Browse Articles

Prion-induced ferroptosis is facilitated by RAC3

Abstract Prions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPC creates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPC and infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPC initially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes.

Transcriptomic sequencing and expression verification of identified genes modulating the alkali stress tolerance and endogenous photosynthetic activities of industrial hemp plant

Hemp (Cannabis sativa L.) has a long cultivation history around the world. In northeast part of China, the alkaline soil geology severely reduces crop production. In this study, we tried to evaluate the impacts of alkali-induced stress on the photosynthetic status and physiological indices of hemp plants. The microscopic evaluation of endogenous ultrastructure clearly demonstrated significant oxidative damage to the structure of the photosynthetic tissues associated with the membrane, resulting from an increase in the levels of MGDG and DGDG. The deformed photosynthetic apparatus induced by alkali-stress significantly inhibited the biosynthesis process of photosynthetic pigments, causing 49.25%, 52.72%, 65.31%, and 28.13% loss in total Chl, Chl a, Chl b, and carotenoids, respectively. Meanwhile, the reduction in chlorophyll fluorescence parameters (Pn (74.62%), Gs (39.69%), and Tr (83.77%)) along with the obviously increased MDA (28.57%) and H2O2 (35.18%) content exhibited that the inhibitory effect of alkali-stress not only decreased the photosynthetic efficiency by intercepting the nutrient supply but also generated excessive ROS, resulting in oxidative stress. Transcriptomic analysis (RNA-sequencing) revealed the considerably enriched GO terms as well as KEGG pathways that exposed the significant DEGs. The qPCR expression evaluation of down-regulated chlorophyll biosynthesis-related major genes (GOGAT (LOC115699366) and HEMA (LOC133032634)) and photosystem-related major genes (PSB (LOC115701338) and HCF (LOC115707994)) exhibited important molecular evidence for modulating the photosynthesis activity of hemp plant under devastating mechanism of alkali-stress. However, the transcript patterns of photorespiration-related genes (GOX (LOC115697365) and GDC (LOC115707082)) showed a slower decreasing trend at late stress stage (at 24 ~ 48 h), and the transcription of SGAT gene (LOC115699360) was even enhanced by stress treatment at 48 h, probably in an attempt to adjust cellular carbon balance and elevate the antioxidant properties induced by alkali-stress.

Resistance Gene-Guided Genome Mining Reveals RPL10 as the Target of Ligustrone A

Author Correction: Beta activity in human anterior cingulate cortex mediates reward biases

rbpTransformer: A novel deep learning model for prediction of piRNA and mRNA bindings

An important issue in biotechnology is predicting whether a piRNA and an mRNA will or will not bind. Research and treatment of diseases, drug discovery, and the silencing and regulation of genes, transposons, and genomic stability may all benefit from accurate binding predictions. The literature offers numerous deep-learning models for piRNA and mRNA binding prediction. However, a proper adjustment of the effective transformer model and the impact of important design alternatives has not been evaluated thoroughly. This paper summarizes the models available in the literature, briefly introduces transformers, then offers a novel deep learning model and evaluates various design alternatives, including k-mer size, number of core modules, choice of optimization algorithm, and whether to use self-attention. The results show that rbpTransformer can be a good candidate for building deep AI models to predict the binding of piRNA and mRNA sequences with an AUC value of 94.38%. The test results also reveal how the design affects the model’s accuracy.

Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy

The impact and return-on-investment of evidence-based practice in conservation and environmental management: A machine learning-assisted scoping review protocol

Evidence-based Practice (EBP) is a vital principle, with its origins in the 1970s, that has transformed the disciplines of medicine and healthcare. The use of best available evidence to inform decisions and best practice has since spread across other disciplines, including in the environmental sciences through evidence-based conservation and environmental management. However, ironically there only appears to be a single scoping review on the impacts and return-on-investment of EBP in healthcare and it is unclear whether any such evidence exists in the broad field of conservation and environmental management. In this scoping review, we aim to explore the extent to which evaluations of the impacts and return-on-investment of EBP and evidence use have been conducted in conservation and environmental management on both human and environmental outcomes. We will search at least ten different electronic bibliographic platforms, databases, and search engines for published and grey literature, from 1992 to 2025 – there will be no geographical or language restrictions on the documents included. A machine learning-assisted review process will be followed using open source tools (ASReview and SysRev) and following the comprehensive SYstematic review Methodology Blending Active Learning and Snowballing (SYMBALS). The findings from the scoping review will be useful to inform organisations and practitioners considering implementing EBP on its benefits and costs and will also highlight potential research gaps on the impact of EBP and evidence use.

AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice

Clinical characteristics and outcomes of intraocular lens dislocation: an eight-year retrospective study

Objective To investigate the clinical characteristics, risk factors, and short-term visual outcomes following surgical management of intraocular lens (IOL) dislocation, aiming to inform risk stratification and individualized treatment strategies. Methods A retrospective analysis was conducted on 155 patients (166 eyes) diagnosed with IOL dislocation between 2016 and 2024. Data collected included demographic information, ocular and systemic risk factors, surgical interventions, uncorrected distance visual acuity (UDVA) before and after surgery, and postoperative complications. Comparative analyses were performed to assess the short-term efficacy and safety of different surgical approaches. Results The mean patient age was 55 years, with 86.75% presenting unilateral dislocation. Predominant risk factors identified were high myopia (38.55%) and prior vitrectomy (17.47%). A total of 89.16% of IOL dislocations were classified as late-onset. Of the 154 eyes that underwent surgical intervention, both IOL repositioning and exchange procedures resulted in significant improvements in UDVA (P < 0.05). Postoperative transient intraocular pressure elevations were observed without significant differences between surgical methods, resolving within three days in all cases. Conclusion High myopia and prior vitrectomy are significant risk factors for IOL dislocation. Surgical correction, whether through repositioning or exchange, is effective and safe, leading to substantial visual acuity improvements. Proactive identification and management of high-risk individuals are crucial for preventing IOL dislocation and optimizing patient outcomes.

Polymer microbubbles as universal platform to accelerate polymer mechanochemistry

Abstract The flow-induced activation of mechanophores embedded in linear polymers by ultrasound (US) suffers from slow mechanochemical conversions at the commonly used frequency of 20 kHz and in many cases remains ineffective with higher MHz frequencies. Here, we present polymeric microbubbles (PMBs) as a platform that accelerates the mechanochemical activation of several mechanophores under both 20 kHz and MHz irradiation. MHz irradiation generated by biocompatible high-intensity focused US (HIFU). Through their pressure-sensitive gas core, PMBs act as acousto-mechanical transducers for the transformation of sound energy into stretching and compression forces as well as fracturing the polymer shell by the volume oscillation of PMB. We investigate three different mechanophores among which one flex-activation derivative was unexpectedly activated by US. Through a combination of experiments and computation, we find that PMBs likely exert compressive force onto the copolymerized mechanophores rather than the typical elongational forces solvated chain fragments experience in flow. We thereby underscore the mechanochemical properties of the PMB platform and its versatility for accelerated mechanochemical transformations with a perspective on biomedical applications.

Adaptive fixed-time fault-tolerant trajectory tracking control for disturbed robotic manipulator

This article introduces a fixed-time trajectory control method for robotic manipulators, aimed at improving trajectory precision despite external disturbances, actuator faults, and uncertainties. Initially, a fast fixed-time nonsingular terminal sliding surface (FFNTSS) is utilized, featuring a bounded convergence time that remains unaffected by the initial conditions. This sliding surface not only prevents the occurrence of singularity but also guarantees fast convergence. Subsequently, building upon the FFNTSS and adaptive methodology, a novel approach termed continuous adaptive fixed-time nonsingular terminal sliding mode fault-tolerant control (CAFNTSMFTC) is introduced. According to the Lyapunov theorem, rigorous analysis demonstrates that the sliding mode variables and tracking errors of the closed-loop system converge to a small neighborhood of the origin within a fixed-time frame. Moreover, by approximating the square of the uncertainty’s upper bound, the devised CAFNTSMFTC approach eliminates the need for the boundary layer commonly imposed in existing adaptive fixed-time control approaches. Lastly, comprehensive comparative simulations are conducted employing the PUMA560 robot. These simulations validate the proposed control strategy, underscoring its ability to achieve precise trajectory tracking and fast convergence, even when facing uncertainties, disturbances, and actuator faults. Moreover, the proposed control strategy for the robot manipulator is distinguished by its continuity and demonstrates dynamics in which chattering is mitigated.

How a Single Atom Influences the Spatiotemporal Response of Flexible MOFs: Insights from Theory and Experiment

Screening macrocyclic peptide libraries by yeast display allows control of selection process and affinity ranking

Estimation of bimodal soil-water characteristics curve under wetting process

Soil-water characteristics curve (SWCC) is hysteretic. The hysteretic curves represent the soil conditions during drying and wetting processes. Almost all failure of geotechnical structures, particularly in soils with dual porosity (bimodal soils) occurs during soil wetting, making the wetting curve more relevant to geotechnical applications than the drying curve. Still, due to the high-cost implications, time require, and difficulties associated with measuring SWCC under wetting process, the wetting curve has been continuously neglected. This leads to analyses that do not reflect the actual soil condition, which may result in structural failure. Although bimodal soils are encountered in many areas across the globe, there is no mathematical model for estimating bimodal SWCC under wetting process. This work developed a new mathematical equation to estimate a bimodal SWCC under wetting process. The proposed model also has parameters with physical meaning in relation to the variables of the wetting SWCC, which is very important in practical applications and numerical analyses. Six soil types were used in the model validation. The overall model performance has been evaluated through statistical methods using the coefficient of determination (R2) and Root Mean Square Error (RMSE). The evaluation also indicates a good performance of the model, with an average RMSE of 0.0263 and an average R2 of 0.9945 for the six soil samples used in the validation. Given the significance of wetting-induced failures, the proposed model is highly relevant in engineering applications.

Polyglutamylation of microtubules drives neuronal remodeling

Abstract Developmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. Regulation of the cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a post-translational tubulin modification enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation—TTLL glutamylases vs. CCP deglutamylases—accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as a cytoskeletal rheostat of remodeling that shapes neuronal morphology and connectivity.

Effects of age on the neural correlates of auditory working memory in cochlear implant users

Following a conversation in a noisy environment is challenging, especially for individuals who received cochlear implants (CIs) to remediate severe-to-profound hearing loss. CI users likely work harder than their normal-hearing counterparts to understand speech in adverse listening conditions. Recruiting cognitive resources can be taxing and may interfere with attentional regulation and working memory processes. Few studies have, however, examined the impact of CIs on the neural correlates of attention and working memory. We used a high-density electroencephalogram to investigate behavioural and neural correlates of auditory attention and working memory in 14 CI users and age-matched normal hearing (NH) controls (age ranges: 21–75). All participants completed an auditory n-back task with zero- and two-back memory load conditions. Behaviourally, CI users were slower in identifying targets during the two-back condition, especially older adults. The sensory-evoked responses were reduced in CI users compared to NH. With increasing memory load, younger CI users and NH controls displayed decreased amplitudes, while older CI users showed no change in amplitude. We also observed reduced frontal theta synchrony and greater alpha/beta desynchrony in CI users where alpha/beta in the left inferior frontal gyrus was related to slower response times in CI users. Attenuated frontotemporal connectivity was also evident compared to NH. These findings suggest that CI users adapt to higher task demands by allocating more attentional resources while encoding and maintaining stimuli in working memory. This pattern of activity potentially indexes a delay in identification and possible neural correlates of cognitive deficits while aging with a CI.

Excited State Dynamics of Odd [<i>n</i>]Cumulenes: Chain Length and Conformational Effects

ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a lethal embryonal brain tumor entity. To investigate the intratumoral heterogeneity and cellular communication in the tumor microenvironment (TME), we analyze in this work single-cell RNA sequencing of about 250,000 cells of primary human and murine ETMR, in vitro cultures, and a 3D forebrain organoid model of ETMR, supporting the main findings with immunohistochemistry and spatial transcriptomics of human tumors. We characterize three distinct malignant ETMR subpopulations - RG-like, NProg-like and NB-like - positioned within a putative neurodevelopmental hierarchy. We reveal PDGFRβ+ pericytes as key communication partners in the TME, contributing to stem cell signaling through extracellular matrix-mediated interactions with tumor cells. PDGF signaling is upregulated in chemoresistant RG-like cells in vivo and plays a role in recruiting pericytes to ETMR TME by finalizing a signaling cascade which promotes the differentiation of non-malignant radial glia cells, derived from our 3D model, into pericyte-like cells. Selective PDGFR-inhibition blocked the lineage differentiation into pericytes in vitro and reduced the tumor cell population in vivo. Targeting ETMR-pericyte interactions in the TME presents a promising therapeutic approach.

Organisational kindness and compassion: what are the barriers, enablers and outcomes for clients and stakeholders?

Unkind bureaucratic policies such as the Australian Robodebt policy, which targeted welfare recipients with automatic debt letters, and are geared towards economic savings, can significantly harm those impacted by them. Compassion and kindness are receiving increased research attention related to how organisations work internally. However, a greater investment in studies is needed to increase understandings about how compassion and kindness can underpin interactions with external stakeholders. Addressing this research gap, we aimed to identify barriers, enablers and outcomes to organisational kindness and compassion informed by the literature, and to propose future research directions related to organisational kindness and compassion towards external stakeholders. A search of four scholarly databases identified 25 relevant publications. Thematic analysis of included publications revealed barriers of commodification, personal risks, dysfunctional environments, inauthentic attempts at, and a lack of understanding of the need to be compassionate or kind. Enablers included building compassion into organisational policies, processes, practices and activities, compassion contagion, training of staff, leading with compassion, and kind and compassionate communication. Outcomes of kindness included building positive and healthy relationships with stakeholders, supporting positive experiences among stakeholders, and contributing to an organisation’s profitability, productivity, performance and standing in the community. We conclude by recognising that kindness is essential for ongoing trust in health and social care institutions and government policy.

Iron regulatory pathways differentially expressed during Madurella mycetomatis grain development in Galleria mellonella

Abstract Mycetoma is a chronic granulomatous infection of the subcutaneous tissue, most often caused by the fungal pathogen Madurella mycetomatis. Characteristic of the infection is the formation of grains. However, knowledge of the function and formation of the grain is limited. Here, we use a Galleria mellonella larvae infection model and transcriptomic profiling to identify processes associated with M. mycetomatis grain formation. Larvae were infected with M. mycetomatis and, after 4, 24, 72 and 168 h post-inoculation, RNA was extracted from larval content and sequenced. We found that 3498 G. mellonella and 136 M. mycetomatis genes were differentially expressed during infection. In particular, genes encoding proteins related to iron transport were highly expressed by both G. mellonella (transferrin and ferritin) and M. mycetomatis (SidA, SidD and SidI). LC-MS/MS analysis of M. mycetomatis cultured under iron-limiting conditions revealed the presence of SidA and SidD orthologs, and concurrent RP-HPLC and LC-MS identified a singly charged, putative siderophore in culture supernatant. Furthermore, we show that M. mycetomatis can obtain iron from holoferritin. Thus, our results highlight the importance of iron acquisition pathways during grain formation, suggesting potential avenues for development of new diagnostic and therapeutic strategies for mycetoma.