The industrial translation of liposome production processes remains challenging, particularly in achieving scalability while maintaining critical quality attributes and formulation stability. In this study, a supercritical CO2-based PGSS process was successfully transferred from the laboratory to the pilot scale (50 to 500 mL reactor). Using a Quality by Design approach and a design of experiments on a simplified soy phosphatidylcholine formulation, we identified optimal production process parameters. These parameters were then validated and transferred to other drug-encapsulating liposome formulations, demonstrating process robustness. Under these conditions, liposomes measuring less than 200 nm and polydispersity indices close to 0.30 were reproducibly obtained at pilot scale. The process was successfully applied to drug-loaded formulations, achieving high encapsulation efficiencies while maintaining suitable physicochemical properties. Cryo-TEM confirmed the formation of consistent vesicular structures. Importantly, lipid chemical stability was preserved, with minimal hydrolysis and no significant increase in oxidation, even for unsaturated lipids. Overall, this study demonstrates the robustness, scalability, and relevance of the PGSS process as a solvent-free, single-step technology for liposome production.
Maternal nutrition and lifestyle during pregnancy critically influence health outcomes for mother and child. While many countries developed national dietary and lifestyle guidelines (DGs) for pregnant women, in the Eastern Mediterranean Region (EMR), the availability, quality, and coverage of such guidelines remain largely undocumented and inconsistent. This review assesses national DGs for pregnant women in the EMR, identifying gaps, strengths, and opportunities for enhancement. A scoping review was conducted between October 2024 and January 2025, following the PRISMA-ScR framework. Systematic searches were performed across general search engines (Google Search and Google Scholar) and academic databases (PubMed and Scopus). National DGs were included if they addressed nutrition or lifestyle recommendations for pregnant women in any of the 22 EMR countries. Thematic analysis was used to map and evaluate content and structure. Themes were identified inductively from the EMR guidelines and contextualized against established international guidelines. Eleven EMR countries had DGs targeting pregnant women. Fourteen key themes were identified. Most guidelines covered diet, supplements, and gestational weight gain; meanwhile, hydration, physical activity, food safety, religious fasting, and gestational diabetes (GDM) were partially-addressed or absent. Lebanon and Saudi Arabia had the most comprehensive guidelines, addressing over 11 themes each. Only Lebanon adopted a dietary pattern-based approach. Few guidelines included medical consultation for supplementation or culturally-sensitive messaging. This review revealed that several EMR countries lack national DGs for pregnant women, highlighting the importance of encouraging and supporting their development. Few existing guidelines were comprehensive, with key themes like GDM, hydration, and religious fasting often absent. There is a need for more structured, context-specific, and inclusive guidelines across the region.
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Effective training is essential in the life sciences industry, to ensure product quality and safety by preventing contamination and errors, meeting regulatory requirements, reducing operational risks, and enhancing overall efficiency.Validation activities for Building, Planning and Logistics platforms like Enterprise Resource Planning (ERP) systems benefit from a careful planning effort to ensure that the approach is well-suited to the diverse users and functional groups accessing the application. As an ERP system includes quality critical and business critical functions, the dynamics of Enterprise-Level Computerized System Validation (CSV) testing must be adapted to address this duality - and training plays a key role.Clearly differentiating the quality critical features from the business-critical features, authoring both detailed and unscripted tests based on quality criticality, and ensuring that functional groups and the test execution team are well trained on the methods of testing can greatly impact the success of your effort and accelerate speed to market.
The integration of data-driven continuous monitoring into chronic disease management is often presented as a solution for clinical efficiency. However, this technological shift may substantially reshape care relations, power, and intimacy. Prevailing research, focused on technical validation, fails to capture how such systems operate as social forces. A critical, theory-informed examination of these lived transformations is needed. This study goes beyond documenting ethical dilemmas by critically investigating how data-driven surveillance restructures nurse-patient dynamics. We aim to uncover the mechanisms through which data-driven surveillance disciplines both caregivers and recipients, and to identify where and how the irreducible elements of humanistic care persist and resist. A critical qualitative design was employed, guided by Foucault's concept of governmentality as a sensitising lens. Semi-structured interviews were conducted with 12 registered nurses and 15 patients with hypertension or type 2 diabetes in one Chinese tertiary hospital that had, for six months, implemented real-time automated physiological monitoring. Data were analysed using reflexive thematic analysis with a hybrid (deductive-inductive) approach. Our analysis reveals three core mechanisms: (1) systematic arbitration (nurses as constant negotiators between automated alerts and situated clinical judgment); (2) datafied self-surveillance, patients internalise the data-driven gaze, policing their own behaviour; (3) a shared convergence around the human boundary, both nurses and patients actively defend empathy, contextual interpretation, and emotional recognition as domains irreducible to data. This boundary is not a passive remnant but an active, shared accomplishment. Digital surveillance in chronic care does not act as a neutral adjunct. Instead, it operates as a disciplinary technology that asymmetrically disciplines nurses and patients. However, the identified human boundary represents a critical site of resistance and re-humanisation. The future of humane digital health depends on deliberately designing socio-technical systems that strengthen, rather than erode, the relational and interpretive core of clinical practice.
Golden hamster (Mesocricetus auratus) and ferret (Mustela putorius furo) are important animal models in studies of human infectious disease. They are used widely to investigate pathogen-spreading mechanisms and host immunology to evaluate the safety and efficacy of small molecules, biologic drugs and vaccines. To this end, immunoglobulin A (IgA) and its Fcα receptor (FcαR) play critical roles in humans but are not well characterized in these 2 species. Golden hamster and ferret IgA and FcαR were recombinantly expressed, purified, and characterized for N-linked glycosylation site occupancy and binding affinity. Based on sequence and structural alignments, hamster IgA showed greater similarity to human IgA than did ferret, and hinge domains in both small animal models suggested greater structural homology to human IgA2 than IgA1. Despite considerable sequence divergence in both immunoglobulins and receptors, and the lack of binding between ferret FcαR and ferret IgA, human IgA bound to both hamster and ferret FcαR with high affinity. Further, differences in dissociation rates were dependent on test format, suggesting that the 2:1 stoichiometry of human FcαR: IgA is recapitulated in these animals. Overall, this work suggests the suitability of these animals to model protection or pathology driven by interactions between human IgA and host FcαR and will aid in critical and confident interpretation of infection and immunization studies in each species.
Microplastics (MPs) are emerging foodborne contaminants with increasing implications for gastrointestinal health. However, the mechanistic basis linking dietary MP exposure to gut dysbiosis and intestinal dysfunction remains poorly resolved, limiting robust human health risk assessment. This review critically synthesizes current evidence on foodborne MPs, dietary exposure, and the physicochemical determinants of gastrointestinal fate, bioavailability, and toxicity. We examine the molecular and microbiome-mediated mechanisms linking MPs exposure to intestinal dysbiosis, barrier dysfunction, oxidative stress, immune activation, and metabolic reprogramming. Particular attention is given to the role of MPs as vectors for co-contaminants, which can amplify toxicity through synergistic interactions and reshape host-microbiome responses. We highlight advances in dynamic colon simulation and integrated multi-omics that unravels the mechanism underlying MP-induced intestinal toxicity. Current evidence indicates that gut microbiome dysregulation is a key mechanism driving foodborne MP-induced intestinal dysfunction and systemic toxicity. This review integrates multidisciplinary evidence to identify critical knowledge gaps and guide future research on the mechanisms, exposure, and health risks of foodborne microplastics.
The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing but clinical outcomes remain poor and new treatments are required. IGF2BP3 is an oncofetal m6A-reading RNA regulatory protein whose expression is commonly observed in PDAC and which may represent an important therapeutic target. IGF2BP3 protein is expressed in >95% of primary tumours whilst RNA expression ranges from 3 to 3000-fold above normal epithelium. siRNA knockdown reveals IGF2BP3 to strongly support expression of gene programs related to DNA replication, cell cycle and apoptosis, TNF signalling and epithelial-mesenchymal transition. Direct sequencing of native RNA further reveals IGF2BP3-mediated enhancement of 863 RNA isoforms with suppression of 389 isoforms. m6A, m5C and pseudouridine (ψ) RNA modifications were seen in 97% of transcripts within the PDAC transcriptome and enriched within MYC gene targets. IGF2BP3 regulated the pattern of RNA modification with a substantial impact on m5C modifications of miRNA and scRNA, and genes associated with regulation of TNF signalling. Knockdown of IGF2BP3 expression in primary tumour organoid cultures suppressed proliferation and elicited apoptosis, indicating a critical requirement for IGF2BP3 within malignant stem cells. These data show that IGF2BP3 is expressed consistently in PDAC, plays a dominant role in regulation of RNA splicing and modification, and supports cancer stem cell proliferation and survival. IGF2BP3 therefore occupies a critical position within the RNA regulon of PDAC and represents an important therapeutic target in this tumour of unmet need.
Vocal fold fibrosis (VFF), characterized by excessive extracellular matrix deposition, leads to permanent voice impairment, with current therapies often failing to restore vocal function. Current treatments are limited by suboptimal efficacy and high recurrence rates. Dysregulated energy metabolism is emerging as a critical driver of fibrosis. AMP-activated protein kinase (AMPK), a central cellular energy sensor, exerts broad antifibrotic effects in multiple organs, yet the therapeutic potential of novel AMPK activators, such as Aldometanib, in VFF remains to be fully characterized. This study aimed to evaluate the therapeutic potential and mechanisms of Aldometanib, a novel AMPK activator, in vocal fold fibrosis. A controlled animal study was conducted using an SD rat vocal fold injury model. Animals were randomly allocated into four groups: control, injury, and injury treated with low or high doses of Aldometanib. Primary vocal fold fibroblasts were isolated and cultured, then stimulated with TGF-β1 to induce fibroblast activation, followed by treatment with different concentrations of the AMPK activator Aldometanib. Key outcome measures included histopathological analysis of collagen deposition (Alcian blue and EVG staining), protein and gene expression levels of fibrotic markers (α-SMA, COL1A1, FN1), and components of the JAK2/STAT3 signaling pathway (p-AMPK, p-JAK2, p-STAT3). In vivo, compared with the injury only group, Aldometanib treatment significantly improved the histological architecture of the vocal fold lamina propria. These changes were accompanied by increased p-AMPK levels and decreased expression of p-JAK2, p-STAT3, α-SMA, COL1A1, and FN1. In vitro, Aldometanib attenuated TGF-β1-induced fibroblast activation, and these effects were effectively reversed by co-treatment with the AMPK inhibitor DOX, confirming AMPK pathway dependency. Pharmacological activation of AMPK with Aldometanib effectively alleviates vocal fold fibrosis by inhibiting the JAK2/STAT3 signaling axis. This study identifies AMPK as a promising novel therapeutic target for vocal fold fibrosis, supporting future development of more potent or specific AMPK activators and localized delivery systems for clinical translation.
Persistent avoidance plays a major role in maintaining anxiety disorders. The few studies that have explored the neural basis of avoidance have predominantly examined established avoidance behaviours rather than the learning processes that establish avoidance responses. We aimed to characterise the temporal dynamics and neural mechanisms of avoidance learning using a novel paradigm combined with 7-Tesla functional magnetic resonance imaging (fMRI) in 82 healthy participants (37 male and 45 female). Participants were first conditioned to two threat stimuli and a compound safety stimulus. Next, they were trained to avoid one threat stimulus while the other remained unavoidable. Behavioural data confirmed accurate learning of task contingencies. Successful avoidance was associated with prominent activation of the ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), and ventrolateral prefrontal cortex compared to unsuccessful avoidance, with additional nucleus accumbens and orbitofrontal cortex engagement when compared to safety learning (P FDR whole-brain corrected). Critically, early compared to late avoidance learning was distinctly associated with activation of midbrain-striatal circuits, including the periaqueductal grey (PAG), mediodorsal thalamus, substantia nigra, and anterior insular cortex-regions associated with threat processing and learning-related signalling. These findings suggest that initial avoidance learning relies on subcortical threat-responsive and learning-related circuits whereas established avoidance responses engage cortical safety-processing regions. This dissociation parallels recent findings in safety learning and provides novel mechanistic insights for interventions targeting maladaptive avoidance patterns.Significance statement Avoidance behaviour is central to anxiety disorders, yet the neural mechanisms through which avoidance is learned remain poorly understood. Using 7-Tesla fMRI and a novel paradigm in 82 participants, we show that initial human avoidance learning engages midbrain-striatal circuits-including the periaqueductal grey, substantia nigra, and thalamus-while established avoidance relies on cortical safety-processing regions centred on the ventromedial prefrontal cortex. This temporal dissociation parallels recent findings in Pavlovian safety learning and identifies a potential mechanistic window during which maladaptive avoidance patterns may be most amenable to intervention.
The rapid one step detection of cancer markers at early stages of cancer is critical to increase the efficiency of the treatments and survival. miRNA-21 is the most commonly upregulated microRNA in solid tumours and haematological malignancies and is associated with poor prognosis and survival rate. Therefore, its detection at the early stage is vital, ideally using a rapid, simple method with a low detection limit. Current methods often require sophisticated method and labelling to detect miRNAs. Here, we show that nanosized molecularly imprinted polymers (nanoMIPs), can selectively and sensitively detect miRNA-21 without labelling. NanoMIPs were synthesised via solid-phase polymerization. The template molecule of 5' phosphor-capped miRNA-21 was attached to a functionalised glass bead via phosphorylimidazolide chemistry. Selected functional monomers/cross-linkers were used to generate selective nanoMIPs with recognition based on electrostatic and ionic interactions. NanoMIPs were characterized to investigate their physicochemical properties and interaction with target molecule. These nanoMIPs were then used for miRNA-21 detection studies exploring affinity and selectivity to the target with Surface Plasmon Resonance in both buffer and serum. High affinity materials (equilibrium dissociation constants - KD' s in the nM/pM range) were demonstrated with high selectivity and when linked to the SPR sensor, a theoretical lower detection limit (LOD) of miRNA-21 was calculated as 0.49 pM in serum. This work provides new perspectives in developing miRNA-21 specific synthetic molecular recognition materials using nanoMIPs. The nanoMIPs has potential to be suitable sensor platform, that could be promising tools for early cancer diagnostics in complex matrices.
CCR2+ monocytes are recruited to sites of acute myocardial injury, where they play a critical role in clearing necrotic debris and replenishing the depleted resident macrophage population. Although this response is necessary for early tissue repair, prolonged activation of inflammatory pathways and persistent recruitment of CCR2+ monocytes have been associated with accelerated ventricular remodeling and adverse outcomes. Inhibition of CCR2 has shown promise in preclinical models of myocardial injury and represents a potential therapeutic target. Cardiosphere-derived cell extracellular vesicles (CDC-EVs) have demonstrated cardioprotective effects partly through modulation of the immune response. We investigated whether CDC-EVs regulate inflammatory monocyte trafficking through effects on CCR2 signaling. We found that CDC-EVs reduce the surface availability of CCR2 on human monocytes through an miR-146a-dependent mechanism, resulting in decreased monocyte migration toward CCL2. These findings identify a previously unrecognized mechanism by which CDC-EVs modulate CCR2-dependent monocyte trafficking and provide new insight into how EVs regulate innate immune responses after myocardial injury.
In laboratory-based injury risk assessments, there is always a small and not entirely avoidable risk of injury to participants. This case report describes an anterior cruciate ligament (ACL) re-rupture of a female participant during the approach run of a stimulus-response change-of-direction (COD) task. Marker-based kinematic data from the injury trial were compared with 14 successful trials of the same participant. These trials included unanticipated CODs in response to an opponent's kicking action with varying cognitive demands, including one trial under identical high-demand conditions involving a feint. The participant approached at a speed of 4.08 m/s and the feint was initiated 475 ms before the injury step. The injury trial differed from the non-injury trials in terms of a markedly prolonged flight phase preceding initial contact in combination with deviations in lower-limb and trunk kinematics during the flight phase and the step before. These deviations exceeded the participant's typical movement range observed during the non-injury trials and included temporally pre-shifted flexion-extension patterns at the knee and hip, a more extended trunk at initial contact, an altered pelvic drop, and reduced ankle inversion. During the injury stance phase, pronounced hip adduction, knee abduction and ankle eversion were observed. The findings substantiate previously theorized mechanisms of non-contact ACL injury and show in a within-subject comparison that critical proximal and distal kinematic deviations at the trunk and lower limbs arise already during the preparatory phase. The occurrence after an opponent's feint further suggests and highlights the importance of a neurocognitive contribution for ACL injuries. The study protocol was preregistered on Open Science Framework ( https://doi.org/10.17605/OSF.IO/4Z5R8 ).
The rapid emergence of antibiotic resistance represents a critical global health challenge, particularly in biofilm-associated infections caused by Pseudomonas aeruginosa (P. aeruginosa). Quorum sensing plays a pivotal role in regulating bacterial virulence and biofilm formation. Consequently, targeting quorum sensing-regulated virulence factors represents a promising anti-virulence strategy to combat antibiotic resistance. In this study, the FDA-approved drugs vardenafil, valsartan, and olmesartan did not significantly affect the growth of ten clinical P. aeruginosa isolates. At sub-inhibitory concentrations, these drugs significantly reduced the production of key virulence factors, including hemolysin, proteases, pyocyanin, lipases, as well as impairing swarming motility, and biofilm formation. Gene expression analysis confirmed marked downregulation of quorum sensing-associated genes in five selected isolates. In vivo experiments revealed a substantial reduction in bacterial pathogenicity following treatment. Molecular docking analyses further supported these findings, revealing favorable interactions of the tested drugs with key quorum sensing regulatory proteins. Collectively, these results highlight the anti-quorum sensing, anti-virulence, and antibiofilm potential of these repurposed drugs and suggest their possible application in topical formulations as adjunctive therapies to conventional antibiotics for managing severe pseudomonal infections.
Detecting localized prostate cancer (PC) with metastatic potential-defined as unfavorable-histology PC (uhPC), comprising Grade Group (GG) ≥3 disease or GG 2 disease with cribriform/intraductal features-is critical for guiding appropriate intervention. We evaluated the utility of the Prostate Imaging Reporting and Data System (PI-RADS) and the automated Restriction Spectrum Imaging restriction score (RSIrs; a biophysics-based quantitative MRI biomarker) for uhPC detection and localization. We evaluated patient-level detection of uhPC in a multicenter cohort with biopsy as the reference standard and lesion-level localization in a separate cohort with whole-mount histopathology (WMHP) from radical prostatectomy. The area under the receiver operating characteristic curve (AUC) was calculated to compare patient-level detection of uhPC using PI-RADS and RSIrs. PI-RADS and RSIrs were used to evaluate sensitivity for the most aggressive tumor within the prostate (index tumor) and for all uhPC tumors on WMHP. The AUC for patient-level detection of uhPC did not differ significantly between PI-RADS and RSIrs in 1022 patients from five centers (p = 0.13). At the lesion level (n = 103 patients), sensitivity for the index tumor was 87% (95% confidence intervals [CI], 79-94) for PI-RADS, 85% (95% CI, 78-93) for RSIrs, and 93% (95% CI, 86-98) for the two combined. For all uhPC tumors, sensitivity was 81% (95% CI, 73-90) for PI-RADS, 86% (95% CI, 78-93) for RSIrs, and 90% (95% CI, 82-97) for the two combined. A limitation of the lesion-level analyses was that only patients who opted for surgery could be included. MRI showed high sensitivity for detecting uhPC, reinforcing its value for identifying biologically aggressive disease. Both PI-RADS and automated RSIrs may be useful for targeted biopsy and tumor-focused treatment, such as focal radiation dose escalation to aggressive intraprostatic lesions.
Post-COVID-19 syndrome is a major long-term sequela of severe SARS-CoV-2 infection, potentially involving persistent angiogenic and thromboinflammatory dysfunction, though long-term biomarker behavior remains unclear. To evaluate the evolution of angiogenic and thromboinflammatory biomarkers in post-COVID-19 syndrome patients. This ambispective cohort study was conducted at the National Institute of Respiratory Diseases in Mexico City. Thirty-two adults hospitalized for severe or critical COVID-19 in 2020 were followed for three and a half years. Paired plasma samples were collected during hospitalization and at long-term follow-up. Endothelial dysfunction markers included soluble P-selectin, vascular endothelial growth factor receptor 2, vascular endothelial growth factor D, and angiopoietin-1. Hemostasis was assessed by prothrombin time. Acute-phase proteins alpha-2-macroglobulin and haptoglobin were measured via immunoassay. Persistent symptoms were documented at follow-up. At three and a half years, persistent symptoms were common: fatigue in sixty-five point 6%, dyspnea in sixty-two point 5%, and concentration difficulties in sixty-five point 6%. Vascular endothelial growth factor D and angiopoietin-1 remained elevated. Alpha-2-macroglobulin stayed high, and prothrombin time was prolonged in a subset of patients. Severe COVID-19 survivors show sustained angiogenic dysregulation and thromboinflammatory imbalance. Elevated vascular endothelial growth factor D and angiopoietin-1 indicate ongoing angiogenic perturbations, while increased alpha-2-macroglobulin and prolonged prothrombin time reflect persistent coagulation disturbances. These biomarkers may help identify long-term vascular alterations in post-COVID-19 syndrome.
Triclosan (TCS) is an antimicrobial compound widely used in pharmaceutical and personal care products (PPCPs). It is classified as a contaminant of emerging concern (CEC) due to its environmental health implications. However, significant knowledge gaps remain regarding the toxic effects of environmentally relevant concentrations of TCS in coastal and marine species, such as bivalves. In this study, the impact of triclosan on the primary heart cell cultures derived from the euryhaline coastal bivalve, Magallana bilineata, was investigated. The heart cells were exposed to various concentrations of TCS, and the IC50 value was determined to be 2.1494 mg L-1. Following this, sub-lethal toxicity tests based on cellular and molecular parameters were conducted using environmentally relevant TCS concentrations. The results demonstrated that TCS induces ROS (reactive oxygen species) production at environmentally relevant levels and also alters gene expression, as evident from the mRNA profiling of superoxide dismutase (Cu/Zn sod), catalase (cat), glutathione peroxidase (gpx), calmodulin (calm), and heat shock protein 70 (hsp70). Furthermore, cardiomyocyte beating patterns varied (contraction impairment, arrhythmic activity, or absence of cardiomyocyte clusters) depending on the TCS concentrations. The results point to ROS-mediated disruptions in excitation-contraction coupling as a likely contributor, and further studies will strengthen mechanistic understanding. Overall, these findings provide critical insights into the cellular and molecular toxicity of environmentally relevant TCS concentrations and support the utility of M. bilineata heart cell cultures for advancing aquatic toxicology research.
Pulmonary hypertension is a malignant cardiovascular disease characterized by pulmonary vascular remodeling, with core pathological features including pulmonary arterial wall thickening and elevated pulmonary vascular remodeling due to aberrant proliferation of pulmonary arterial smooth muscle cells (PASMCs). The molecular regulatory mechanisms underlying pulmonary vascular remodeling remain incompletely understood. Transcriptome sequencing was employed to screen for differentially expressed genes in lung artery tissues of control and Sugen5416 combined hypoxia-induced rat models. A series of in vitro and in vivo experiments, including scratch assays, EdU staining, Cell Counting Kit-8cell proliferation assays, immunofluorescence, immunoblotting, and overexpression/knockdown techniques, were performed to investigate the molecular mechanism by which KRT17 (keratin 17) induces PASMCs proliferation and promotes pulmonary hypertension vascular remodeling. KRT17 was found to be highly expressed in lung tissues of patients with pulmonary hypertension, as well as in pulmonary arterial tissue and hypoxic PASMCs models. Both in vivo and in vitro experiments demonstrated that KRT17 was a critical regulator of PASMCs proliferation. METTL14 (methyltransferasean14, an m6A methyltransferase complex subunit) was identified as a potential modulator of KRT17 RNA methylation, enhancing its RNA stability and protein expression. Furthermore, KRT17 promoted PASMCs proliferation through upregulation of LCN2 (lipocalin-2). Our study reveals a novel molecular mechanism by which KRT17 expression is regulated via METTL14-mediated m6A methylation, and further elucidates the role of KRT17 in inducing PASMCs proliferation through the LCN2 signaling pathway. These findings provide significant theoretical insights for the development of innovative therapeutic targets for pulmonary hypertension.
The unfolded protein response (UPR) preserves endoplasmic reticulum proteostasis through coordinated signaling pathways, including the IRE1α-XBP1 axis, which promotes adaptive transcriptional programs via noncanonical XBP1 mRNA splicing. However, upstream mechanisms regulating this pathway remain incompletely defined. Here, we apply CRASP-seq, a scalable RNA-coupled CRISPR screening platform, to systematically identify regulators of XBP1 splicing. We uncovered the U2 snRNP auxiliary factor RBM39 as a critical positive regulator of this process. Perturbation of RBM39 or U2 snRNP components induces alternative splicing of ERN1, leading to exon-18 skipping and the production of an unstable transcript subject to nonsense-mediated decay, as well as a truncated IRE1α isoform that acts in a dominant-negative manner to suppress XBP1 splicing. Mechanistically, we show that heat shock reduces RBM39 functional activity and promotes ERN1 exon-18 skipping, thereby attenuating IRE1α-XBP1 signaling. Functionally, hyperactivation of this pathway is detrimental under proteotoxic stress, suggesting that exon-18 skipping serves as a stress-adaptive mechanism to limit UPR output. Together, our findings reveal a previously unrecognized regulatory axis linking the canonical splicing machinery to UPR signaling and establish alternative splicing of ERN1 as a key modulator of cellular stress responses.
Artificial intelligence (AI), digital health technologies, and neuroengineering are rapidly transforming the diagnosis and management of movement disorders. By 2050, these innovations, together with profound demographic, cultural, and economic changes, are expected to reshape the role of neurologists far beyond current clinical practice. movement disorder specialists may evolve from a primarily diagnostic clinician into an orchestrator of personalized neurocare, integrating multimodal digital biomarkers, AI-driven decision support systems, wearable technologies, closed-loop neuromodulation,and disease-modifying therapies. We argue that future neurological care will increasingly rely on continuous home-based monitoring, predictive modeling, and individualized therapeutic strategies based on biological, clinical and 'social' information rather than purely clinical disease definitions. At the same time, population aging, healthcare sustainability, and disparities in access toadvanced technologies will require neurologists to assume broader responsibilities as multidisciplinary coordinators, integrating clinicalexpertise with data science, ethics, and health economics. Despite the growing role of AI, clinical reasoning, empathy, communication,and shared decision-making will remain irreplaceable components of neurological care. Rather than replacing neurologists, AI is likelyto increase the need for highly trained specialists capable of critically interpreting algorithmic outputs, recognizing their limitations, andcontextualizing recommendations within each patient's biological, psychological, and social framework. The neurologist of 2050 willtherefore become not only a clinician, but also a guarantor of trustworthy, equitable, and human centered precision neurology.