Microglial SIRT6 confers protection against neuroinflammation-associated depression through NRF2-HO1 signaling

A detoxifying multi-strain probiotic formula attenuates toxicity induced by heavy metals and phthalates.

Age-related B cell dysfunction at the aging-cancer nexus: from shared manifestations to therapeutic potential.

Global growth hormone receptor knockout (GHR-/-) extends lifespan but also causes adverse effects. As a key target of growth hormone (GH), adipose tissue may mediate aging, though the underlying mechanisms remain unclear. We investigated how adipose-specific GHR ablation influences multisystem aging, with a focus on metabolic health and cognitive function. We generated adipose-specific GHR knockout (Ad-GHRKO) mice and assessed healthspan parameters including cognitive function, musculoskeletal integrity and metabolic profiles. Adipose tissue remodelling and inflammation were examined by histology and protein analysis. Subcutaneous white adipose transcriptomics identified gene expression changes. The role of the AMPK-SIRT1-Ac-PPARγ pathway in metabolic elasticity and aging was elucidated by Western blot and invitro assays. Ad-GHRKO mice exhibited extended healthspan, with enhanced cognitive performance, improved muscle strength and bone mass and a lifespan increase trend. Mechanistically, GHR ablation remodelled adipose tissue, reducing age-related lipid redistribution, restoring glucose homeostasis and creating a low-inflammation, high-plasticity depot. This reprogramming boosted systemic metabolic elasticity primarily via AMPK-SIRT1-Ac-PPARγ activation. AMPK inhibition abolished benefits, confirming its pivotal role. Our findings identify adipose-specific GH signalling antagonism as a regulatory switch that recalibrates the local balance between GH and IGF-1 actions, thereby reprogramming adipose tissue to promote coordinated systemin metabolic resilience during aging. This tissue-targeted strategy circumvents the developmental and endocrine limitations associated with global GH/IGF-1 suppression. Rather than merely extending lifespan, adipose-specific GHR ablation supports healthier aging by preserving metabolic homeostasis, maintaining multisystem functional integrity and reducing age-associated inflammatory and fibrotic remodelling. Collectively, these results highlight a potentially translatable approach for mitigating age-related metabolic and cognitive decline.

While antisense oligonucleotide (ASOs) therapies have emerged as promising tools to modulate gene expression in neurological diseases, these new agents face challenges in the context of the central nervous system, particularly regarding distribution and duration of action. Translational approaches that enable the tracking of ASO effects in the whole brain are therefore needed to guide their preclinical and clinical development. In the present study, we used PET imaging as a translational tool to study the pharmacodynamics of an ASO targeting a metabotropic receptor, namely, the dopamine D2 receptor. We selected an ASO sequence directed toward D2 mRNA in the rat brain and optimized its chemical backbone by a gapmer design. This anti-D2R ASO was administered directly into the striatum of adult rats via intracerebral stereotaxic injection at different doses. The longitudinal pharmacodynamic effects of the ASO were assessed using successive PET acquisitions with the D2R radiotracer [11C]raclopride to quantify changes in D2R receptor expression in the striatum. Our PET findings indicated a reduction of D2R availability from 3 weeks to 10 weeks postinjection. The apomorphine-induced rotation test confirmed that the postsynaptic striatal dopaminergic imbalance was behaviorally relevant and persisted for three months after the ASO injection. This work provides novel insights into the potential of PET neuroimaging to explore the in vivo efficacy and longevity of modified ASOs delivered directly into the brain, opening translational applications.

Ferroptotic tumor cells reprogram tumor-associated macrophage antigen presentation to enhance the efficacy of immune checkpoint blockade.

STING agonist-primed supramolecular oncolytic hydrogel vaccine for tuning tumors against themselves.

Olfaction-based biosensor technology in cattle reproduction: Current status and future perspectives.

Nanotechnology in oral cancer: a theranostic approach for diagnosis, targeted therapy, and clinical translation

ABSTRACTProstate‐specific membrane antigen (PSMA) is overexpressed in over 90% of prostate cancer tumors, making it a strong target for imaging and therapy. The diagnostic tracer [18F]F‐Piflufolastat provides high affinity and image quality, while the β‐emitter [177Lu]Lu‐PSMA‐617 enables targeted treatment. Despite differences in radioactive half‐life, their shared PSMA‐binding and pharmacokinetic profiles suggest potential for translational pharmacokinetic modeling. We hypothesized that the published full‐body physiologically based pharmacokinetic (PBPK) model could be directly translated across the investigated PSMA ligands to predict tracer distribution within the same patient. A PBPK model was developed by rebuilding and modifying a published [68Ga]Ga‐PSMA‐11/[177Lu]Lu‐PSMA‐617 model to simulate [18F]F‐Piflufolastat PK. Patient‐specific factors included tumor volume, PSMA receptor density, organ blood flow, and renal clearance. Verification used published data, dynamic positron emission tomography (PET) from eight patients, and static total‐body PET/computed tomography (CT) at 2 h from five patients. Extrapolation to [177Lu]Lu‐PSMA‐617, using fitted receptor density, was evaluated against 24‐h and 7‐day Single‐Photon Emission Computed Tomography (SPECT) data from two patients using mean prediction error (PE). The model accurately predicted [18F]F‐Piflufolastat tumor uptake (median PE −3.44% (IQR −3.79 to −3.17) and −3.53% (IQR −3.78 to −3.00) in internal and external cohorts) and showed consistency with 7‐day [177Lu]Lu‐PSMA‐617 SPECT observations. However, predictions for other organs were variable (median PE ranging between −89.7 and 144), indicating limitations of a one‐to‐one molecular translational approach. These findings demonstrate that PBPK modeling can capture key determinants of PSMA tracer distribution, and link [18F]F‐Piflufolastat imaging to [177Lu]Lu‐PSMA‐617 predictions. However, improved representation of systemic and organ‐level kinetics is required. Future work should explore a limited PBPK approach, focusing on accurate blood kinetics and organ‐specific modeling.

Disrupted RNA processing is increasingly recognized as a key driver of severe neurodevelopmental disorders. Variants in the Integrator catalytic subunit INTS11 and its binding partner BRAT1 lead to clinically overlapping phenotypes, yet only the molecular function of INTS11 has been relatively well characterized. In contrast, the mechanistic contribution of BRAT1 to RNA metabolism and disease has remained unclear, leaving major gaps in variant interpretation and diagnostic classification. We employed an integrated genetic, molecular, and in vivo approach to investigate the impact of INTS11 and BRAT1 mutations on U small nuclear RNA (U snRNA) processing. Patient-derived fibroblasts and lymphoblastoid cells were analysed by western blotting, RT-qPCR and fluorescence in situ hybridization to assess U1 snRNA 3'-end processing and nuclear retention. To validate the functional consequences of Integrator deficiency in vivo, we generated and characterized an ints11 knockout zebrafish model. We identified novel biallelic variants in INTS11 and BRAT1 in individuals with overlapping neurodevelopmental features. While defective snRNA processing is anticipated in INTS11 deficiency, this study provides the first direct demonstration of impaired U1 snRNA processing across multiple INTS11-mutated patient cells. Critically, we show that BRAT1 mutations also compromise U1 snRNA 3'-end processing, leading to nuclear accumulation of unprocessed transcripts. These findings provide direct evidence of BRAT1's role in RNA processing and establish Integrator dysfunction as a primary pathogenic mechanism in BRAT1-associated neurological disease. The magnitude of U1 snRNA misprocessing closely correlates with clinical severity across the BRAT1 cohort, highlighting its potential as a diagnostic biomarker. Consistently, the ints11 knockout zebrafish model recapitulates core patient features - including microcephaly, neurodevelopmental defects, and U snRNA processing defects - further validating the causal role of Integrator deficiency in vivo. Our results redefine BRAT1-associated neurological disorders as Integrator-related diseases driven by RNA processing defects. Nuclear accumulation of unprocessed U1 snRNAs emerges as a robust biomarker for variant interpretation, disease severity, and patient stratification, particularly in BRAT1 cases. These findings broaden the clinical and molecular spectrum of Integrator dysfunction and provide a foundation for improved diagnostic and translational approaches.

Although sonodynamic therapy (SDT) has shown promise in reducing atherosclerotic plaque burden, its clinical application remains confined to superficial lesions, as deep-seated plaques such as those in coronary arteries lack precise imaging guidance and lesion-specific energy delivery. Here, we report an intravascular ultrasound (IVUS)-guided SDT strategy that integrates high-resolution imaging and precise treatment within a single catheter system. Osteopontin (OPN)-targeted bismuth-based nanoparticles (BSNPs), endowed with piezoelectricity through defect-induced symmetry breaking, selectively accumulate in foam cells. Pulsed ultrasound emitted by the IVUS catheter triggers BSNPs to generate reactive oxygen species (ROS) through the modulation of pulse-repetition time (PRT) and pulse width (PW), thereby inducing foam cell apoptosis and promoting plaque regression. With IVUS guidance, the SDT process can be visualized in real time, ensuring precise lesion-specific treatment. Systematic in vitro and in vivo studies demonstrate the effective antiatherosclerotic effect with minimal adverse effects. This imaging-integrated piezo-sonodynamic platform establishes a multifunctional catheter-based ultrasound theranostic strategy, providing a precise and clinically translatable approach for treating atherosclerosis.

The development of mRNA vaccines has significantly advanced global health during the COVID-19 pandemic. However, translating effective vaccine doses from preclinical animal models to human clinical use remains poorly understood. In this study, we evaluated antibody responses and repertoire diversity across different BNT162b2 mRNA vaccine doses in mice, while comparing the results with human data through mathematical modeling. We observed that 1μg BNT162b2 dose regimen induced a persistent antibody response and broad antibody repertoire for up to 16weeks in mice. Conversely, 0.05μg BNT162b2 dose regimen resulted in waning antibody responses and narrowed antibody repertoires over the same period, resembling responses observed in humans vaccinated with 30μg BNT162b2 dose regimen. An empirical dose translation approach revealed a discrepancy in dose relevance between the 1μg commonly used in the in vivo mice model and the 30μg used for vaccination in human. Therefore, it is crucial to re-evaluate the appropriate mRNA vaccine dose for in vivo mice models to accurately reflect human responses.

Viral orchitis and male infertility: A comprehensive review of pathogenic mechanisms and outcomes.

Given the prevalence of metabolic perturbations in a variety of neurological and neurodegenerative diseases, understanding and monitoring brain metabolism is a key step in our advancement of therapies. The details of the citric acid cycle were established at the beginning of the last century but only recently have its metabolic intermediates been observed in vivo in the brain. In this study, we employed orthogonal analyses to investigate metabolic alterations in response to acute neuroinflammation in vivo, demonstrating a multi-technique approach that could be used for future studies.Hyperpolarized [1-13C] pyruvate spectroscopy revealed an early decline in pyruvate metabolism via pyruvate dehydrogenase (PDH), leading to reduced 13C-bicarbonate formation. This metabolic disruption occurred despite the absence of structural or perfusion changes on conventional MRI. Further analysis of polar metabolites in the ipsilateral hemisphere confirmed ongoing inflammatory processes. These findings highlight the potential of this dual technique approach to inform upon metabolic changes due to neuroinflammation.Combining methods to probe metabolism in invasive (metabolomics) and non-invasive (hyperpolarized MRI) manners, this represents a promising translational approach for real-time metabolic assessments in an area of the body, the brain, where studying processes such as metabolism has traditionally been challenging. This study has demonstrated the approach to monitor changes in metabolism in response to inflammation in the brain.

Manganese (Mn2+) serves as an inorganic activator of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, its activation efficiency remains lower than conventional organic STING agonists, hindering widespread applications in immune modulation and therapy. Herein, we report an intermediate-crystalline phase manganese layered double hydroxide/oxide (Mn-LDH/O150) nanocomposite, featuring both LDH and LDO structural phases, as a potent cGAS-STING activator. Surprisingly, Mn-LDH/O150 induced a type-I interferon level significantly higher than pure Mn-LDH or LDO phase nanocomposites, and comparable to organic STING agonists (cGAMP/diABZI). Mechanistically, conventional Mn nanocomposite impairs energy metabolism in dendritic cells and significantly reduces mitochondrial ATP production. In contrast, Mn-LDH/O150 modulates mitochondrial metabolism by normalizing the electron transport chain (ETC) process, which is termed "immunometabolism normalization", thereby promoting ATP production that in turn facilitates cGAMP synthesis and STING activation. In mice models, Mn-LDH/O150 acts as a potent immune adjuvant in inducing antibodies production and T cell responses. Using a model antigen (ovalbumin) and melanoma neoantigens, we further demonstrate the excellent activity of Mn-LDH/O150-based vaccine in inducing antitumor immunity to prevent tumor progression and metastasis. Our discoveries highlight the crucial involvement of energy metabolism in modulating STING activation, and present a simple yet translational material engineering approach for boosting metalloimmunotherapy.

The immune system undergoes profound age-related changes that manifest as impaired immune function (immunosenescence) and chronic low-grade inflammation (inflammaging), both of which may influence the tumor biology of head and neck squamous cell carcinoma. While phenotypic analyses of peripheral and intratumoral immune cells have so far shown few age-associated differences, omics studies have identified senescence-related signatures linked to poor prognosis and reduced immune activity. Emerging translational data suggest that senolytic therapies may overcome mechanisms of immunosenescence-driven resistance to immune checkpoint inhibitors. Clinical trials and real-world evidence consistently demonstrate that current immunotherapies are effective and well tolerated in older patients. Overall, biological age-captured, for example, through geriatric frailty assessments or molecular markers-appears more relevant for tumor biology and therapeutic decision-making than mere chronological age.

Microfluidic synthesis offers precise control over liposome self-assembly, however the transfer of optimized formulations between different chip geometries still remains limited by geometry-dependent hydrodynamics. This work presents for the first time a Computational Fluid Dynamics (CFD) guided framework enabling predictive translation of DSPC:Cholesterol liposome production across microfluidic platforms without empirical reformulation. CFD simulations reproduced the local solvent exchange and mixing environments governing liposomes formation during ethanol dilution. Transferable hydrodynamic descriptors were extracted to quantitatively link flow conditions with liposome formation dynamics and morphological evolution. Experimental validation using dynamic light scattering and transmission electron microscopy demonstrated consistent size distributions and morphologies across different device geometries after optimal BCs selection. Using curcumin as a model cargo, we demonstrated that CFD-guided translation effectively identifies processes that yield drug-loaded liposomes with nearly identical features. Although absolute size prediction is not yet achieved, the proposed methodology enables rational comparison of microfluidic designs, reduces trial-and-error optimization, and supports scalable liposome manufacturing. The framework provides a general strategy for CFD-assisted translation of liposome self-assembly processes in microfluidic systems. • Computational optimization protocol for the definition of liposome formulation. • Brand new CFD-based descriptors for the translation of liposome synthesis across microfluidic geometries. • Experimental validation confirmed computational driven liposome manufacturing across devices. • Numerical approach reduces empirical optimization and supports scalable microfluidic manufacturing.

Targeting MUC16 suppresses malignant progression and chemoresistance in large-duct type intrahepatic cholangiocarcinoma.

Gingiva-Derived Decellularised Extracellular Matrix Hydrogel Supports Osteogenic and Angiogenic Phenotypes of 3D STRO-1+ GMSC/HUVEC Spheroids In Vitro.