Simple aneuploidy evades p53 surveillance and promotes niche factor-independent growth in human intestinal organoids.

Aneuploidy is nearly ubiquitous in tumor genomes, but the role of aneuploidy in the early stages of cancer evolution remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigated how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Previous work implicated p53 activation as a downstream response to aneuploidy induction. We found that simple aneuploidy, characterized by 1-3 gained or lost chromosomes, resulted in little or modest p53 activation and cell cycle arrest when compared with more complex aneuploid cells. Single-cell RNA sequencing analysis revealed that the degree of p53 activation was strongly correlated with karyotype complexity. Single-cell tracking showed that cells could continue to divide despite the observation of one to a few lagging chromosomes. Unexpectedly, colonoids with simple aneuploidy exhibited impaired differentiation after niche factor withdrawal. These findings demonstrate that simple aneuploid cells can escape p53 surveillance and may contribute to niche factor-independent growth of cancer-initiating colon stem cells.

Exploring Multiple Perspectives on Psychological Health of Adolescents in Relation to Gender and School Grade - Jiangsu Province, China, 2022.

What is already known about this topic?: Mental health issues in Chinese children and adolescents have emerged as a substantial public health concern, causing distress and strain among families and society. What is added by this report?: This study examines the effects of gender and school grade on mental health symptoms and risky behaviors among Chinese children and adolescents, with a particular focus on the role of family and school environments. What are the implications for public health practice?: Caregivers and educators should enhance their awareness and skills in supporting the mental health of children. These findings offer critical insights for the early detection and intervention of mental health issues in Chinese children and adolescents.

Bedtime music therapy for college students with insomnia: A randomized assessor-blinded controlled trial.

BACKGROUND: Insomnia, a prevalent sleep disorder in contemporary society, frequently coexists with other mental health conditions such as depression, schizophrenia, and obsessive-compulsive disorder. Sleep disorders can compromise daytime functioning and overall quality of life. While music has been explored as an adjunct therapy for insomnia, its efficacy in improving insomnia among students remains unclear. METHODS: Seventy-five students, aged between 18 and 30 years with an average age of 20.97 years (SD: 1.92), presenting sleep issues were randomly allocated to one of three groups: the classical music group, the jazz music group, and the control group, each with 25 participants. Participants in the classical and jazz music group were instructed to listen to classical or jazz music for a minimum of 30 min preceding bedtime. This was paired with deep breathing and relaxation techniques, practiced two consecutive nights per week from 23:00 to 01:00 over a five-week intervention period. Conversely, participants in the control group were only directed to follow the deep breathing and relaxation techniques before sleep on two consecutive nights weekly. Insomnia severity with the Insomnia Severity Index (ISI), sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), depressive symptoms with the Beck Depression Inventory-II (BDI- II), and anxiety symptoms with the Self-rating Anxiety Scale (SAS). Measurements were taken at baseline, after the second week of intervention, at the intervention's conclusion (five weeks), and two months post-intervention (follow-up). RESULTS: 1. The music groups showed a significant difference in insomnia severity compared with the control group after five weeks of intervention(p < .05). 2. music groups exhibited significant enhancements in sleep quality relative to the control group after a five-week intervention (p < .05). 3. Regarding mood enhancement, music groups showed significant improvements in depression and anxiety symptoms compared to the baseline after the five-week intervention. Notably, the control group also displayed improvements in these symptoms post-intervention. CONCLUSION: 1. Integrating music into a consistent bedtime routine ameliorates sleep quality and insomnia severity. However, no specific genre of music emerged as the superior choice for pre-sleep listening. 2. While music can considerably enhance mood indicators like depression and anxiety, techniques such as deep breathing and mindfulness also contribute positively. 3. Incorporating music before sleep tangibly elevates overall quality of life and daytime functioning. TRIAL REGISTRATION: ChiCTR2300073953.

Water-filtered infrared A radiation hyperthermia combined with immunotherapy for advanced gastrointestinal tumours.

This study pioneered the use of WIRA whole-body infrared hyperthermia combined with ICI therapy to treat GIT and verified the feasibility and safety of HIT. The final results showed a DCR of 55.6%, with a median PFS of 53.5 days, median OS of 134 days, and an irAE incidence of 22.2%. Therefore, we believe that HIT can exert multiple synergistic sensitisation effects, thereby providing clinical benefits to patients with advanced GITs, increasing overall safety, and improving patients' QOL.

INTRODUCTION: This study aimed to validate the effectiveness, safety and feasibility of water­filtered infrared A radiation (WIRA) whole­body hyperthermia combined with immune checkpoint inhibitor (ICI) therapy (HIT) and evaluate the real­world clinical application prospects. METHODS: This open­label single­arm phase 2 clinical trial (NCT06022692) aimed to enrol advanced gastrointestinal tumour (GIT) patients with the MSS/pMMR phenotype. The patients were treated with whole­body hyperthermia on Days 1 and 8 of each HIT cycle along with administration of tislelizumab on Day 2. RESULTS: Between 1 June 2020 and 31 May 2022, 18 patients were enrolled in the study, including those with gastric cancer (n = 6), colon cancer (n = 7), rectal cancer (n = 3) and appendiceal cancer (n = 2). As of 19 May 2023, 17 of the 18 patients had died, including 14 deaths caused by tumour progression and three deaths caused by diseases other than cancer, while one patient was still undergoing follow­up. In terms of efficacy, the median DCR was 55.6%, while the median PFS and OS were 53.5 days and 134 days, respectively. Four patients (22.2%) experienced immune­related adverse events, and none of the patients reported grade 3 or higher irAEs. Hyperthermia was followed by an increase in the number of tumour immune­activated cells. CONCLUSIONS: HIT can provide survival benefits in patients with GITs by activating antitumour immune function and shows good safety and feasibility.

Cell-Driven Fluid Dynamics: A Physical Model of Active Systemic Circulation.

Active fluid circulation and transport are key functions of living organisms, which drive efficient delivery of oxygen and nutrients to various physiological compartments. Because fluid circulation occurs in a network, the systemic flux and pressure are not simple outcomes of any given component. Rather, they are emergent properties of network elements and network topology. Moreover, consistent pressure and osmolarity gradients across compartments such as the kidney, interstitium, and vessels are known. How these gradients and network properties are established and maintained is an unanswered question in systems physiology. Previous studies have shown that epithelial cells are fluid pumps that actively generate pressure and osmolarity gradients. Polarization and activity of ion exchangers that drive fluid flux in epithelial cells are affected by pressure and osmolarity gradients. Therefore, there is an unexplored coupling between the pressure and osmolarity in the circulating network. Here we develop a mathematical theory that integrates the influence of pressure and osmolarity on solute transport and explores both cell fluid transport and systemic circulation. This model naturally generates pressure and osmolarity gradients across physiological compartments, and demonstrates how systemic transport properties can depend on cell properties, and how the cell state can depend on systemic properties. When epithelial and endothelial pumps are considered together, we predict how pressures at various points in the network depend on the overall osmolarity of the system. The model can be improved by including physiological geometries and expanding solute species, and highlights the interplay of fluid properties with cell function in living organisms.

Pentacyclic triterpenoids as potential ACL inhibitors from the rare medicinal plant Semiliquidambar cathayensis.

An extensive phytochemical investigation on the rare medicinal plant Semiliquidambar cathayensis (family: Hamamelidaceae) led to the isolation of four new (1-4, named semiliquidacids A-D, respectively) and 25 related known pentacyclic triterpenoids. The new structures with absolute configurations were elucidated by spectroscopic methods, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. Compound 1 represents the first naturally occurring ursane-type triterpenoid featuring an uncommon C-25 formyl group. Compound 4 and oleanolic acid (13) exhibited remarkable inhibitory effects against the ATP-citrate lyase (ACL, an emerging drug target for hyperlipidemia and related metabolic disorders) with IC50 values of 6.5 and 11.9 µM, respectively. The molecular interaction and binding mode between the bioactive triterpenoids and ACL were elaborated by conducting a molecular docking study. Meanwhile, the chemotaxonomic significance of the isolated triterpenoids has been briefly discussed.

Using deep learning-based artificial intelligence electronic images in improving middle school teachers' literacy.

With the rapid development of societal information, electronic educational resources have become an indispensable component of modern education. In response to the increasingly formidable challenges faced by secondary school teachers, this study endeavors to analyze and explore the application of artificial intelligence (AI) methods to enhance their cognitive literacy. Initially, this discourse delves into the application of AI-generated electronic images in the training and instruction of middle school educators, subjecting it to thorough analysis. Emphasis is placed on elucidating the pivotal role played by AI electronic images in elevating the proficiency of middle school teachers. Subsequently, an integrated intelligent device serves as the foundation for establishing a model that applies intelligent classification and algorithms based on the Structure of the Observed Learning Outcome (SOLO). This model is designed to assess the cognitive literacy and teaching efficacy of middle school educators, and its performance is juxtaposed with classification algorithms such as support vector machine (SVM) and decision trees. The findings reveal that, following 600 iterations of the model, the SVM algorithm achieves a 77% accuracy rate in recognizing teacher literacy, whereas the SOLO algorithm attains 80%. Concurrently, the spatial complexities of the SVM-based and SOLO-based intelligent literacy improvement models are determined to be 45 and 22, respectively. Notably, it is discerned that, with escalating iterations, the SOLO algorithm exhibits higher accuracy and reduced spatial complexity in evaluating teachers' pedagogical literacy. Consequently, the utilization of AI methodologies proves highly efficacious in advancing electronic imaging technology and enhancing the efficacy of image recognition in educational instruction.

Microwave hyperthermia enhances radiosensitization by decreasing DNA repair efficiency and inducing oxidative stress in PC3 prostatic adenocarcinoma cells.

PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.

BAP31 Promotes Angiogenesis via Galectin-3 Upregulation in Neuroblastoma.

Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis remains unexplored. This study investigated BAP31 modulation of pro-angiogenic factors in SH-SY5Y NB cells. Through protein overexpression, knockdown, antibody blocking, and quantification experiments, we demonstrated that overexpression of BAP31 led to increased levels of vascular endothelial growth factor A (VEGFA) and Galectin-3 (GAL-3), which are known to promote angiogenesis. Conditioned medium derived from BAP31-overexpressing neuroblastoma cells stimulated migration and tube formation in endothelial cells, indicating its pro-angiogenic properties. Also, we demonstrated that BAP31 enhances capillary tube formation by regulating hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream target, GAL-3. Furthermore, GAL-3 downstream proteins, Jagged 1 and VEGF receptor 2 (VEGFR2), were up-regulated, and blocking GAL-3 partially inhibited the BAP31-induced tube formation. These findings suggest that BAP31 promotes angiogenesis in NB by modulating GAL-3 and VEGF signaling, thereby shaping the tumor microenvironment. This study provides novel insights into the pro-angiogenic role of BAP31 in NB.

SiRNA-HIF-1α delivered by attenuated Salmonella enhances the efficacy of Lenvatinib against hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.

The use of deep learning integrating image recognition in language analysis technology in secondary school education.

This work aims to investigate the application of advanced deep learning algorithms and image recognition technologies to enhance language analysis tools in secondary education, with the goal of providing educators with more effective resources and support. Based on artificial intelligence, this work integrates data mining techniques related to deep learning to analyze and study language behavior in secondary school education. Initially, a framework for analyzing language behavior in secondary school education is constructed. This involves evaluating the current state of language behavior, establishing a framework based on evaluation comments, and defining indicators for analyzing language behavior in online secondary school education. Subsequently, data mining technology and image and character recognition technology are employed to conduct data mining for online courses in secondary schools, encompassing the processing of teaching video images and character recognition. Finally, an experiment is designed to validate the proposed framework for analyzing language behavior in secondary school education. The results indicate specific differences among the grouped evaluation scores for each analysis indicator. The significance p values for the online classroom discourse's speaking rate, speech intelligibility, average sentence length, and content similarity are -0.56, -0.71, -0.71, and -0.74, respectively. The aim is to identify the most effective teaching behaviors for learners and enhance the support for online course instruction.

A Novel Signature Based on m6A Regulator-Mediated Genes Along Glycolytic Pathway Predicts Prognosis and Immunotherapy Responses of Gastric Cancer Patients.

N6-methyladenosine (m6A) modification is involved in many aspects of gastric cancer (GC). Moreover, m6A and glycolysis-related genes (GRGs) play important roles in immunotherapeutic and prognostic implication of GC. However, GRGs involved in m6A regulation have never been analyzed comprehensively in GC. Herein, the study aims to identify and validate a novel signature based on m6A-related GRGs in GC patients. Therefore, a m6A-related GRGs signature is established, which can predict the survival of patients with GC and remain an independent prognostic factor in multivariate analyses. Clinical significance of the model is well validated in internal cohort and independent validation cohort. In addition, the expression levels of risk model-related GRGs in clinical samples are validated. Consistent with the database results, all model genes are up-regulated in expression except DCN. After regrouping the patients based on this risk model, the study can effectively distinguish between them in respect to immune-cell infiltration microenvironment and immunotherapeutic response. Additionally, candidate drugs targeting risk model-related GRGs are confirmed. Finally, a nomogram combining risk scores and clinical parameters is created, and calibration plots show that the nomogram can accurately predict survival. This risk model can serve as a reliable assessment tool for predicting prognosis and immunotherapeutic responses in GC patients.

Deep segmentation of OCTA for evaluation and association of changes of retinal microvasculature with Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Optical coherence tomography angiography (OCTA) enables fast and non-invasive high-resolution imaging of retinal microvasculature and is suggested as a potential tool in the early detection of retinal microvascular changes in Alzheimer's Disease (AD). We developed a standardised OCTA analysis framework and compared their extracted parameters among controls and AD/mild cognitive impairment (MCI) in a cross-section study. METHODS: We defined and extracted geometrical parameters of retinal microvasculature at different retinal layers and in the foveal avascular zone (FAZ) from segmented OCTA images obtained using well-validated state-of-the-art deep learning models. We studied these parameters in 158 subjects (62 healthy control, 55 AD and 41 MCI) using logistic regression to determine their potential in predicting the status of our subjects. RESULTS: In the AD group, there was a significant decrease in vessel area and length densities in the inner vascular complexes (IVC) compared with controls. The number of vascular bifurcations in AD is also significantly lower than that of healthy people. The MCI group demonstrated a decrease in vascular area, length densities, vascular fractal dimension and the number of bifurcations in both the superficial vascular complexes (SVC) and the IVC compared with controls. A larger vascular tortuosity in the IVC, and a larger roundness of FAZ in the SVC, can also be observed in MCI compared with controls. CONCLUSION: Our study demonstrates the applicability of OCTA for the diagnosis of AD and MCI, and provides a standard tool for future clinical service and research. Biomarkers from retinal OCTA images can provide useful information for clinical decision-making and diagnosis of AD and MCI.

Liriogerphines E-U, further unique sesquiterpene-alkaloid hybrids from the rare Chinese tulip tree.

Seventeen undescribed sesquiterpene-alkaloid hybrids (liriogerphines E-U, 1-17) were isolated and identified during a further phytochemical investigation on the branches and leaves of Chinese tulip tree (Liriodendron chinense), a rare medicinal and ornamental plant endemic to China. These unique heterodimers are conjugates of germacranolide-type sesquiterpenoids with structurally diverse alkaloids [i.e., aporphine- (1-15), proaporphine- (16), and benzyltetrahydroisoquinoline-type (17)] via the formation of a C-N bond. The previously undescribed structures were elucidated by comprehensive spectroscopic data analyses and electronic circular dichroism calculations. Such a class of sesquiterpene-alkaloid hybrids presumably biosynthesized via an aza-Michael addition is quite rare from terrestrial plants. In particular, the sesquiterpene-benzyltetrahydroisoquinoline hybrid skeleton has never been reported until the present study. All the isolates were evaluated for their cytotoxic effects against a small panel of leukemia cell lines (Raji, Jeko-1, Daudi, Jurkat, MV-4-11 and HL-60), and some of them exhibited considerable activities.

Large Microsphere Structure of a Co/C Composite Derived from Co-MOF with Excellent Wideband Electromagnetic Microwave Absorption Performance.

In the field of electromagnetic wave (EMW) absorption, carbon matrix materials based on metal-organic frameworks (MOFs) have drawn more interest as a result of their outstanding advantages, such as porous structure, lightweight, controlled morphology, etc. However, how to broaden the effective absorption bandwidth [EAB; reflection loss (RL) ≤ -10 dB] is still a challenge. In this paper, large microsphere structures of a Co/C composite composed of small particle clusters were successfully prepared by the solvothermal method and annealing treatment. At a filling ratio of 40 wt %, the Co/C composite shows attractive microwave absorption (MA) performance after being annealed at 600 °C in an atmosphere of argon. With an EAB of 6.32 GHz (9.92-16.24 GHz) and a thickness of just 2.57 mm, the minimum RL can be attained at -54.55 dB. Most importantly, the EAB can attain 7.12 GHz (10.88-18.0 GHz) when the thickness is 2.38 mm, which is larger than that of the majority of MOF-derived composites. The superior MA performance is strongly related to excellent impedance matching and a higher attenuation constant. This study provides a simple strategy for synthesizing a MOF-derived Co/C composite with a wide EAB.

BAP31-Mediated miR-206/133b Cluster Promotes Transendothelial Migration and Metastasis of Colorectal Cancer.

Dysregulated B cell receptor-associated protein 31 (BAP31) plays a crucial role in tumor progression. This study aimed to investigate the functions and molecular mechanism of BAP31 on the miR-206/133b cluster in colorectal cancer (CRC). qPCR was conducted to detect miRNA and mRNA levels in tissues and cells. Western blot assays were used to assess the levels of biomarkers and targets, as well as the levels of BAP31 and HOXD10. Wound healing, coculture and transwell assays were conducted to assess the transendothelial migration abilities of CRC cells. A luciferase assay was employed to assess miRNA binding effects on targets, as well as the initiating transcription effect of genomic fragments. Tumor growth and lung metastatic models were established through an in vivo animal study. BAP31 overexpression in CRC cells led to a reduction in the expression of the miR-206/133b cluster. The expression of the miR-206/133b cluster was correlated with the transendothelial migration capability of CRC cells. The miR-206/133b cluster was found to directly regulate cell division cycle 42 (CDC42) and actin-related protein 2/3 complex subunit 5 (ARPC5) in the tight junction pathway (hsa04530). Moreover, a potential transcription regulator of the miR-206/133b cluster was also found to be Homeobox D10 (HOXD10). We further elucidated the molecular mechanisms and functional mechanisms of BAP31's regulatory role in the expression levels of the miR-206/133b cluster by inhibiting HOXD10 translocation from the cytoplasm to the nucleus. In conclusion, this study provides valuable insights into how BAP31 regulates the transcription of the miR-206/133b cluster and how BAP31-related lung metastases arise in CRC.

The Relationship between Wellbeing, Self-Determination, and Resettlement Stress for Asylum-Seeking Mothers Attending an Ecosocial Community-Based Intervention: A Mixed-Methods Study.

Psychosocial support programs have been increasingly implemented to protect asylum seekers' wellbeing, though how and why these interventions work is not yet fully understood. This study first uses questionnaires to examine how self-efficacy, satisfaction of basic psychological needs, and adaptive stress may influence wellbeing for a group of asylum-seeking mothers attending a community-based psychosocial program called Welcome Haven. Second, we explore mothers' experiences attending the Welcome Haven program through qualitative interviews. Analysis reveals the importance of relatedness as a predictor of wellbeing as well as the mediating role of adaptive stress between need satisfaction and wellbeing. Further, attending Welcome Haven is associated with reduced adaptive stress and increased wellbeing, which correspond with the thematic analysis showing that attendance at the workshops fostered a sense of belonging through connection with other asylum seekers and service providers as well as empowerment through access to information and self-expression. The results point to the importance of community-based support that addresses adaptive stress and the promotion of social connection as key determinants of wellbeing. Nonetheless, the centrality of pervasive structural stressors asylum seekers experience during resettlement also cautions that relief offered by interventions may be insufficient in the face of ongoing systemic inequality and marginalization.

Rhodium(III)-catalyzed three-component C(sp2)-H activation for the synthesis of amines.

Rhodium-catalyzed three-component C-H bond activation of aromatics with amides and aldehydes to synthesize amines was established. The addition of copper was found to be essential to ensure the high reactivity. The mechanistic studies indicated that key intermediates formed by the transmetallization between rhodium and copper could further promote the addition between 2-(pyridin-2-yl)-phenyl-metal species and imines. A series of densely substituted amines could be conveniently prepared by this one-step, three-component procedure from commercially available substrates via C-H bond activation with water as the only by-product.

Mechano-induced homotypic patterned domain formation by monocytes.

Matrix stiffness and corresponding mechano-signaling play indispensable roles in cellular phenotypes and functions. How tissue stiffness influences the behavior of monocytes, a major circulating leukocyte of the innate system, and how it may promote the emergence of collective cell behavior is less understood. Here, using tunable collagen-coated hydrogels of physiological stiffness, we show that human primary monocytes undergo a dynamic local phase separation to form highly regular, reversible, multicellular, multi-layered domains on soft matrix. Local activation of the ß2 integrin initiates inter-cellular adhesion, while global soluble inhibitory factors maintain the steady state domain pattern over days. Patterned domain formation generated by monocytes is unique among other key immune cells, including macrophages, B cells, T cells, and NK cells. While inhibiting their phagocytic capability, domain formation promotes monocytes' survival. We develop a computational model based on the Cahn-Hilliard equation of phase separation, combined with a Turing mechanism of local activation and global inhibition suggested by our experiments, and provides experimentally validated predictions of the role of seeding density and both chemotactic and random cell migration on domain pattern formation. This work reveals that, unlike active matters, cells can generate complex cell phases by exploiting their mechanosensing abilities and combined short-range interactions and long-range signals to enhance their survival.

Differential effects of aneuploidy on growth and differentiation in human intestinal stem cells.

Aneuploidy, a near ubiquitous genetic feature of tumors, is a context-dependent driver of cancer evolution; however, the mechanistic basis of this role remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigate how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Single-cell RNA sequencing reveals that the gene expression signature across over 100 unique aneuploid karyotypes is enriched with p53 responsive genes. The primary driver of p53 activation is karyotype complexity. Complex aneuploid cells with multiple unbalanced chromosomes activate p53 and undergo G1 cell-cycle arrest, independent of DNA damage and without evidence of senescence. By contrast, simple aneuploid cells with 1-3 chromosomes gained or lost continue to proliferate, demonstrated by single cell tracking in colonoids. Notably, simple aneuploid cells exhibit impaired differentiation when niche factors are withdrawn. These findings suggest that while complex aneuploid cells are eliminated from the normal epithelium due to p53 activation, simple aneuploid cells can escape this checkpoint and may contribute to niche factor-independent growth of cancer-initiating cells.