Circulating tumor cells (CTCs), shed from primary tumors into the peripheral bloodstream, are important biomarkers for early cancer diagnosis and disease monitoring. Deterministic lateral displacement (DLD) microfluidic devices enable label-free CTC isolation through continuous, size-based separation. However, DLD performance is highly sensitive to coupled geometric and operating parameters, making optimal design challenging. Conventional trial-and-error approaches are computationally expensive and provide limited insight into parameter interactions, necessitating data-driven optimization. Here, a Bayesian optimization (BO) framework integrating high-fidelity numerical simulations with Gaussian process (GP) surrogate modeling is developed for efficient DLD design. Using pillar gap size, post-array tilt parameter and flow rate as design variables, BO iteratively constructs a surrogate of the nonlinear target-particle lateral-displacement response and guides adaptive sampling. The GP model achieved high predictive accuracy, with an [Formula: see text] of 0.9873 and a mean absolute error of [Formula: see text] on an independent validation dataset. Compared with Evolution Strategy (ES), BO reduced the evaluations required to identify the best-performing design within the prescribed design space by 67.2% and the time-to-solution by 80.0%, while outperforming Genetic Algorithm (GA), Differential Evolution (DE), Particle Swarm Optimization (PSO) and conventional parametric sweep approaches. The BO-identified design produced a target-particle lateral displacement of [Formula: see text]. Post-optimization particle-size and outlet-region analyses identified an effective critical diameter of approximately [Formula: see text] and demonstrated distinct collection of the investigated NSCLC CTC target surrogate and smaller blood-cell-relevant background-size particles across three release positions. The GP surrogate also enables response-surface mapping, global sensitivity analysis and uncertainty quantification. Results identify the post-array tilt parameter as the dominant factor governing target-particle lateral displacement, while flow rate strongly interacts with geometric variables. Uncertainty analysis confirms stable performance under perturbations. The proposed framework provides an efficient, interpretable, and reliability-aware approach for DLD microfluidic device design.

MHC restriction - the requirement for αβ T cell receptors (TCRs) to recognize Major Histocompatibility Complex (MHC) molecules when presenting peptide antigens - is a pillar of adaptive immunity. Here, we provide direct structural evidence for TCR germline-encoded recognition of MHC molecules irrespective of antigenic peptide. We engineered "germline-like" TCRs to eliminate CDR3 specificity for peptide, and a molecular clamping strategy to trap ultra-low-affinity complexes with peptide-MHC for cryo-EM. We find that germline-like TCR/pMHC docking modes are identical to wild-type T cell receptors with intact CDR3 loops, across distinct peptide antigens and MHC alleles. Analysis of human TCR repertoires reveals enrichment of specific V genes and Vα-Vβ pairing patterns associated with HLA-A*02 contexts. Thus, the TCR germline encodes the blueprint for MHC restriction, providing a sequence-based framework that could inform computational and AI-driven prediction of TCR specificity.

γδ T cells are promising cancer-immunotherapy effectors because they recognize tumors without major histocompatibility complex (MHC) restriction and carry low graft-versus-host-disease risk in allogeneic settings, yet few bibliometric studies have integrated immunotherapy-specific research trends with clinical-trial mapping and translational-gap analysis. We characterized the global research output, intellectual foundations, emerging frontiers, and clinical translation of γδ T cells in cancer immunotherapy (2000-2025) by combining bibliometric analysis of 3,273 Web of Science publications (bibliometrix, VOSviewer, CiteSpace), a Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR)-guided evidence map of 26 interventional cancer trials (ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform [WHO ICTRP], regional registries), and an integrative step linking bibliometric hotspots to the pipeline. Annual output grew from 18 (2000) to 418 (2024) publications (compound annual growth rate [CAGR], 14.0%) across three phases; China (33.1%) and the United States (27.3%) led production. Co-citation analysis identified five intellectual pillars: phosphoantigen recognition, subset heterogeneity, clinical adoptive transfer, tumor-microenvironment suppression, and engineered γδ T therapy. Chimeric antigen receptor-engineered γδ T cells (CAR-γδ T cells), allogeneic platforms, and single-cell RNA sequencing were the leading 2022-2025 frontier terms. Trials shifted toward allogeneic cell sources; early-phase studies consistently met safety and feasibility endpoints, but monotherapy efficacy was modest. The LAVA-051 and LAVA-1207 programs were discontinued for disclosed business or internal-benchmark reasons, whereas allogeneic CAR-Vδ1 therapy (ADI-001) produced the most encouraging early signals before oncology reprioritization in 2024. Three persistent translational gaps-single-cell/T-cell receptor (TCR) profiling, metabolic reprogramming, and γδT17 biology-frame a proposed roadmap to convert bibliometric hotspots into mechanism-guided γδ T-cell cancer immunotherapy.

A compelling and paradoxical body of evidence challenges the traditional view of parasites solely as pathogens. This narrative review synthesizes a growing literature suggesting that specific, chronic parasitic infections-particularly by helminths, but also certain protozoa-can, under precise ecological conditions, confer a spectrum of protective and ameliorative effects on the host. We comprehensively detail these effects across two interconnected domains. First, we examine organ-specific immunomodulation, focusing on the attenuation of inflammatory and autoimmune pathologies within the cardiovascular, neuroinflammatory, renal, hepatic, and pulmonary systems. Second, we explore systemic physiological modulations that extend beyond classic immunology, including enhanced tissue repair, improved metabolic homeostasis, neuroprotection, anti-tumor activity, and the engineering of a health-promoting gut microbiome. Underpinning these benefits are shared mechanistic pillars: the induction of regulatory T cells (Tregs) and anti-inflammatory cytokines (IL-10, TGF-β), polarization of macrophages toward an M2 reparative phenotype, and profound remodeling of the gut microbiota. Crucially, we emphasize that these "benefits" are incidental by-products of host-parasite co-evolution, observed only in contexts of low-burden, chronic infection with particular species, and are vastly outweighed by the direct morbidity of active parasitosis. The true translational promise lies in parasite-inspired pharmacology: the identification, synthesis, and therapeutic application of discrete parasite-derived molecules to treat inflammatory, metabolic, degenerative, and neoplastic diseases, offering a novel paradigm for drug discovery inspired by nature's most adept manipulators of host biology.

Microbial bioelectrocatalysis demands more than electron-conducting surfaces-it demands living microenvironments that hydrate, protect, and nourish whole-cell biocatalysts. This biological imperative remains unaddressed by conventional electrode design. Here, we fundamentally reframe microbial biobattery architecture through living habitat engineering, drawing inspiration from the human small intestine-a biological interface evolutionarily optimized to sustain dense, metabolically active microbial communities through high-surface-area villi, mucus-mediated hydration, and short-path nutrient exchange. We translate these principles into spore-programmed conductive hydrogel pillar arrays, in which dormant Bacillus subtilis endospores are embedded within poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)-poly(vinyl alcohol)/reduced graphene oxide hydrogel villi that simultaneously serve as microbial reservoirs, bioelectrochemical scaffolds, and electron-harvesting conduits. Upon nutrient contact, spores germinate on demand into electroactive cells. This villi topology delivers an 8.3-fold volumetric power density enhancement (8.04 to 66.45 µW cm[-] [3]) over planar controls under volume-matched conditions. A 24-device geometry matrix uncovers a coupled radius-height design rule, with peak single-villus power of 8.35 µW at optimal dimensions. Conformable villi patches demonstrate nutrient-triggered electricity generation in a simulated pipe environment using a wastewater-mimicking nutrient/electrolyte solution, while a separate self-powered array achieves spatially resolved bioelectrochemical sensing. This work establishes living habitat engineering as a transformative paradigm for activatable, architecture-programmed, and potentially shelf-stable microbial biobatteries.

Mechanical forces play a key role in regulating cell behaviour, with dynamically changing mechanical cues governing processes such as morphogenesis, wound healing, and cancer progression in vivo. However, there is a lack of experimental platforms that enable localized, dynamic, and tuneable mechanical stimulation under real-time imaging. Here, we present a large deflection magnetic artificial cilia (ldMAC) platform that enables dynamic, microscale mechanical stimulation of cells with high spatial and temporal control. Arrays of ldMAC are fabricated via femtosecond lasermachining and hot embossing of a magnetic polymer, yielding robust ldMAC capable of tip deflections up to 25 μm under actuation by a custom-made, compact permanent magnet-based system, representing a several-fold increase in displacement compared to most reported magnetic pillar platforms. The setup is compatible with standard cell culture conditions and live fluorescence microscopy, a feature that is typically challenging due to the bulky and complex nature of conventional actuation systems. Using human dermal fibroblasts, we demonstrate that ldMAC actuation induces changes in cell morphology without affecting viability. Dynamic stimulation by cyclic ldMAC deflection leads to a shift toward more compact, rounded cell phenotypes, accompanied by reduced cell area. Time-lapse imaging reveals that cells actively reorganize cytoskeletal structures and reduce the amount of cilia attachments upon stimulation, reminiscent of strain avoidance behaviour. Compared to existing approaches, the presented platform uniquely combines localized, dynamic, controllable actuation with real-time imaging in a compact, user-friendly format. Importantly, it enables active and reversible ldMAC deformation with independently tuneable frequency and amplitude. This approach offers a practical tool for studying cellular responses to dynamic mechanical environments and opens new possibilities for mechanobiology research.

The biocatalytic production of nicotinic acid using nitrilases has emerged as a promising alternative to conventional chemical synthesis, offering improved selectivity and environmental sustainability. In this study, we developed a continuous-flow millireactor system employing Escherichia coli cells expressing a nitrilase from Paraburkholderia phymatum (NitPhym) for the continuous production of nicotinic acid. To enhance catalytic efficiency and stability, whole cells were immobilized using two different strategies: covalent attachment to the reactor walls and encapsulation in alginate microbeads. The performance of these immobilization techniques was evaluated in millireactors with two different geometries: pillar and zigzag configurations. Encapsulation of NitPhym-expressing E. coli cells in alginate microbeads was achieved through a centrifuge-assisted microencapsulation method, yielding beads with diameters of up to 350 µm. Continuous-flow reactions demonstrated that the microencapsulated cells maintained their activity over at least 7 days, achieving stable conversion rates of approximately 30% in both pillar and zigzag millireactors. Compared to direct covalent immobilization, microencapsulation significantly reduced cell leaching and contamination of the reaction product. These findings highlight the potential of whole-cell microencapsulation for enhancing the stability and efficiency of biocatalytic processes in continuous-flow millireactors.

Metastatic clear cell renal cell carcinoma (mRCC) has undergone a fundamental therapeutic transformation over the past two decades. Following a prolonged period during which treatment options were limited to immunomodulatory therapies with modest efficacy due to the marked chemoresistance of this malignancy, the introduction of vascular endothelial growth factor receptor (VEGF)-targeted tyrosine kinase inhibitors (TKIs) led to a substantial improvement in clinical outcomes. Currently, targeted therapies and the newer immune checkpoint inhibitors (ICIs) represent the central pillars of systemic treatment for mRCC. These combination therapies have increased the 5-year overall survival rate to over 40% and are now considered the standard of care (CheckMate 214, CheckMate 9ER, CLEAR, KEYNOTE-426). Nevertheless, there remains a significant unmet therapeutic need, particularly in later-line treatment settings, making the development of novel therapeutic strategies and more precise patient stratification essential for further improving clinical outcomes.

Drought-mediated declines in grain nutritional quality and cereal yield put global food security at risk, yet the rhizosphere microbiome provides an alternative solution for improving crop tolerance. Our review synthesised existing knowledge on how soil microbiomes, particularly arbuscular mycorrhizal fungi (AMF) and plant-growth-promoting rhizobacteria (PGPR), simultaneously regulate three interlinked pillars of crop performance (stress tolerance, grain nutrient uptake, and yield) under drought. Our in-depth analysis showed that such relationships were governed by synergies (improved root architecture improves all three traits) and trade-offs (i.e., ABA-induced stomatal closure improves water efficiency but restricts carbon assimilation). Furthermore, these relationships were governed at different biological layers through multi-omics (metagenomics, transcriptomics, proteomics, and metabolomics) to identify biomarkers and pathways. With the application of an integrated framework through bioinformatics, it is now possible to reveal the hidden molecular layout between cereals and their underground partners, identify drought-responsive pathways, and discover biomarkers (nutrient transporter gene, microbial abundance, osmolyte accumulation, and root exudates). Despite advancements, critical technical gaps hinder data integration and standardised pipelines to identify complex traits through heterogeneous databases of omics. Our review proposes an integrated framework linking multi-omics tools, microbiome traits, and crop outcomes. Furthermore, we provide a research roadmap prioritising drought biofortification, synthetic communities (SynComs), microbial consortia, and spatial omics. Such research directly supports hidden hunger and food security agendas, while progressing climate-resilient agriculture.

Human settlements, urban centers, and critical infrastructure in Alpine regions are increasingly exposed to natural hazards. In Austria, while disaster risk management is coordinated nationally, institutional governance is currently distributed across nine federal provinces, resulting in a patchwork of regional datasets and mapping practices. To support greater consistency at the national scale, this study proposes an ecogeomorphological conceptual framework (EGCF) for risk-informed spatial planning, structured around three thematic pillars: ecology, geomorphology, and hydrology. The framework is operationalized through spatial multi-criteria evaluation (SMCE), combining 1) development-only frequency ratio (FR) scores with 2) principal component analysis (PCA)-based within-theme predictor weights and 3) analytic hierarchy process (AHP) theme weights. It is implemented for national-scale landslide susceptibility assessment in Austria using a 17-factor EGCF-informed configuration and a literature-derived 9-factor baseline evaluated within the same workflow. The resulting 17-factor landslide susceptibility index covered 89.88% of national grid cells. In the primary spatial holdout evaluation, the full 17-factor configuration did not outperform the 9-factor baseline; the area under the curve (AUC) values were 0.787 and 0.806 for the 17-factor and 9-factor configurations, respectively. However, development-only factor-addition diagnostics showed that the contribution of the added predictors was heterogeneous, with additional hydrological predictors providing the most consistent improvement across five spatial folds. These findings show that broader predictor coverage does not necessarily translate into better overall discrimination, but that additional ecogeomorphological information can provide distinct analytical value when evaluated systematically. The framework therefore provides a reproducible national susceptibility baseline and a transparent structure for evaluating the contribution of additional ecogeomorphological information. This supports national-scale screening and risk-informed spatial planning.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the pathological accumulation of Lewy bodies composed predominantly of aggregated α-synuclein (αSyn). Despite decades of progress in genetics and neuropathology, the mechanisms driving disease initiation and progression remain incompletely understood, and no disease-modifying therapy has yet demonstrated conclusive efficacy. Neuroinflammation and metabolic dysfunction have emerged as two central and mechanistically intertwined pillars of PD pathogenesis. We propose an integrative model in which these processes function not merely in parallel, but as mutually reinforcing components of a self-amplifying pathological circuit, while acknowledging that this model remains to be fully validated and that alternative causal architectures are possible. This review systematically addresses the mechanistic coupling between neuroinflammation and metabolic dysregulation in PD, covering: (1) the molecular basis of innate immune activation via DAMPs, pattern recognition receptors, and inflammasome signaling; (2) microglial metabolic reprogramming and the NLRP3/NF-κB inflammatory axis; (3) αSyn-driven innate and adaptive immune responses; (4) mitochondrial dysfunction and oxidative stress as bidirectional amplifiers; (5) the gut-brain axis as a conduit for peripheral immunometabolic disruption; (6) the AMPK/mTOR/HIF-1α molecular network integrating metabolism and inflammation; (7) sphingolipid metabolism and the GBA-lysosomal axis; and (8) translational evidence from animal models and randomized controlled trials. A concise section integrates key fluid biomarkers as clinical surrogates of the underlying mechanisms.

RNA vaccines-comprising linear mRNA, self-amplifying RNA, and circular RNA (circRNA)-constitute a core next-generation platform for the prevention and control of viral diseases; among these, circRNA vaccines possess notable structural stability, yet their technical bottlenecks and application prospects in veterinary medicine have not been systematically reviewed. This review synthesizes current research on circRNA vaccine design, circularization strategies, translation mechanisms, delivery systems, and immunological outcomes, and compares their antiviral performance with that of linear mRNA vaccines. Owing to their covalently closed circular conformation, circRNA vaccines exhibit enhanced resistance to nucleases and superior thermal stability, enabling sustained transfection activity at ambient temperatures without reliance on strict cold chains; through cap-independent translation driven by internal ribosome entry sites or N[6]-methyladenosine modifications, and in conjunction with optimized circularization protocols and lipid nanoparticle carriers, circRNA vaccines elicit substantially higher antiviral IgG titers and durable antigen-specific T-cell memory relative to linear mRNA vaccines. These vaccines have been deployed against COVID-19, monkeypox, influenza, and livestock viral diseases, demonstrating strong adaptability to viral variants and compatibility with mucosal or needle-free administration routes. CircRNA vaccines are well suited for both emergency outbreak response and routine immunization programs; nevertheless, challenges persist, including low circularization efficiency for long sequences, elevated manufacturing costs, and inadequate quality control standards. Addressing these issues through improved production workflows and delivery technologies adapted to resource-limited settings will be critical to establishing circRNA vaccines as a pillar of livestock disease management and as a strategic reserve for emerging zoonotic threats.