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Modern microscopy enables us to measure structural and dynamical properties of many biological processes and is therefore an indispensable research tool. However, the amount and complexity of the produced imaging data is steadily increasing. Thus, handling the data as well as reproducibly and automatically extracting accurate scientific information require dedicated 'bioimage analysis' expertise. To facilitate the dissemination of this ubiquitously required expertise we developed an open-access bioimage analysis training resource. The resource is designed to help trainers to design and run courses on bioimage analysis for life scientists. The material is modular where each module covers one concise topic and provides corresponding activities using microscopy images from biological samples. The activities can be executed using various popular software packages (e.g. ImageJ, Python). The material is hosted on a public software repository allowing the bioimaging community to readily contribute new training modules or improve existing modules. Within the last 3 years, the material has been used by several trainers in numerous courses and continuously improved.

Unhealthy alcohol use is prevalent in chronic liver disease (CLD). This randomized controlled trial evaluated the efficacy of telehealth stepped alcohol treatment (SAT) in three healthcare systems. Participants (N=157) with CLD and unhealthy alcohol use (>7 drinks/week or ≥4/day for women; >14/week or ≥5/day for men; or heavy episodic drinking, using timeline follow back), were enrolled at a safety-net and 2 Veterans Affairs hepatology clinics from 3/1/2022-2/28/2024. Participants were randomized to SAT (N=81; Step 1: three motivational interviewing sessions, Step 2: addiction medicine referral if no drinking reduction at month 3) or usual care (UC; N=76); evaluated at months 3 and 6. Alcohol use reduction was analyzed using bivariate tests and multivariable modeling. Baseline characteristics were: median age 61, 86% male, 48% with cirrhosis (37% decompensation), and 78% with alcohol use disorder. Compared to UC, SAT had no difference in percentage of alcohol use below moderate level (primary outcome) but had greater reduction in drinks/week from baseline to month 3 (estimate -0.66, P=0.03) and month 6 (estimate -0.67, P=0.03) (secondary outcome). The 6-month effect of SAT (vs UC) on alcohol use reduction remained significant (P=0.02), controlling for covariates. At month 6, 30-day abstinence rates were 29% for SAT and 18% for UC (P=0.14). Baseline motivation to reduce alcohol use was positively associated with treatment response. SAT was not superior on the primary outcome, yet reduced alcohol use more than UC at six months in this difficult-to-engage population and may be valuable in hepatology.

Biologists and physicists have a rich tradition of modeling dynamics of living systems with simple models composed of a few interacting components. Despite the remarkable success of this approach, it remains unclear how to use such finely tuned models to study complex biological systems composed of numerous heterogeneous, interacting components. One possible strategy for taming this biological complexity is to embrace the idea that many biological behaviors we observe are "typical" and can be modeled using random systems that respect biologically motivated constraints. Here, we review recent works showing how this approach can be used to make close connection with experiments in biological systems ranging from neuroscience to ecology and evolution and beyond. Collectively, these works suggest that the "random-with-constraints" paradigm represents a promising new modeling strategy for capturing experimentally observed dynamical and statistical features in high-dimensional biological data and provides a powerful minimal modeling philosophy for biology.

Atrazine is a widely used herbicide whose persistence and mobility have led to frequent contamination of soils and water bodies. Atrazine can be degraded in soils through two primary biotic pathways: an oxidative route that produces the relatively persistent metabolites desethylatrazine and deisopropylatrazine, and a hydrolytic route mediated by chlorohydrolases encoded by atzA or trzN, leading to the less recalcitrant intermediate hydroxyatrazine. This study quantified atrazine degradation rates in 17 agricultural soils overlying a regional aquifer and evaluated degradation potential through complementary laboratory experiments. The soils contained hydroxyatrazine and desethyl-2-hydroxyatrazine, indicating active hydrolytic transformation in the fields, while varying proportions of dealkylated metabolites suggested concurrent oxidative degradation. Field-derived half-lives ranged from 36 to 225 days, with evidence of biphasic kinetics, as younger atrazine residues degraded more rapidly than aged residues. Finally, laboratory enrichment cultures of all soils confirmed the capability of indigenous bacteria to hydrolyze atrazine, with a clear predominance of trzN over atzA across cultures. The findings of the current study indicate that while the predominance of the hydrolytic pathway suggests reduced risk of rapid atrazine migration to groundwater, the observed biphasic degradation behavior indicates that residual atrazine may continue leaching over extended timescales with prolonged risk for groundwater quality. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Primary bone cancer is a relatively rare malignant tumor that manifests in the bone and affects the normal functioning of the bone tissue. Primary bone cancer can be characterized into three subtypes, which are osteosarcoma, chondrosarcoma, and Ewing sarcoma. Notably, the treatment of primary bone cancer with conventional modalities, like chemotherapy and surgical interventions, has been overwhelmed with dismal clinical outcomes. The conventional therapies are challenged with non-specificity, resulting in off-target effects and ultimate harm to healthy tissue. Particularly, chemotherapy as a first-line treatment option is riddled with poor drug bioavailability, limited tumor accumulation, and increasing drug resistance. Several innovative drug delivery systems, including nano-based carriers, have been investigated to overcome the systemic drug delivery challenges in primary bone cancer. Accordingly, with most reviews focusing on bone metastasis (secondary bone cancer), this current narrative review aims to provides critical insights on nanocarrier strategies for drug delivery in primary bone cancer, comprehensively expounding on the epidemiology, cellular mechanisms, and etiological effects of primary bone cancer, as well as the current therapies and new drug nanocarriers prototyped to optimize the clinical outcomes in bone cancer management.

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Land-based military deployers to Afghanistan and/or Southwest Asia (SWA) encountered exposure to high concentrations of respirable particulate matter (PM) from multiple sources, including desert dust, burn pit smoke, and military occupations. Adverse lung health effects following deployment have been noted, including upper and lower respiratory tract symptoms, asthma, and small airway and other abnormalities on lung biopsy. The American Thoracic Society (ATS) convened a Workshop in 2018 to review studies assessing post-deployment respiratory health, describe emerging research, and highlight knowledge gaps. Progress on understanding post-deployment health prompted a second ATS Workshop to update current knowledge by 1) reviewing new studies linking exposure assessments to symptoms and/or clinical disease; 2) describing the spectrum of lung pathology reported in previously deployed personnel; 3) evaluating current knowledge of long-term health outcomes after deployment; 4) reviewing data from recent experimental models of deployment-related respiratory diseases (DRRDs); and 5) providing recommendations for future research priorities. Workshop participants agreed that there is substantial evidence linking deployment-related exposures to respiratory symptoms, pulmonary diagnoses, and lung pathology. Knowledge gaps include understanding: 1) the extent and mechanisms through which specific exposures result in impaired pulmonary function, small airways disease, and potentially future chronic pulmonary diseases; 2) the contribution of exposure-related foreign material in the lung to clinical and pathologic findings; and 3) the relationship of pathologic findings to respiratory health, especially those involving small airways.

BCG vaccination against TB may also reduce malaria incidence through non-specific innate immune activation. We investigated whether giving BCG alongside an adenoviral-vectored malaria vaccine improves protection against malaria in mice. Co-immunisation broadened and strengthened the early innate cytokine responses, enabling strong CD8+ T cell-dependent protection. Our findings suggest co-immunisation with BCG and adenoviral vector as a promising strategy to combat both TB and malaria in double-endemic regions.

Increasing cell size drives proteomic changes that impact cell physiology. However, the molecular basis of size-dependent proteome remodeling has remained unclear. Here, we develop an inducible Cyclin D1 expression system in human cells to generate proliferating cells spanning over a 2-fold size range. We use this system to make comprehensive genome-wide measurements of mRNA and protein concentrations and stability. We find that protein and mRNA turnover rates are weakly related to cell size but that mRNA concentrations are strongly size-dependent. This establishes that transcriptional regulation is the basis of proteome remodeling. Live-cell imaging of nascent mRNAs using the MS2 system is used to measure how transcriptional dynamics change with cell size. Larger cells prolong transcriptional bursts but maintain similar burst amplitudes to achieve transcriptional scaling. Together, our results show how transcription is modulated by cell size to remodel the proteome and alter cell physiology.

The key advantage of spatial transcriptomics (ST) technologies lies in the spatial domain: these techniques not only offer an unprecedented opportunity to interrogate intact biological samples in a spatially informed manner, but also set the stage for integration with other imaging-based modalities. However, how to most effectively exploit spatial context and integrate ST with imaging-based modalities that capture morphological insight remains an open and heavily investigated question. To address this, particularly under real-world experimental constraints such as limited dataset size, class imbalance, and bounding-box-based segmentation, we used a publicly available murine ileum Multiplexed Error-Robust Fluorescence In Situ Hybridisation (MERFISH) dataset to evaluate whether a minimally tuned variational autoencoder (VAE) could extract informative low-dimensional representations from cell crops of spot counts, nuclear stain, membrane stain, or a combination thereof. We assessed the resulting embeddings through PERMANOVA, cross-validated classification, and unsupervised clustering, and compared them to classical image-based feature vectors extracted via CellProfiler. While transcript counts (TC) generally outperformed other feature spaces, the VAE-derived latent spaces (LSs) captured meaningful biological variation and enabled improved label recovery for specific cell types. LS2, in particular, trained solely on morphological input, also exhibited moderate predictive power for a handful of genes in a ridge regression model. Notably, combining TC with LSs improved clustering outcomes in a strategy-dependent manner, yielding gains in either cluster homogeneity or label recovery under graph- or factor-based clustering approaches, respectively. In contrast, CellProfiler-derived features provided little benefit, highlighting the advantage of learned representations over handcrafted features. Collectively, these findings demonstrate that even under constrained conditions, VAEs can extract biologically meaningful signals from imaging data and constitute a promising strategy for multi-modal integration.

Stem cell-derived neuron-glia models provide a robust platform for studying brain physiology, developing therapeutics, and exploring biocomputation. Extracellular vesicles (EVs) containing neurotrophic factors, also derived from stem cells, have the capacity to facilitate the formation of neural networks within these systems. However, their bioactivity is often compromised by the propagation of oxidative stress between cells during their manufacture, limiting reproducibility. Here, the Cellular Redox Spreading Shield (CROSS) is introduced as a droplet microfluidic-assembled antioxidant crystal-loaded microgel that sustains antioxidant activity for up to 6-7 days in stem cell cultures. In mesenchymal stromal cell (MSC) cultures, CROSS mitigates oxidation propagation and preserves potent neurotrophic EV production. These EVs, specifically enriched with neurotrophic microRNAs, enhance neural stem cell differentiation into neuron-glia networks, characterized by increased synaptic density and functional connectivity, as determined by calcium transient imaging combined with graph theory. In contrast, EVs from untreated, oxidatively stressed MSCs impair neural stem cell differentiation and network formation. This work highlights the importance of CROSS in stabilizing cellular production of neurotrophic EVs, with broad implications for neural tissue regeneration and biohybrid technologies.

Genome-edited human pluripotent stem cells (hPSCs) provide a powerful platform to study complex diseases such as Parkinson's disease (PD). Here, we describe iSCORE-PD, an isogenic collection of 65 genome-edited hPSC lines carrying disease-causing or high-risk variants in 11 PD-linked genes (SNCA, PRKN, PINK1, DJ1/PARK7, LRRK2, ATP13A2, FBXO7, DNAJC6, SYNJ1, VPS13C, and GBA1). All lines are derived from a well-characterized female hESC line and subjected to extensive quality control. Whole-genome sequencing reveals that genetic variation between lines, largely confined to non-coding regions, is minimal relative to inter-individual differences in patient-derived hiPSCs, with most variation arising from random mutations acquired during cell culture rather than genome-editing-induced off-target effects. Including multiple independently derived clones per mutation can control for this random genetic drift. Our systematic approach ensures high quality of this publicly available iSCORE-PD resource, highlights the advantages of prime editing over conventional CRISPR/Cas9 methods, and establishes best practices for generating disease-modeling hPSC collections.

Industrial painters (IPs) are routinely exposed to complex mixtures of reactive chemicals, including isocyanates and epoxy resins used in metal coating systems and spray polyurethane foam (SPF) applicators. Oxidative stress (OS), resulting from an imbalance between reactive oxygen species and antioxidant defenses, is a key mechanism of toxic injury linked to numerous diseases like cancer, asthma, dermatitis, and neurotoxicity. However, data on OS markers among IPs are limited. To characterize urinary OS biomarker concentrations in IPs and SPF applicators and evaluate their associations with urinary biomarkers of isocyanate and epoxy exposure. Pre- and post-shift urine samples were collected from 50 workers applying either isocyanate-based top-coats or epoxy-based mid-coats and SPF. Nine urinary OS biomarkers were analyzed to reflect DNA/RNA damage (8-hydroxy-2'-deoxyguanosine [8OHdG], 8-hydroxyguanosine [8OHG], 5-hydroxymethyluracil [5OHMeU]), protein oxidation (o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine), and lipid peroxidation (8-isoprostane, 4-hydroxynonenal [4-HNE], malondialdehyde [MnDAI]). Associations between OS and exposure biomarkers were evaluated using multivariable linear regression adjusted for creatinine and age. Top-coat painters exhibited significant post-shift increases in 8OHdG, 8OHG, and 3-nitrotyrosine, whereas o-tyrosine and 4-HNE decreased. After adjustment, 8OHdG was positively associated with isocyanate (top-coat) and epoxy (mid-coat) exposure, while 4-HNE was inversely associated with isocyanate exposure. Workers with severe dehydration (specific gravity >1.030) had significantly higher composite OS scores. Exposure to reactive coating formulations in IPs and SPF induces measurable oxidative stress, likely via multiple mechanisms, including depletion of the antioxidant pools, impaired antioxidant defenses and direct attack on sensitive biomolecules. Elevated urinary OS biomarkers and their association with exposure metrics highlight the need for improved exposure controls and increased risk of chronic disease development in this workforce.

Hedgehog (HH) signaling in vertebrates is dependent on the primary cilium, an organelle that scaffolds signal transduction. HH signals induce ciliary enrichment of Smoothened (SMO) and ciliary departure of the G protein-coupled receptor (GPCR) GPR161 to trigger GLI activation of the HH transcriptional program. Recently, SMO has been shown to inhibit protein kinase A (PKA). To test the hypothesis that SMO inhibits PKA at cilia to activate the HH signal transduction pathway, we developed a ciliary PKA reporter. Ciliary PKA activity was graded during zebrafish development. Activation of the HH signal transduction pathway by either Sonic hedgehog (SHH) or SMO agonist (SAG) inhibited ciliary PKA activity. Blocking SMO phosphorylation by GRK2/3 prevented ciliary SMO from inhibiting ciliary PKA activity. Converting the SMO C-terminal PKA pseudosubstrate site into a consensus PKA substrate blocked SMO-mediated inhibition of ciliary PKA activity. A ciliary GPCR, SSTR3, activated ciliary PKA and induced HH transcriptional responses in NIH/3T3 cells via a different mechanism: activation of Gαi/o. A different ciliary GPCR, GPR161, possesses an A-Kinase Anchoring Protein (AKAP), which we found was critical for the ciliary localization of the catalytic subunit of PKA (PKA-C) to promote ciliary PKA activity. We propose that HH signal transduction is inhibited by GPR161-mediated ciliary enrichment of PKA-C, and activated by GRK2/3-phosphorylated SMO inhibition of ciliary PKA activity.

To evaluate health care utilization in veterans with Alzheimer disease (AD) in the Veterans Affairs health system (VAHS). This retrospective analysis identified veterans with AD using clinical notes extracted from the VAHS electronic health record from fiscal years 2010 to 2019. The first note identifying AD was the index date. Health care utilization in veterans with AD and a 1:1 matched comparison group without AD was evaluated at 2 years preindex, 1 year preindex, 1 year post index, and 2 years post index. From clinical notes, we identified 571,671 veterans with AD and 571,671 for the comparison group (overall: mean age, 74 years; 96% male; 75% White). In those with AD, outpatient visits per patient per year peaked 1 year post index at 67 and remained elevated 2 years post index at 57; without AD, the rate was approximately 19 at all time points. Hospitalization rates peaked at 1 year post index with AD but were lower and generally stable without AD. Nursing home utilization was relatively low overall. Veterans meeting the 2-code criteria (n = 56,305), defined as having 2 diagnostic codes for AD recorded at least 30 days apart, had consistently higher utilization than veterans without AD (especially post index). Veterans with AD have higher health care utilization than veterans without AD, especially around the time of AD diagnosis.

West Nile virus (WNV) is a mosquito-borne pathogen of global concern that can cause fatal neuroinvasive disease, and no specific prophylaxis or treatment exists for infections by WNV and most related orthoflaviviruses. Here, we isolated and characterized antibodies from WNV convalescent individuals and report that neutralizing autoantibodies against type I interferons did not impair antiviral antibody development. Among the monoclonal antibodies with potent neutralizing activity against WNV that were identified, W010 targeted a distinct epitope within the envelope protein domain III (EDIII) and conferred both pre- and post-exposure protection in a murine WNV model, even when interferon signaling was impaired. A second protective antibody, W014, exhibited broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.

Annexin A6 (AnxA6) is a predominantly intracellular calcium-dependent membrane-binding multifunctional protein that is also detected extracellularly and in small extracellular vesicles (exosomes). We previously demonstrated that lapatinib resistance in triple-negative breast cancer (TNBC) cells is associated with AnxA6 upregulation and accumulation of cholesterol in late endosomes. Here, we investigated the fate of AnxA6 and cholesterol in lapatinib-resistant (LAP-R) cells and whether extracellular AnxA6 influences TNBC cell survival. We demonstrate that reduced expression of AnxA6 in LAP-R cells decreased the secretion of MCP-1/CCL2, CCL8/IL-8, DKK1, TSP-1, and OPN by antibody arrays. The secretion of exosomes was also markedly reduced in AnxA6-depleted LAP-R cells, while AnxA6 upregulation stimulated the release of MCP-1 and exosomes. Compared to the respective controls, exosome-associated AnxA6, Rab7, and cholesterol levels were increased in exosomes isolated from AnxA6-expressing LAP-R cells. Mechanistically, we demonstrated by co-immunoprecipitation, GST pulldown, and proximity ligation assays that AnxA6 interacts with SNAP23, a component of the membrane fusion machinery. Finally, blocking extracellular AnxA6 with neutralizing antibodies reduced the viability of AnxA6-low TNBC cells but had little effect on AnxA6-high cells. These findings suggest that extracellular AnxA6 is critical for the survival of highly proliferative AnxA6-low basal-like breast cancer cells and that AnxA6 influences TNBC progression by facilitating the secretion of pro-inflammatory cytokines and cholesterol-enriched exosomes.

Microfluidic devices enable high-throughput sample processing with remarkable parallelization and miniaturization. While fluorescence microscopy provides a convenient method for reading out signal from microfluidic assays, commercially-available microscopes impose a fundamental tradeoff between temporal resolution, spatial resolution, and numerical aperture (NA). Spatially tiled imaging enables high-resolution and high-NA imaging over a large area but reduces temporal resolution. Conversely, low magnification, low NA imaging captures large areas in one shot, but typically sacrifices spatial resolution and fluorescence sensitivity. To address this, we introduce an automated transfluorescence tandem-macro-lens optomechanical system (macroscope) capable of sensitive, multi-channel fluorescence imaging over a very large field of view (34 mm diameter, 740 mm2), with resolution determined by the sensor pixel size. We demonstrate bright-field resolution of low-micron features and detection of low- to mid-nanomolar concentrations of common fluorophores within microfluidic device channels. To demonstrate the utility of this macroscope, we image enzyme turnover within valved microfluidic devices (the HT-MEK system, for High-Throughput Microfluidic Enzyme Kinetics) and achieve >50-fold increased temporal resolution over common commercial instruments while maintaining high sensitivity. This macroscope imaging solution costs substantially less than the price of commercially available alternatives, providing a powerful new imaging approach for microfluidic applications requiring sensitive and rapid wide-field fluorescence imaging.

As part of a Global BioImage Analysts' Society (GloBIAS) initiative, we evaluated the reproducibility of a Graph Neural Network (GNN) study on cell dynamics using structured, community-developed checklists from the Quality Assessment and Reproducibility for Instruments and Images in Light Microscopy (QUAREP-LiMi) initiative. Notably, these checklists were published after the 2022 Target Paper, meaning our assessment is necessarily retrospective. Our assessment revealed a gap between recent reporting standards and practical execution. Reproduction attempts across multiple environments confirmed deficiencies, including the absence of explicit image metadata (pixel size and timestamps), which limits quantitative interpretation. Furthermore, the absence of a software container, which was typical for the time of publication and the incomplete dependency list, necessitated complex manual environment configuration, increasing the barrier to entry. This experience highlights the contrast between the reproducibility expectations at the time and newer standards achieved by minimal compliance and true functional access. We conclude by presenting a detailed discussion of the broader implications for the quantitative biology community and propose actionable recommendations including robust environment containerisation and standardised data deposition to ensure complex computational workflows become scientifically sound and reusable resources. This retrospective case study evaluates a legacy computational paper against modern reproducibility framework, not to critique past non-compliance, but to extract actionable lessons for future research standards.