrated normal tissue-sparing effects while maintaining tumor control with electrons, photons, and protons. However, limited biological data are available regarding its effects with heavy ions. This study aimed to investigate the biological effects of carbon-ion FLASH irradiation by assessing acute skin reactions in mice. C3H/He mice received irradiation to the right hind limb with 34–58 Gy of carbon-ion pencil beam scanning at the entrance region (dose-averaged LET: 13 keV/µm), delivered at either conventional dose rate (CONV: 0.047–0.051 Gy/s) or ultra-high dose rate (FLASH: 166.7–190.8 Gy/s). Skin reactions were evaluated every other day for up to 5 weeks to monitor early responses. The temporal patterns of skin response were similar between the CONV and FLASH groups. However, FLASH group consistently resulted in lower reaction scores across all doses and time points. Dose–response curve indicated a tissue-sparing effect with FLASH group, requiring approximately 1.5 times higher dose to produce the same biological effect as CONV group. These findings confirm the normal tissue-sparing potential of carbon-ion FLASH irradiation, with the FLASH effect quantitatively demonstrated through dose–response comparisons.

MBCS: A few-shot intent detection model for manual inspection records

Addressing the bottleneck issue of low accuracy and poor generalization in cargo risk intent detection caused by annotation scarcity in manual inspection scenarios within the import-export trade supervision domain, this study proposes an intent detection model named MBCS (Multi-task Learning with BERT for Classification and Semantic Similarity Comparison), designed for few-shot scenarios. To tackle the challenges of scarce domain-specific data and inadequate text representation capabilities, the research introduces a multi-task learning framework that integrates text classification with semantic similarity comparison. By incorporating semantic contrastive learning as an auxiliary task, the model’s semantic representation capability is enhanced. Concurrently, an attention-weight-based synonym substitution strategy was introduced, replacing the highest-attention words in the sequence by integrating contextual information. Experiments conducted on real-world customs business datasets demonstrate that MBCS achieves significant accuracy improvements of over 4.19% (4.91%) in 5-shot (10-shot) scenarios, substantially outperforming baseline models. This method provides an optimized solution for intent detection tasks plagued by the annotation scarcity dilemma.

Enhanced neural plasticity in monkey TE compared to TEO during learning of a feature-ambiguous visual categorization task

Abstract Primates can rapidly categorize images by visual feature similarity. We previously showed that inferior temporal cortex (IT) subregions TEO and TE contribute to visual categorization to differing extents. To investigate the neural plasticity underlying visual categorization, we recorded simultaneously from both areas while two male monkeys learned a visual categorization task. Category specificity and generalization are initially stronger in TEO than in TE but increase with learning only in the TE neuronal population, whose neural representations correlate with behavioral performance. TE and TEO can contribute complementary, partially independent category information. However, TEO does not add learning-relevant variance across days. TE exhibits greater categorical enhancement for correct than error trials compared with TEO. Single-neuron analyses revealed that TE category selectivity strengthens with learning, primarily through enhanced encoding of one category. Combined with lesion evidence, our results suggest that TE plasticity likely plays a more fundamental role in supporting visual category learning.

Sex-based differences in biomarker trajectories in acute coronary syndrome patients from the BIOMArCS study

Radiogenic strontium isotope variability in the Valley of Oaxaca: A predictive isoscape for Mesoamerican paleomobility studies

Radiogenic strontium ( 87 Sr/ 86 Sr) isotope analysis is a well-established method for reconstructing the mobility of human populations in the past and present. Baseline 87 Sr/ 86 Sr data are fundamental to the method, as Sr varies across the landscape according to local geology and geoenvironmental factors. The method’s application within studies of ancient Mesoamerican paleomobility, however, has concentrated on two key regions—Teotihuacan and the Maya region—despite its potential broader relevance across greater Mesoamerica. This is due in part to a lack of available baseline 87 Sr/ 86 Sr data for the region at large. Using the Valley of Oaxaca as a case study, we use Bayesian Additive Regression Trees (BART) to generate a locally calibrated predictive 87 Sr/ 86 Sr isoscape model of Mesoamerica in general and the Valley of Oaxaca in particular. We integrate (1) observed 87 Sr/ 86 Sr data from modern plant samples ( n  = 95) from 17 sites across the Valley, (2) a compiled database of continental North and South American 87 Sr/ 86 Sr data, (3) geological bedrock maps, and (4) high resolution spatial data on geoenvironmental Sr covariates to iteratively develop and test a high performing predictive model for Mesoamerica, highlighting the importance of regional calibration in developing predictive 87 Sr/ 86 Sr isoscapes. Our results indicate that though overlap exists, 87 Sr/ 86 Sr can be used to detect migration within the Valley of Oaxaca as well as between the Valley and greater Mesoamerica. We then apply our isoscape to previously published human 87 Sr/ 86 Sr data from Monte Albán, Oaxaca to demonstrate how our model’s explicit quantification of uncertainty in local 87 Sr/ 86 Sr ranges allows for more nuanced interpretation of paleomobility in archaeological samples.

PTEN regulates vagal-insulin signaling to optimize autonomic output determining peripheral inflammatory and metabolic homeostasis

Trajectory of serum osmolality changes and 28-day mortality risk in patients with sepsis-associated delirium based on the MIMIC-IV database

Identification of transposable elements and satellite DNA in the Neotropical species Drosophila amaguana from the Ecuadorian Andean Forests

Genome size variation in eukaryotic species is largely influenced by repetitive DNA sequences such as transposable elements (TEs), simple repeats, and satellite DNAs (satDNAs), which do not necessarily correlate with organismal complexity. In insects, TEs are crucial to evolutionary processes and are correlated with variations in genome size. In this study, we describe, for the first time, the mobilome and satellitome of Drosophila amaguana , an Ecuadorian Neotropical species with a large, unexplored genome size, to assess the contribution of these repetitive DNA sequences to its genome composition. Using a draft genome assembly of approximately 455.5 Mb, generated from Illumina short-read sequences obtained from 10 wild specimens of D. amaguana collected at the Refugio de Vida Silvestre Pasochoa, we employed a de novo approach to create a manually curated TE library of 737 consensus sequences. We identified 716 novel TE families that had not been previously described, 20 TEs previously characterized in other Drosophila species, and one DNA transposon previously described in the Lepeophtheirus genus. The total TE content in the D. amaguana genome was 21.54%, distributed as follows: 6.35% Helitrons (1 superfamily), 5.13% LTR retrotransposons (5 superfamilies), 3.63% TIRs (9 superfamilies), 3.61% LINEs (7 superfamilies), 1.17% MITEs, 0.94% Maverick, 0.67% PLE, 0.02% SINEs, and 0.01% DIRS. We also identified 11.8% of simple repeats. Additionally, we estimated the satDNA content using Illumina raw reads and identified 16 satDNA families, all unique to the Drosophila genus, which comprise 4.90% of the genome. Overall, our results based on short-read data suggest that the large genome size of D. amaguana may not be the consequence of a high amount of TEs or satDNAs. Instead, its large genome size could be attributed to other factors (e.g., noncoding DNA occupying substantial portions of the genome or a high percentage of duplicated genes) that remain to be determined or explored in future studies using long-reads to overcome short-reads limitations. These findings may currently offer valuable insights into the adaptative and evolutionary processes of the mesophragmatica species group in the Andean forests.

Replicon-based genome-wide CRISPR knockout screening for the identification of host factors involved in viral replication

Abstract We describe a viral replicon-based CRISPR knockout (KO) screening approach to specifically identify host factors essential for viral replication which are often missed in live virus screens. We benchmark the replicon screening using a stable fluorescent dengue virus type 2 (DENV-2) replicon cell line and successfully identify host genes known to be required for viral DENV-2 replication (e.g., endoplasmic reticulum membrane complex and oligosaccharyltransferase complex components), along with additional genes that have not been reported in prior CRISPR KO screens with DENV-2. We extend this replicon screening approach to chikungunya virus (CHIKV), a positive-sense RNA virus, and Ebola virus (EBOV), a negative-sense RNA virus, and identify distinct sets of genes required for replication of each virus. Our findings indicate that viral replicon-based CRISPR screens are a useful approach to identify host factors essential for replication of diverse viruses and to elucidate potential novel targets for host-directed medical countermeasures.

Enhanced pedestrian walkway object detection using deep learning and pelican optimization algorithm for assisting disabled persons

Study protocol: MRI-based assessment of cerebral blood flow under pharmacologically elevated blood pressure in patients under general anesthesia, and in sedated ICU patients with aneurysmal subarachnoid hemorrhage

Background Maintaining cerebral perfusion during anesthesia and intensive care is critical, yet the relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF) remains poorly defined. In patients with aneurysmal subarachnoid hemorrhage (aSAH), pharmacologically induced hypertension is commonly applied to support cerebral perfusion, but its effects are uncertain. Methods This protocol describes two parallel clinical studies using identical methodology. The first study population includes adults undergoing elective general anesthesia (MAP-ANE), and the second comprises sedated intensive care patients with aSAH (MAP-SAH). In both study populations, MAP will be increased stepwise with norepinephrine (NE) infusion under continuous invasive blood pressure monitoring, and CBF measured with phase-contrast MRI (PCMRI) and arterial spin labeling (ASL), while near-infrared spectroscopy (NIRS) will be performed in parallel to evaluate its validity as a surrogate marker. The primary outcome is the change in total CBF between baseline and elevated MAP, directly testing whether induced hypertension increases CBF. Secondary outcomes include ASL perfusion changes, the slope of the MAP–CBF relationship, systemic–cerebral hemodynamic correlations, and NIRS responses. Expected impact These studies test the hypothesis that pharmacological MAP augmentation does not predictably increase CBF. By combining quantitative MRI with invasive monitoring, it aims to clarify MAP–CBF interactions, define the physiological basis of induced hypertension, and assess whether NIRS can serve as a clinically useful proxy. Findings are expected to inform safer and more individualized blood pressure management in perioperative and neurocritical care. The studies are registered at ClinicalTrials.gov (MAP-ANE: NCT06855407; MAP-SAH: NCT06033378). Trial registration ClinicalTrials.gov, MAP-ANE NCT06855407 , MAP-SAH NCT06033378

GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function

Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and β-cell functional adaptation. Here, we present a comprehensive study in β-cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticulum (ER) membrane contact site (MCS) tether VAPB at ER-mitochondria MCSs (ERMCSs), where active GLP-1R engages with SPHKAP, an A-kinase anchoring protein (AKAP) previously linked to T2D and adiposity risk in genome-wide association studies (GWAS). The inter-organelle complex formed by endosomal GLP-1R, ER VAPB and SPHKAP triggers a pool of ERMCS-localised cAMP/PKA signalling via the formation of a PKA-RIα biomolecular condensate which leads to changes in mitochondrial contact site and cristae organising system (MICOS) complex phosphorylation, mitochondrial remodelling, and β-cell functional adaptation, with important consequences for the regulation of β-cell insulin secretion and survival to stress.

A spatiotemporal transformer with cross-frame encoding and trajectory-aware decoding for multi-target fish tracking

Abstract In response to the challenges of multi-object fish tracking in complex underwater environments, where performance is easily affected by illumination changes, suspended particles, occlusion, and high inter-target visual similarity, this paper proposes a unified Transformer framework that integrates cross-frame spatiotemporal encoding with trajectory-aware decoding. In the encoding stage, temporal difference and frame position embeddings are introduced and combined with a residual motion enhancement mechanism to explicitly align appearance, scale, and displacement across frames. In the decoding stage, trajectory extrapolation priors and temporal association attention are employed to restrict cross-frame feature aggregation within reasonable candidate regions, achieving joint optimization of detection and association. On our self-constructed underwater fish tracking dataset, the proposed method achieves MOTA, IDF1, and Recall scores of 0.719, 0.693, and 0.742, improving over the strong baseline model GTR (0.688, 0.671, 0.720) by 0.031, 0.022, and 0.022 absolute points. On the UOT32 dataset, it attains 0.697, 0.680, and 0.730, surpassing ByteTrack (0.675, 0.650, 0.700) by 0.022, 0.030, and 0.030 absolute points, respectively. These results demonstrate that the proposed approach effectively integrates cross-frame spatiotemporal modeling with trajectory-guided decoding, enabling accurate detection and reliable identity association even under occlusion and dense target conditions. The method exhibits strong robustness and generalization in complex underwater environments, outperforming existing state-of-the-art approaches in both tracking accuracy and stability.