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As cancers progress, they become increasingly aggressive—metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3, 4–5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1licenses non-canonical reprogramming.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.

This work presents a new algorithm for detecting and classifying data anomalies in operational measurements using statistical, clustering, and outlier-based approaches. Base detectors explored in this work includes density-based spatial clustering of applications with noise, K-Means, local outlier factor, feature bagging, and robust random cut forests using real distribution system datasets. An ensemble approach is proposed to achieve high detection accuracy and precision compared with any of the base detector and with less dependency on hyperparameter tuning. Also, developed ensemble architecture can integrate additional base detectors. In addition, a simplistic anomaly classification approach is developed, utilizing the clustering concept, while considering the physics of the power distribution systems. The developed schemes are rigorously tested and validated using data from multiple distribution phasor measurement unit devices in the Bronzeville community microgrid, with a diverse set of events and distributed energy resources at dispersed locations. Performance analysis using three test cases are provided to showcase superiority of the proposed approaches.

While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Tregcell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Tregcell ‘connectivity’ to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Tregcell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Tregcell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Tregcell deprivation in either setting, as well as in Tregcell-poor versus Tregcell-rich human lung adenocarcinomas. Accordingly, punctual Tregcell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers.

This article presents a new control structure for bidirectional power electronic converters. Commonly, a proportional-integrating (PI) controller is used in the dc capacitor voltage loop, to generate the set point for the current controller, which tightly regulates this voltage to a given value. This article shows that such an approach causes stability issues that are aggravated during reverse power flow operation and intensify during weak grid conditions and uncertainties. The proposed controller allows small variations of dc capacitor voltage in proportion to the power flowing through the converter. This improves the stability of the converter irrespective of the power direction and in the presence of uncertainties and weak grid conditions. The proposed control structure also simplifies the design process, and it can be applied to dc/dc and dc/ac (single-phase and three-phase) converters. Moreover, the proposed method grants an inherent power-sharing capability when multiple converters share the same dc bus. The article also adopts full state feedback and an optimal control approach, i.e., the linear-quadratic tracker (LQT), for systematic design of the current control loop and enhanced robustness. Detailed analyses, simulations, comparisons, and experimental results are included to demonstrate the effectiveness of the proposed approach.

Upon antigenic stimulation, naïve CD4+ T cells can give rise to phenotypically distinct effector T helper cells and long-lived memory T cells. We computationally reconstructed the in vivo trajectory of CD4+ T cell differentiation during a type I inflammatory immune response and identified two distinct differentiation paths for effector and precursor central memory T cells arising directly from naïve CD4+ T cells. Unexpectedly, our studies revealed heterogeneity among naïve CD4+ T cells, which are typically considered homogeneous save for their diverse T cell receptor usage. Specifically, a previously unappreciated population of naïve CD4+ T cells sensing environmental type I IFN exhibited distinct activation thresholds, suggesting that naïve CD4+ T cell differentiation potential may be influenced by environmental cues. This population was expanded in human viral infection and type I IFN response-lined autoimmunity. Understanding the relevance of naïve T cell heterogeneity to beneficial and maladaptive T cell responses may have therapeutic implications for adoptive T cell therapies in cancer immunotherapy and vaccination.

The operational condition at the Dalsfoss power station is complicated due to many requirements related to environmental regulations and safety constraints such as the seasonally varying water level requirement at the reservoir. However, the operation becomes more difficult due to uncertainties in the system. In this paper, at first a certainty equivalent MPC is applied to the uncertain hydro power system and it has been shown that its robustness property is poor. Secondly, to prevent the constraint violations due to the uncertainties in the system, two measures are taken. One measure is to introduce a safety margin for the constraints and further design a certainty equivalent MPC. The other measure is to implement a multi-stage MPC for robust constraint satisfaction. Two types of multi-stage MPC are considered in this paper. The first employs all of the possible 50 scenarios of the uncertainty of an input disturbance variable, and the latter generates and uses three synthetic scenarios to approximate all of the possible 50 scenarios. All of the simulation results are compared for their robust performances and computational time.

This study aimed to characterize the tumor-infiltrating immune cells population in Kras/tumor protein 53 (Trp53)-driven lung tumors and to evaluate the combinatorial antitumor effect with MEK inhibitor (MEKi), trametinib, and immunomodulatory monoclonal antibodies (mAbs) targeting either programmed death -1 (PD-1) or programmed cell death ligand 1 (PD-L1) in vivo.

Here we delineate the ontogeny of the mammalian endoderm by generating 112,217 single-cell transcriptomes, which represent all endoderm populations within the mouse embryo until midgestation. We use graph-based approaches to model differentiating cells, which provides a spatio-temporal characterization of developmental trajectories and defines the transcriptional architecture that accompanies the emergence of the first (primitive or extra-embryonic) endodermal population and its sister pluripotent (embryonic) epiblast lineage. We uncover a relationship between descendants of these two lineages, in which epiblast cells differentiate into endoderm at two distinct time points—before and during gastrulation. Trajectories of endoderm cells were mapped as they acquired embryonic versus extra-embryonic fates and as they spatially converged within the nascent gut endoderm, which revealed these cells to be globally similar but retain aspects of their lineage history. We observed the regionalized identity of cells along the anterior–posterior axis of the emergent gut tube, which reflects their embryonic or extra-embryonic origin, and the coordinated patterning of these cells into organ-specific territories.

Persistent atrial fibrillation (AF) is not effectively treated due to a lack of adequate tools for identifying patient-specific AF substrates. Recent studies revealed that in 30–50% of patients, persistent AF is maintained by localized drivers not only in the left atrium (LA) but also in the right atrium (RA). The chamber-specific atrial wall thickness (AWT) features underlying AF remain elusive, though the important role of AWT in AF is widely acknowledged. We aimed to provide direct evidence of the existence of distinguished RA and LA AWT features underlying AF drivers by analysing functionally and structurally mapped human hearts ex vivo. Coronary-perfused intact human atria (n= 7, 47 ± 14 y.o.; two female) were mapped using panoramic near-infrared optical mapping during pacing-induced AF. Then the hearts were imaged at approximately 170 µm3resolution by 9.4 T gadolinium-enhanced MRI. The heart was segmented, and 3D AWT throughout atrial chambers was estimated and analysed. Optical mapping identified six localized RA re-entrant drivers in four hearts and four LA drivers in three hearts. All RA AF drivers were anchored to the pectinate muscle junctions with the crista terminalis or atrial walls. The four LA AF drivers were in the posterior LA. RA (n= 4) with AF drivers were thicker with greater AWT variation than RA (n= 3) without drivers (5.4 ± 2.6 mm versus 5.0 ± 2.4 mm, T-test p< 0.05; F-test p< 0.05). Furthermore, AWT in RA driver regions was thicker and varied more than in RA non-driver regions (5.1 ± 2.5 mm versus 4.4 ± 2.2 mm, T-test p< 0.05; F-test p< 0.05). On the other hand, LA (n= 3) with drivers was thinner than the LA (n= 4) without drivers. In particular, LA driver regions were thinner than the rest of LA regions (3.4 ± 1.0 mm versus 4.2 ± 1.0 mm, T-test p< 0.05). This study demonstrates chamber-specific AWT features of AF drivers. In RA, driver regions are thicker and have more variable AWT than non-driver regions. By contrast, LA drivers are thinner than non-drivers. Robust evaluation of patient-specific AWT features should be considered for chamber-specific targeted ablation.

This study aimed to use multi-scale atrial models to investigate pulmonary arterial hypertension (PAH)-induced atrial fibrillation mechanisms. The results of our computer simulations revealed that, at the single-cell level, PAH-induced remodelling led to a prolonged action potential (AP) (ΔAPD: 49.6 ms in the right atria (RA) versus 41.6 ms in the left atria (LA)) and an increased calcium transient (CaT) (ΔCaT: 7.5 × 10−2µM in the RA versus 0.9 × 10−3µM in the LA). Moreover, heterogeneous remodelling increased susceptibility to afterdepolarizations, particularly in the RA. At the tissue level, we observed a significant reduction in conduction velocity (CV) (ΔCV: −0.5 m s–1in the RA versus −0.05 m s–1in the LA), leading to a shortened wavelength in the RA, but not in the LA. Additionally, afterdepolarizations in the RA contributed to enhanced repolarization dispersion and facilitated unidirectional conduction block. Furthermore, the increased fibrosis in the RA amplified the likelihood of excitation wave breakdown and the occurrence of sustained re-entries. Our results indicated that the RA is characterized by increased susceptibility to afterdepolarizations, slow conduction, reduced wavelength and upregulated fibrosis. These findings shed light on the underlying factors that may promote atrial fibrillation in patients with PAH.

Fibrosis has been mechanistically linked to arrhythmogenesis in multiple cardiovascular conditions, including atrial fibrillation (AF). Previous studies have demonstrated that fibrosis can create functional barriers to conduction which may promote excitation wavebreak and the generation of re-entry, while also acting to pin re-entrant excitation in stable rotors during AF. However, few studies have investigated the role of fibrosis in the generation of AF triggers in detail. We apply our in-house computational framework to study the impact of fibrosis on the generation of AF triggers and trigger–substrate interactions in two- and three-dimensional atrial tissue models. Our models include a reduced and efficient description of stochastic, spontaneous cellular triggers as well as a simple model of heterogeneous inter-cellular coupling. Our results demonstrate that fibrosis promotes the emergence of focal excitations, primarily through reducing the electrotonic load on individual fibre strands. This enables excitation to robustly initiate within these single strands before spreading to neighbouring strands and inducing a full tissue focal excitation. Enhanced conduction block can allow trigger–substrate interactions that result in the emergence of complex, re-entrant excitation patterns. This study provides new insight into the mechanisms by which fibrosis promotes the triggers and substrate necessary to induce and sustain arrhythmia.

Regulatory T (Treg) cells prevent autoimmunity by limiting immune responses and inflammation in the secondary lymphoid organs and nonlymphoid tissues. While unique subsets of Treg cells have been described in some nonlymphoid tissues, their relationship to Treg cells in secondary lymphoid organs and circulation remains unclear. Furthermore, it is possible that Treg cells from similar tissue types share largely similar properties. We have identified a short-lived effector Treg cell subset that expresses the α2 integrin, CD49b, and exhibits a unique tissue distribution, being abundant in peripheral blood, vasculature, skin, and skin-draining lymph nodes, but uncommon in the intestines and in viscera-draining lymph nodes. CD49b+ Treg cells, which display superior functionality revealed by in vitro and in vivo assays, appear to develop after multiple rounds of cell division and TCR-dependent activation. Accordingly, single-cell RNA-seq analysis placed these cells at the apex of the Treg developmental trajectory. These results shed light on the identity and development of a functionally potent subset of mature effector Treg cells that recirculate through and survey peripheral tissues.

Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for investigating cellular diversity and gene expression profiles at the individual cell level. However, to ensure accurate analysis of scRNA-seq data, it is crucial to generate high-quality single-cell suspensions by effectively removing dead cells, debris, and ambient RNA. This study aims to assess and compare the performance of five commercially available methods for dead cell removal: Fluorescence activated cell sorting (FACS), Akadeum Microbubble kit, StemCell EasySep kit, Miltenyi Biotec Dead Cell Removal Kit, and LevitasBio Levicell Live Cell Enrichment.

Crypt apoptosis and regeneration are characteristic findings in GI-GVHD. Intestinal stem cells (ISCs) are critical for maintaining the intestinal epithelium, but their frequencies are reduced in experimental GVHD, and the mechanisms driving crypt regeneration in this context are poorly understood.

Hanash: Evive Biotech: Ended employment in the past 24 months.

Changing the type of T cell used to generate CAR-T cells avoids the deleterious effects of antigen-independent signaling.