Cancer-associated fibroblast-derived Dickkopf-1 suppresses NK cell cytotoxicity in breast cancer.

Breast cancer is poorly immunogenic, hence able to evade T cell recognition and respond poorly to immune checkpoint blockade. Breast cancer cells can also evade NK cell-mediated immune surveillance, but the mechanism remains enigmatic. Dickkopf-1 (DKK1) is a Wnt/b-catenin inhibitor, whose levels are increased in breast cancer patients and correlate with reduced overall survival. DKK1 is expressed by cancer-associated fibroblasts (CAFs) in orthotopic breast tumors and patient samples, and at higher levels by bone cells. While bone-derived DKK1 contributes to the systemic elevation of DKK1 in tumor-bearing mice, CAFs represent the primary source of DKK1 at the tumor site. Systemic or bone-specific DKK1 targeting reduces primary tumor growth. Intriguingly, specific deletion of CAF-derived DKK1 also limits breast cancer progression, regardless of its elevated levels in circulation and in the bone. DKK1 does not support tumor proliferation directly but rather suppresses the activation and tumoricidal activity of NK cells. Importantly, increased DKK1 levels and reduced number of cytotoxic NK cells are detected in breast cancer patients with progressive bone metastases compared to those with stable disease. Our findings indicate that DKK1 creates a tumor-supporting environment through the suppression of NK cells in breast cancer.

Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. SIGNIFICANCE: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo- or immunotherapy. See related article by Ye et al.

Gpr37 modulates the severity of inflammation-induced GI dysmotility by regulating enteric reactive gliosis.

The enteric nervous system (ENS) is contained within two layers of the gut wall and is made up of neurons, immune cells, and enteric glia cells (EGCs) that regulate gastrointestinal (GI) function. EGCs in both inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) change in response to inflammation, referred to as reactive gliosis. Whether EGCs restricted to a specific layer or region within the GI tract alone can influence intestinal immune response is unknown. Using bulk RNA-sequencing and in situ hybridization, we identify G-protein coupled receptor Gpr37 , as a gene expressed only in EGCs of the myenteric plexus, one of the two layers of the ENS. We show that Gpr37 contributes to key components of LPS-induced reactive gliosis including activation of NF-kB and IFN-y signaling and response genes, lymphocyte recruitment, and inflammation-induced GI dysmotility. Targeting Gpr37 in EGCs presents a potential avenue for modifying inflammatory processes in the ENS.

Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer.

PDAC therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we employed a LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction.

Senescent CAFs mediate immunosuppression and drive breast cancer progression.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast cancer associated fibroblasts (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in Her2+, ER+, and triple negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development.

Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. SIGNIFICANCE: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression.

MAD-Former: A Traceable Interpretability Model for Alzheimer's Disease Recognition Based on Multi-Patch Attention.

The integration of structural magnetic resonance imaging (sMRI) and deep learning techniques is one of the important research directions for the automatic diagnosis of Alzheimer's disease (AD). Despite the satisfactory performance achieved by existing voxel-based models based on convolutional neural networks (CNNs), such models only handle AD-related brain atrophy at a single spatial scale and lack spatial localization of abnormal brain regions based on model interpretability. To address the above limitations, we propose a traceable interpretability model for AD recognition based on multi-patch attention (MAD-Former). MAD-Former consists of two parts: recognition and interpretability. In the recognition part, we design a 3D brain feature extraction network to extract local features, followed by constructing a dual-branch attention structure with different patch sizes to achieve global feature extraction, forming a multi-scale spatial feature extraction framework. Meanwhile, we propose an important attention similarity position loss function to assist in model decision-making. The interpretability part proposes a traceable method that can obtain a 3D ROI space through attention-based selection and receptive field tracing. This space encompasses key brain tissues that influence model decisions. Experimental results reveal the significant role of brain tissues such as the Fusiform Gyrus (FuG) in AD recognition. MAD-Former achieves outstanding performance in different tasks on ADNI and OASIS datasets, demonstrating reliable model interpretability.

Ultrasound image-guided cancer gene therapy using iRGD dual-targeted magnetic cationic microbubbles.

The gene therapy attracted more and more attention for the tumor therapy. To obtain a safe gene therapy system, the new gene vectors beyond the virus were developed for a high gene therapy efficiency. The ultrasound mediated gene therapy was safer and the plasmid DNA could be delivered by the microbubbles and combined with the ultrasound to increase the gene transfection efficiency. In this work, the cationic microbubbles decorated with Cyclo(Cys-Arg-Gly-Asp-Lys-Gly-Pro-AspCys) (iRGD peptides) and magnetic Fe3O4 nanoparticles (MBiM) was designed for targeted ultrasound contrast imaging guided gene therapy of tumors. The ultrasound image intensity was dramatically enhanced at the tumor site that received MBiM with the magnet applied, compared to those administrated the non-targeted microbubbles (MBb) or the microbubbles with only one target material on the surface (MBM and MBbi). The pGPU6/GFP/Neo-shAKT2 was used as a sample gene, which down regulate the AKT2 protein expression for the cancer therapy. It illustrated that MBiM/AKT2 had the highest gene transfection efficiency in the studied microbubbles mediated by the ultrasound, leading to the AKT2 protein expression downregulation and the strongest tumor killing effect in vitro and in vivo. In summary, a novel and biocompatible gene delivery platform via MBiM with both the endogenous and external targeting effects for breast cancer theranostics was developed.

The Antidepressant Effect of Magnolol on Depression-Like Behavior of CORT-Treated Mice.

Although the antidepressant-like effect of magnolol has been revealed in previous reports, the mechanism remains unclear. In this study, the antidepressant-like effect of magnolol on corticosterone-induced (CORT-induced) mice was investigated in vivo. After 21 days of CORT induction, the mice showed marked depressive-like behaviors, with a decrease in sucrose preference score and an increase in immobility time in the tail suspension test (TST) and forced swimming test (FST). Pretreatment with either magnolol (50 mg/kg, i.p.) or the kappa opioid receptor (KOR) antagonist nor-BNI (10 mg/kg, i.p.) prevented CORT-induced depression-like behavior and reduced CORT-induced dynorphin (DYN A) elevation in the hippocampal ventral DG. However, no depression-like behavior was observed in mice with KOR downregulation in the ventral DG. We further found that upregulation of DYN A in the DG caused depression-like behavior, which was blocked by intraperitoneal injection of nor-BNI and modulated by magnolol. The present study demonstrated that magnolol could ameliorate CORT-induced depression-like behaviors, by modulating the DYN A/KOR system in the ventral DG of the hippocampus.

Feedback-related brain activity in individual decision: evidence from a gambling EEG study.

In this study, based on scalp electroencephalogram (EEG), we conducted cortical source localization and functional network analyses to investigate the underlying mechanism explaining the decision processes when individuals anticipate maximizing gambling benefits, particularly in situations where the decision outcomes are inconsistent with the profit goals. The findings shed light on the feedback monitoring process, wherein incongruity between outcomes and gambling goals triggers a more pronounced medial frontal negativity and activates the frontal lobe. Moreover, long-range theta connectivity is implicated in processing surprise and uncertainty caused by inconsistent feedback conditions, while middle-range delta coupling reflects a more intricate evaluation of feedback outcomes, which subsequently modifies individual decision-making for optimizing future rewards. Collectively, these findings deepen our comprehension of decision-making under circumstances where the profit goals are compromised by decision outcomes and provide electrophysiological evidence supporting adaptive adjustments in individual decision strategies to achieve maximum benefit.

A neural circuit associated with anxiety-like behaviors induced by chronic inflammatory pain and the anxiolytic effects of electroacupuncture.

AIMS: Negative emotions induced by chronic pain are a serious clinical problem. Electroacupuncture (EA) is a clinically proven safe and effective method to manage pain-related negative emotions. However, the circuit mechanisms underlying the effect of EA treatment on negative emotions remain unclear. METHODS: Plantar injection of complete Freund's adjuvant (CFA) was performed to establish a rat model of chronic inflammatory pain-induced anxiety-like behaviors. Adeno-associated virus (AAV) tracing was used to identify excitatory synaptic transmission from the rostral anterior cingulate cortex (rACC) to the dorsal raphe nucleus (DRN). Employing chemogenetic approaches, we examined the role of the rACC-DRN circuit in chronic pain-induced anxiety-like behaviors and investigated whether EA could reverse chronic pain-induced dysfunctions of the rACC-DRN circuit and anxiety-like behaviors. RESULTS: We found that chemogenetic activation of the rACC-DRN circuit alleviated CFA-induced anxiety-like behaviors, while chemogenetic inhibition of the rACC-DRN circuit resulted in short-term CFA-induced anxiety-like behaviors. Further research revealed that the development of CFA-induced anxiety-like behaviors was attributed to the dysfunction of rACC CaMKII neurons projecting to DRN serotonergic neurons (rACCCaMKII-DRN5-HT neurons) but not rACC CaMKII neurons projecting to DRN GABAergic neurons (rACCCaMKII-DRNGABA neurons). This is supported by the findings that chemogenetic activation of the rACCCaMKII-DRN5-HT circuit alleviates anxiety-like behaviors in rats with chronic pain, whereas neither chemogenetic inhibition nor chemogenetic activation of the rACCCaMKII-DRNGABA circuit altered CFA chronic pain-evoked anxiety-like behaviors in rats. More importantly, we found that EA could reverse chronic pain-induced changes in the activity of rACC CaMKII neurons and DRN 5-HTergic neurons and that chemogenetic inhibition of the rACCCaMKII-DRN5-HT circuit blocked the therapeutic effects of EA on chronic pain-induced anxiety-like behaviors. CONCLUSIONS: Our data suggest that the reversal of rACCCaMKII-DRN5-HT circuit dysfunction may be a mechanism underlying the therapeutic effect of EA on chronic pain-induced anxiety-like behaviors.

Delayed Leaf Senescence Improves Radiation Use Efficiency and Explains Yield Advantage of Large Panicle-Type Hybrid Rice.

Super hybrid rice with predominantly large panicle types has achieved remarkable success in enhancing crop yield. However, when compared with multi-panicle-type varieties, the yield stability of large panicle-type varieties remains a challenge, and limited information is available on the comparative advantages of multi-panicle types. Consequently, a two-year experiment was conducted to evaluate the grain yield, biomass production, leaf area index (LAI), and radiation use efficiency (RUE) of large panicle-type hybrid rice (Y-liangyou 900, YLY900) and multi-panicle-type hybrid rice (C-liangyouhuazhan, CLYHZ) under three nitrogen (N) treatments (0, 180, 270 kg N ha-1). The effects of increased N fertilization were more pronounced in the large panicle-type varieties. YLY900 outperformed CLYHZ in terms of average yield (6% higher), and its yield advantage was attributed to higher spikelets per panicle (28%). Due to YLY900's RUE being 9% higher than CLYHZ, it results in a 12% greater accumulation of dry matter than CLYHZ. Furthermore, YLY900 exhibited significant improvements of 16%, 4%, and 14% in specific leaf weight, effective leaf area ratio, and LAI at 20 days after the heading stage (20DAH), respectively, compared with CLYHZ. YLY900 also demonstrated a stronger correlation between rice yield and intercepted photosynthetically active radiation (IPAR) compared with CLYHZ, with R2 values of 0.80 and 0.66, respectively. These findings highlight the superior performance of YLY900, resulting from higher light interception percentage (IP) and IPAR values, which consequently led to enhanced RUE and grain yield. Our research reveals that delayed leaf senescence by increasing LAI at the post-heading stage for large panicle-type hybrid rice, thereby contributing to greater RUE, led to higher biomass production and grain yield.

The claustrum-prelimbic cortex circuit through dynorphin/κ-opioid receptor signaling underlies depression-like behaviors associated with social stress etiology.

Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit.

Optimizing Grain Yield and Radiation Use Efficiency through Synergistic Applications of Nitrogen and Potassium Fertilizers in Super Hybrid Rice.

The remarkable yield performance of super hybrid rice has played a crucial role in ensuring global food security. However, there is a scarcity of studies investigating the contribution of radiation use efficiency (RUE) to hybrid rice yields under different nitrogen and potassium treatments. In this three-year field experiment, we aimed to evaluate the impact of two hybrid rice varieties (Y-liangyou 900: YLY900 and Quanyouhuazhan: QYHZ) under varying nitrogen regimes (N90: 90 kg N ha-1, N120: 120 kg N ha-1, N180: 180 kg N ha-1) and potassium regimes (K120: 120 kg K2O ha-1, K160: 160 kg K2O ha-1, K210: 210 kg K2O ha-1) on grain yield and its physiological determinants, including RUE, intercepted photosynthetically active radiation (IPAR), aboveground biomass production, and harvest index (HI). Our results revealed that both rice varieties exhibited significantly higher yields when coupled with nitrogen and potassium fertilization. Compared to the N90 × K120 treatment, the N120 × K160 and N180 × K210 combinations resulted in substantial increases in grain yield (12.0% and 21.1%, respectively) and RUE (11.9% and 21.4%, respectively). The YLY900 variety showed notable yield improvement due to enhanced aboveground biomass production resulting from increased IPAR and RUE. In contrast, the QYHZ variety's aboveground biomass accumulation was primarily influenced by RUE rather than IPAR, resulting in higher RUE and grain yields of 9.2% and 5.3%, respectively, compared to YLY900. Importantly, fertilization led to significant increases in yield, biomass, and RUE, while HI remained relatively constant. Both varieties demonstrated a positive relationship between grain yield and IPAR and RUE. Multiple regression analysis indicated that increasing RUE was the primary driver of yield improvement in hybrid rice varieties. By promoting sustainable agriculture and enhancing fertilizer management, elevating nitrogen and potassium levels from a low base would synergistically enhance rice yield and RUE, emphasizing the critical importance of RUE in hybrid rice productivity compared to HI.

Serum brain-derived neurotrophic factor as diagnosis clue for Alzheimer's disease: A cross-sectional observational study in the elderly.

Objective: Brain-derived neurotrophic factor (BDNF) has not been validated as a diagnostic marker for Alzheimer's disease (AD). To provide a different perspective, this study aimed to evaluate the relationship between serum levels of mature BDNF (mBDNF) and precursor BDNF (proBDNF) in AD and to investigate whether serum BDNF levels or the ratio of mBDNF levels to proBDNF levels (M/P) could be a valuable biomarker for determining the risk of AD in elderly individuals. Method: A total of 126 subjects who met the inclusion criteria were assigned to either the AD group (n = 62) or the healthy control group (HC, n = 64) in this cross-sectional observationl study. Serum levels of mBDNF and proBDNF were measured using enzyme immunoassay kits. We analyzed the Mini-Mental State Examination (MMSE) scores from the two groups and examined the associations between AD and BDNF metabolism. Results: The serum concentration of proBDNF was significantly higher in ADs (4140.937 pg/ml) than in HCs (2606.943 pg/ml; p < 0.01). The MMSE significantly correlated with proBDNF (p < 0.01, r = -0.686) and M/P (p < 0.01, r = 0.595) in all subjects. To determine the risk for AD, the area under the receiver operating characteristic curve was calculated, which was 0.896 (95% confidence interval 0.844-0.949) for proBDNF and 0.901 (95% 0.850-0.953) for proBDNF and M/P combined. Conclusion: We observed a correlation between low serum proBDNF levels and higher MMSE scores in AD. The most effective diagnostic strategy was the combination of proBDNF and M/P, whereas mBDNF levels performed poorly when we evaluated the predictive model.

A Mediterranean Diet Pattern Improves Intestinal Inflammation Concomitant with Reshaping of the Bacteriome in Ulcerative Colitis: A Randomised Controlled Trial.

BACKGROUND AND AIMS: Dietary patterns are important in managing ulcerative colitis [UC], given their influence on gut microbiome-host symbiosis and inflammation. We investigated whether the Mediterranean Diet Pattern [MDP] vs the Canadian Habitual Diet Pattern [CHD] would affect disease activity, inflammation, and the gut microbiome in patients with quiescent UC. METHODS: We performed a prospective, randomised, controlled trial in adults [65% female; median age 47 years] with quiescent UC in an outpatient setting from 2017 to 2021. Participants were randomised to an MDP [n = 15] or CHD [n = 13] for 12 weeks. Disease activity [Simple Clinical Colitis Activity Index] and faecal calprotectin [FC] were measured at baseline and week 12. Stool samples were analysed by 16S rRNA gene amplicon sequencing. RESULTS: The diet was well tolerated by the MDP group. At week 12, 75% [9/12] of participants in the CHD had an FC >100 µg/g, vs 20% [3/15] of participants in the MDP group. The MDP group had higher levels of total faecal short chain fatty acids [SCFAs] [p = 0.01], acetic acid [p = 0.03], and butyric acid [p = 0.03] compared with the CHD. Furthermore, the MDP induced alterations in microbial species associated with a protective role in colitis [Alistipes finegoldii and Flavonifractor plautii], as well as the production of SCFAs [Ruminococcus bromii]. CONCLUSIONS: An MDP induces gut microbiome alterations associated with the maintenance of clinical remission and reduced FC in patients with quiescent UC. The data support that the MDP is a sustainable diet pattern that could be recommended as a maintenance diet and adjunctive therapy for UC patients in clinical remission. ClinicalTrials.gov no: NCT0305371.

Analysis and Recognition of Voluntary Facial Expression Mimicry Based on Depressed Patients.

Many clinical studies have shown that facial expression recognition and cognitive function are impaired in depressed patients. Different from spontaneous facial expression mimicry (SFEM), 164 subjects (82 in a case group and 82 in a control group) participated in our voluntary facial expression mimicry (VFEM) experiment using expressions of neutrality, anger, disgust, fear, happiness, sadness and surprise. Our research is as follows. First, we collected a large amount of subject data for VFEM. Second, we extracted the geometric features of subject facial expression images for VFEM and used Spearman correlation analysis, a random forest, and logistic regression-based recursive feature elimination (LR-RFE) to perform feature selection. The features selected revealed the difference between the case group and the control group. Third, we combined geometric features with the original images and improved the advanced deep learning facial expression recognition (FER) algorithms in different systems. We propose the E-ViT and E-ResNet based on VFEM. The accuracies and F1 scores were higher than those of the baseline models, respectively. Our research proved that it is effective to use feature selection to screen geometric features and combine them with a deep learning model for depression facial expression recognition.

p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy.

Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4+ T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies. SIGNIFICANCE: Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design. This article is highlighted in the In This Issue feature, p. 1275.

A Cdh3-ß-catenin-laminin signaling axis in a subset of breast tumor leader cells control leader cell polarization and directional collective migration.

Carcinoma dissemination can occur when heterogeneous tumor and tumor-stromal cell clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system mimicking native breast tumor microenvironment, we developed 3D computational models, which hypothesize that leader cells need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance at the leading edge. From single-cell sequencing analyses, we find that leader cells are heterogeneous and identify and isolate a keratin 14- and cadherin-3-positive subpopulation sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through local production of laminin, which is required for integrin/focal adhesion function. Our findings highlight how a subset of leader cells interact with the microenvironment to direct collective migration.

A method for diagnosing depression: Facial expression mimicry is evaluated by facial expression recognition.

BACKGROUND: Considerable evidence has shown that facial expression mimicry is impaired in patients with depression. We aimed to evaluate voluntary expression mimicry by facial expression recognition for diagnosing depression. METHODS: A total of 168 participants performed voluntary expression mimicry task, posing anger, disgust, fear, happiness, neutrality, sadness, and surprise. 9 healthy raters performed facial expression recognition task through the observer scoring method, and evaluated seven expressions imitated by participants. Emotional scores were calculated to measure any differences between two groups of participants and provided a basis for clinical diagnosis of depression. RESULTS: Compared with the control group, the depression group had lower accuracy in imitating happiness. Compared with the control group, the depression group imitated a higher neutrality bias for sadness, surprise, happiness and disgust, while sadness and surprise had a lower happiness bias; for imitating happiness, the depression group showed higher anger, disgust, fear, neutrality, and surprise bias; for imitating neutrality, the depression group showed higher sadness bias, and lower happiness bias. Compared with the control group, the raters had a higher reaction time to recognize the happiness imitated by depression group, and it was positively correlated with severity of depression. The severity of depression was also negatively correlated with accuracy in imitating happiness, and positively correlated with neutrality bias of imitating surprise. LIMITATIONS: The ecological effectiveness of static stimulus materials is lower than that of dynamic stimuli. Without synchronized functional imaging, there is no way to link brain activation patterns. CONCLUSION: The ability of patients with depression to voluntarily imitate facial expressions declines, which is mainly reflected in accuracy, bias and recognizability. Our experiment has discovered deficits in these aspects of patients with depression, which will be used as a method for diagnosising depression.