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Three-dimensional renal tissues that emulate the cellular composition, geometry, and function of native kidney tissue would enable fundamental studies of filtration and reabsorption. Here, we have created 3D vascularized proximal tubule models composed of adjacent conduits that are lined with confluent epithelium and endothelium, embedded in a permeable ECM, and independently addressed using a closed-loop perfusion system to investigate renal reabsorption. Our 3D kidney tissue allows for coculture of proximal tubule epithelium and vascular endothelium that exhibits active reabsorption via tubular–vascular exchange of solutes akin to native kidney tissue. Using this model, both albumin uptake and glucose reabsorption are quantified as a function of time. Epithelium–endothelium cross-talk is further studied by exposing proximal tubule cells to hyperglycemic conditions and monitoring endothelial cell dysfunction. This diseased state can be rescued by administering a glucose transport inhibitor. Our 3D kidney tissue provides a platform for in vitro studies of kidney function, disease modeling, and pharmacology.

Confined systems ranging from the atomic to the granular are ubiquitous in nature. Experiments and simulations of such atomic and granular systems have shown a complex relationship between the microstructural arrangements under confinement, the short-ranged particle stresses, and flow fields. Understanding the same correlation between structure and rheology in the colloidal regime is important due to the significance of such suspensions in industrial applications. Moreover, colloidal suspensions exhibit a wide range of structures under confinement that could considerably modify such force balances and the resulting viscosity. Here, we use a combination of experiments and simulations to elucidate how confinement-induced structures alter the relative contributions of hydrodynamic and short-range repulsive forces to produce up to a tenfold change in the viscosity. In the experiments we use a custom-built confocal rheoscope to image the particle configurations of a colloidal suspension while simultaneously measuring its stress response. We find that as the gap decreases below 15 particle diameters, the viscosity first decreases from its bulk value, shows fluctuations with the gap, and then sharply increases for gaps below 3 particle diameters. These trends in the viscosity are shown to strongly correlate with the suspension microstructure. Further, we compare our experimental results to those from two different simulations techniques, which enables us to determine the relative contributions of hydrodynamic and short-range repulsive stresses to the suspension rheology. The first method uses the lubrication approximation to find the hydrodynamic stress and includes a short-range repulsive force between the particles while the second is a Stokesian dynamics simulation that calculates the full hydrodynamic stress in the suspension. We find that the decrease in the viscosity at moderate confinements has a significant contribution from both the hydrodynamic and short-range repulsive forces whereas the increase in viscosities at gaps less than 3 particle diameters arises primarily from short-range repulsive forces. These results provide important insights into the rheological behavior of confined suspensions and further enable us to tune the viscosity of confined suspensions by changing properties such as the gap, polydispersity, and the volume fraction.

Shear thickening, an increase of viscosity with shear rate, is a ubiquitous phenomenon in suspended materials that has implications for broad technological applications. Controlling this thickening behavior remains a major challenge and has led to empirical strategies ranging from altering the particle surfaces and shape to modifying the solvent properties. However, none of these methods allows for tuning of flow properties during shear itself. Here, we demonstrate that by strategic imposition of a high-frequency and low-amplitude shear perturbation orthogonal to the primary shearing flow, we can largely eradicate shear thickening. The orthogonal shear effectively becomes a regulator for controlling thickening in the suspension, allowing the viscosity to be reduced by up to 2 decades on demand. In a separate setup, we show that such effects can be induced by simply agitating the sample transversely to the primary shear direction. Overall, the ability of in situ manipulation of shear thickening paves a route toward creating materials whose mechanical properties can be controlled.

Mesenchymal stromal cells (MSCs) are multipotent cells that have great potential for regenerative medicine, tissue repair, and immunotherapy. Unfortunately, the outcomes of MSC-based research and therapies can be highly inconsistent and difficult to reproduce, largely due to the inherently significant heterogeneity in MSCs, which has not been well investigated. To quantify cell heterogeneity, a standard approach is to measure marker expression on the protein level via immunochemistry assays. Performing such measurements non-invasively and at scale has remained challenging as conventional methods such as flow cytometry and immunofluorescence microscopy typically require cell fixation and laborious sample preparation. Here, we developed an artificial intelligence (AI)-based method that converts transmitted light microscopy images of MSCs into quantitative measurements of protein expression levels. By training a U-Net+ conditional generative adversarial network (cGAN) model that accurately (mean r s = 0.77) predicts expression of 8 MSC-specific markers, we showed that expression of surface markers provides a heterogeneity characterization that is complementary to conventional cell-level morphological analyses. Using this label-free imaging method, we also observed a multi-marker temporal-spatial fluctuation of protein distributions in live MSCs. These demonstrations suggest that our AI-based microscopy can be utilized to perform quantitative, non-invasive, single-cell, and multi-marker characterizations of heterogeneous live MSC culture. Our method provides a foundational step toward the instant integrative assessment of MSC properties, which is critical for high-throughput screening and quality control in cellular therapies.

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity. Giafaglione et al. define metabolic regulation of prostate epithelial lineage identity and show that modulation of lactate metabolism alters response to antiandrogen therapy.

Cell morphology heterogeneity is pervasive in epithelial collectives, yet the underlying mechanisms driving such heterogeneity and its consequential biological ramifications remain elusive. Here, we observed a consistent correlation between the epithelial cell morphology and nucleus morphology during crowding, revealing a persistent log-normal probability distribution characterizing both cell and nucleus areas across diverse epithelial model systems. We showed that this morphological diversity arises from asymmetric partitioning during cell division. Next, we provide insights into the impact of nucleus morphology on chromatin modifications. We demonstrated that constraining nucleus leads to downregulation of the euchromatic mark H3K9ac and upregulation of the heterochromatic mark H3K27me3. Furthermore, we showed that nucleus size regulates H3K27me3 levels through histone demethylase UTX. These findings highlight the significance of cell morphology heterogeneity as a driver of chromatin state diversity, shaping functional variability within epithelial tissues. Cell morphology heterogeneity in epithelial tissues, driven by asymmetric cell division, correlates with nucleus morphology and impacts chromatin state diversity through histone modifications.

Artificial intelligence enhances pathology screening efficiency, yet clinical adoption remains limited because most systems operate as opaque black boxes. We aim to resolve this opacity by establishing a framework that generates transparent, evidence-linked reasoning to support diagnostic auditing. We present a framework that shifts off-the-shelf multimodal large language models from passive pattern recognition to active diagnostic reasoning. Using small labeled subsets from breast and prostate cancer datasets, we employ a two-phase self-learning process to derive diagnostic criteria without updating model weights. We integrate expert feedback from board-certified pathologists to ensure the generated descriptions align with established medical standards. Here we show that our framework produces audit-ready rationales while achieving over 90% accuracy in distinguishing normal tissue from invasive carcinoma. Beyond binary classification, the model effectively differentiates complex subtypes like ductal carcinoma in situ by autonomously identifying hallmark histological features, including nuclear irregularities and structural disruption. These computer-generated descriptions closely match expert assessments. Our approach delivers substantial performance gains over conventional baselines and adapts effectively across diverse tissue types and independent foundation models. By uniting visual understanding with reasoning, our framework provides a promising approach for clinically trustworthy artificial intelligence. This framework helps bridge the gap between opaque classifiers and auditable systems, suggesting a viable path toward evidence-linked interpretation in medical workflows.

Nonlinear stresses surrounding defect cores in three-dimensional colloidal crystals are experimentally determined at the single-particle level. The mechanical, structural and functional properties of crystals are determined by their defects 1 , 2 , 3 , 4 , and the distribution of stresses surrounding these defects has broad implications for the understanding of transport phenomena. When the defect density rises to levels routinely found in real-world materials, transport is governed by local stresses that are predominantly nonlinear 1 , 5 , 6 , 7 , 8 . Such stress fields however, cannot be measured using conventional bulk and local measurement techniques. Here, we report direct and spatially resolved experimental measurements of the nonlinear stresses surrounding colloidal crystalline defect cores, and show that the stresses at vacancy cores generate attractive interactions between them. We also directly visualize the softening of crystalline regions surrounding dislocation cores, and find that stress fluctuations in quiescent polycrystals are uniformly distributed rather than localized at grain boundaries, as is the case in strained atomic polycrystals. Nonlinear stress measurements have important implications for strain hardening 9 , yield 1 , 5 and fatigue 10 .

The mechanical properties of crystalline materials can be substantially modified under confinement. Such modified macroscopic properties are usually governed by the altered microstructures and internal stress fields. Here, we use a parallel plate geometry to apply a quasi-static squeeze flow crushing a colloidal polycrystal while simultaneously imaging it with confocal microscopy. The confocal images are used to quantify the local structure order and, in conjunction with Stress Assessment from Local Structural Anisotropy (SALSA), determine the stress at the single-particle scale. We find that during compression, the crystalline regions break into small domains with different geometric packing. These domains are characterized by a pressure and deviatoric stress that are highly localized with correlation lengths that are half those found in bulk. Furthermore, the mean deviatoric stress almost doubles, suggesting a higher brittleness in the highly-confined samples.

Understanding the correlation between structure and rheology in colloidal suspensions is important as these suspensions are crucial in industrial applications. Moreover, colloids exhibit a wide range of structures under confinement that could considerably alter the viscosity. Here, we use a combination of experiments and simulations to elucidate how confinement induced structures alter the relative contributions of hydrodynamic and repulsive forces to produce up to a ten fold change in the viscosity. We use a custom built confocal rheoscope to image the particle configurations of a colloidal suspension while simultaneously measuring the viscosity. We find a non-monotonic trend to the viscosity under confinement that is strongly correlated with the microstructure. As the gap decreases below 15 particle diameters, the viscosity first decreases from its bulk value, shows fluctuations with the gap, and then sharply increases for gaps below three particle diameters. Further, we compare our experimental results to two simulations techniques that enables us to determine the relative contributions of hydrodynamic and short range repulsive stresses. The first method uses the lubrication approximation to find the hydrodynamic stress and includes a short range repulsive force between the particles and the second is a Stokesian dynamics simulation that calculates the full hydrodynamic stress in the suspension. We find that the decrease in the viscosity at moderate confinements has a significant contribution from both the hydrodynamic and repulsive forces whereas the increase in viscosity at gaps less than three particle diameters arises primarily from short range repulsive forces. These results provide new insights to the unique rheological behavior of confined suspensions and further enable us to tune the viscosity by changing properties such as the gap, polydispersity, and the volume fraction.