The regulatory role of m6A modification in the maintenance and differentiation of embryonic stem cells.

As the most prevalent and reversible internal epigenetic modification in eukaryotic mRNAs, N 6-methyladenosine (m6A) post-transcriptionally regulates the processing and metabolism of mRNAs involved in diverse biological processes. m6A modification is regulated by m6A writers, erasers, and readers. Emerging evidence suggests that m6A modification plays essential roles in modulating the cell-fate transition of embryonic stem cells. Mechanistic investigation of embryonic stem cell maintenance and differentiation is critical for understanding early embryonic development, which is also the premise for the application of embryonic stem cells in regenerative medicine. This review highlights the current knowledge of m6A modification and its essential regulatory contribution to the cell fate transition of mouse and human embryonic stem cells.

Association between cardiac magnetic resonance ventricular strain and left ventricular thrombus in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Myocardial strain can analyze early myocardial dysfunction after myocardial infarction (MI). However, the correlation between left ventricular (LV) strain (including regional and global strain) obtained by cardiac magnetic resonance (CMR) imaging and left ventricular thrombus (LVT) after ST-segment elevation myocardial infarction (STEMI) is unclear. METHODS: The retrospective clinical observation study included patients with LVT (n = 20) and non-LVT (n = 195) who underwent CMR within two weeks after STEMI. CMR images were analyzed using CVI 42 (Circle Cardiovascular Imaging, Canada) to obtain LV strain values. Logistic regression analysis identified risk factors for LVT among baseline characteristics, CMR ventricular strain, and left ventricular ejection fraction (LVEF). Considering potential correlations between strains, the ability of LV strain to identify LVT was evaluated using 9 distinct models. Receiver operating characteristic curves were generated with GraphPad Prism, and the area under the curve (AUC) of LVEF, apical longitudinal strain (LS), and circumferential strain (CS) was calculated to determine their capacity to distinguish LVT. RESULTS: Among 215 patients, 9.3% developed LVT, with a 14.5% incidence in those with anterior MI. Univariate regression indicated associations of LAD infarct-related artery, lower NT-proBNP, lower LVEF, and reduced global, midventricular, and apical strain with LVT. Further multivariable regression analysis showed that apical LS, LVEF and NT-proBNP were still independently related to LVT (Apical LS: OR = 1.14, 95%CI (1.01, 1.30), P = 0.042; LVEF: OR = 0.91, 95%CI (0.85, 0.97), P = 0.005; NT-proBNP: OR = 2.35, 95%CI (1.04, 5.31) ). CONCLUSION: Reduced apical LS on CMR is independently associated with LVT after STEMI.

TCS-Fall: Cross-individual fall detection system based on channel state information and time-continuous stack method.

Background: Falls pose a serious health risk for the elderly, particular for those who are living alone. The utilization of WiFi-based fall detection, employing Channel State Information (CSI), emerges as a promising solution due to its non-intrusive nature and privacy preservation. Despite these advantages, the challenge lies in optimizing cross-individual performance for CSI-based methods. Objective: This study aimed to develop a resilient real-time fall detection system across individuals utilizing CSI, named TCS-Fall. This method was designed to offer continuous monitoring of activities over an extended timeframe, ensuring accurate and prompt detection of falls. Methods: Extensive CSI data on 1800 falls and 2400 daily activities was collected from 20 volunteers. The grouped coefficient of variation of CSI amplitudes were utilized as input features. These features capture signal fluctuations and are input to a convolutional neural network classifier. Cross-individual performance was extensively evaluated using various train/test participant splits. Additionally, a user-friendly CSI data collection and detection tool was developed using PyQT. To achieve real-time performance, data parsing and pre-processing computations were optimized using Numba's just-in-time compilation. Results: The proposed TCS-Fall method achieved excellent performance in cross-individual fall detection. On the test set, AUC reached 0.999, no error warning ratio score reached 0. 955 and correct warning ratio score reached of 0.975 when trained with data from only two volunteers. Performance can be further improved to 1.00 when 10 volunteers were included in training data. The optimized data parsing/pre-processing achieved over 20× speedup compared to previous method. The PyQT tool parsed and detected the fall within 100 ms. Conclusions: TCS-Fall method enables excellent real-time cross-individual fall detection utilizing WiFi CSI, promising swift alerts and timely assistance to elderly. Additionally, the optimized data processing led to a significant speedup. These results highlight the potential of our approach in enhancing real-time fall detection systems.

Self-Assembled Multilayer-Modified Needles Simulate Acupuncture and Diclofenac Sodium Delivery for Rheumatoid Arthritis.

A novel therapeutic approach combining acupuncture and diclofenac sodium (DS) administration was established for the potential treatment for rheumatoid arthritis (RA). DS is a commonly used anti-inflammatory and analgesic drug but has short duration and adverse effects. Acupoints are critical linkages in the meridian system and are potential candidates for drug delivery. Herein, we fabricated a DS-loaded multilayer-modified acupuncture needle (DS-MMAN) and investigated its capacity for inhibiting RA. This DS-MMAN possesses sustained release properties and in vitro anti-inflammatory effects. Experimental results showed that the DS-MMAN with microdoses can enhance analgesia and efficiently relieve joint swelling compared to the oral or intra-articular administration of DS with gram-level doses. Moreover, the combination of acupoint and DS exerts a synergistic improvement in inflammation and joint damage. Cytokine and T cell analyses in the serum indicated that the application of DS-MMAN suppressed the levels of pro-inflammatory factors and increased the levels of anti-inflammatory factors. Furthermore, the acupoint administration via DS-MMAN could decrease the accumulation of DS in the liver and kidneys, which may express better therapeutic efficiency and low toxicity. The present study demonstrated that the acupuncture needle has the potential to build a bridge between acupuncture and medication, which would be a promising alternative to the combination of traditional and modern medicine.

A Demographic-Conditioned Variational Autoencoder for fMRI Distribution Sampling and Removal of Confounds.

Objective: fMRI and derived measures such as functional connectivity (FC) have been used to predict brain age, general fluid intelligence, psychiatric disease status, and preclinical neurodegenerative disease. However, it is not always clear that all demographic confounds, such as age, sex, and race, have been removed from fMRI data. Additionally, many fMRI datasets are restricted to authorized researchers, making dissemination of these valuable data sources challenging. Methods: We create a variational autoencoder (VAE)-based model, DemoVAE, to decorrelate fMRI features from demographics and generate high-quality synthetic fMRI data based on user-supplied demographics. We train and validate our model using two large, widely used datasets, the Philadelphia Neurodevelopmental Cohort (PNC) and Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP). Results: We find that DemoVAE recapitulates group differences in fMRI data while capturing the full breadth of individual variations. Significantly, we also find that most clinical and computerized battery fields that are correlated with fMRI data are not correlated with DemoVAE latents. An exception are several fields related to schizophrenia medication and symptom severity. Conclusion: Our model generates fMRI data that captures the full distribution of FC better than traditional VAE or GAN models. We also find that most prediction using fMRI data is dependent on correlation with, and prediction of, demographics. Significance: Our DemoVAE model allows for generation of high quality synthetic data conditioned on subject demographics as well as the removal of the confounding effects of demographics. We identify that FC-based prediction tasks are highly influenced by demographic confounds.

Global diversity of airborne pathogenic bacteria and fungi from wastewater treatment plants.

Wastewater treatment plants (WWTPs) have been recognized as one of the major potential sources of the spread of airborne pathogenic microorganisms under the global pandemic of COVID-19. The differences in research regions, wastewater treatment processes, environmental conditions, and other aspects in the existing case studies have caused some confusion in the understanding of bioaerosol pollution characteristics. In this study, we integrated and analyzed data from field sampling and performed a systematic literature search to determine the abundance of airborne microorganisms in 13 countries and 37 cities across four continents (Asia, Europe, North America, and Africa). We analyzed the concentrations of bioaerosols, the core composition, global diversity, determinants, and potential risks of airborne pathogen communities in WWTPs. Our findings showed that the culturable bioaerosol concentrations of global WWTPs are 102-105 CFU/m3. Three core bacterial pathogens, namely Bacillus, Acinetobacter, and Pseudomonas, as well as two core fungal pathogens, Cladosporium and Aspergillus, were identified in the air across global WWTPs. WWTPs have unique core pathogenic communities and distinct continental divergence. The sources of airborne microorganisms (wastewater) and environmental variables (relative humidity and air contaminants) have impacts on the distribution of airborne pathogens. Potential health risks are associated with the core airborne pathogens in WWTPs. Our study showed the specificity, multifactorial influences, and potential pathogenicity of airborne pathogenic communities in WWTPs. Our findings can improve the understanding of the global diversity and biogeography of airborne pathogens in WWTPs, guiding risk assessment and control strategies for such pathogens. Furthermore, they provide a theoretical basis for safeguarding the health of WWTP workers and ensuring regional ecological security.

Electrical Stimulations Generated by P(VDF-TrFE) Films Enhance Adhesion Forces and Odontogenic Differentiation of Dental Pulp Stem Cells (DPSCs).

Biophysical and biochemical cues of biomaterials can regulate cell behaviors. Dental pulp stem cells (DPSCs) in pulp tissues can differentiate to odontoblast-like cells and secrete reparative dentin to form a barrier to protect the underlying pulp tissues and enable complete pulp healing. Promotion of the odontogenic differentiation of DPSCs is essential for dentin regeneration. The effects of the surface potentials of biomaterials on the adhesion and odontogenic differentiation of DPSCs remain unclear. Here, poly(vinylidene fluoride-trifluoro ethylene) (P(VDF-TrFE)) films with different surface potentials were prepared by the spin-coating technique and the contact poling method. The cytoskeletal organization of DPSCs grown on P(VDF-TrFE) films was studied by immunofluorescence staining. Using atomic force microscopy (AFM), the lateral detachment forces of DPSCs from P(VDF-TrFE) films were quantified. The effects of electrical stimulation generated from P(VDF-TrFE) films on odontogenic differentiation of DPSCs were evaluated in vitro and in vivo. The unpolarized, positively polarized, and negatively polarized films had surface potentials of -52.9, +902.4, and -502.2 mV, respectively. DPSCs on both negatively and positively polarized P(VDF-TrFE) films had larger cell areas and length-to-width ratios than those on the unpolarized films (P < 0.05). During the detachment of DPSCs from P(VDF-TrFE) films, the average magnitudes of the maximum detachment forces were 29.4, 72.1, and 53.9 nN for unpolarized, positively polarized, and negatively polarized groups, respectively (P < 0.05). The polarized films enhanced the mineralization activities and increased the expression levels of the odontogenic-related proteins of DPSCs compared to the unpolarized films (P < 0.05). The extracellular signal-regulated kinase (ERK) signaling pathway was involved in the odontogenic differentiation of DPSCs as induced by surface charge. In vivo, the polarized P(VDF-TrFE) films enhanced adhesion of DPSCs and promoted the odontogenic differentiation of DPSCs by electrical stimulation, demonstrating a potential application of electroactive biomaterials for reparative dentin formation in direct pulp capping.

Inferior Frontal Sulcal Hyperintensity on Fluid-Attenuated Inversion Recovery Is Related to Cerebrospinal Fluid Clearance via Putative Meningeal Lymphatics.

Inferior frontal sulcal hyperintensity (IFSH) on FLAIR sequence may indicate elevated cerebrospinal fluid (CSF) wastes. The objective of this study was to investigate its association with the clearance function of putative meningeal lymphatic vessels (mLVs). We included patients who underwent FLAIR sequence and dynamic contrast MRI with intrathecal administration of contrast agent. The visibility of IFSH was quantitatively assessed by measuring the mean signal intensity of inferior frontal sulci on 2D FLAIR. The clearance function of putative mLVs was defined as the percentage change of signal unite ratio in the parasagittal dura from baseline to 4.5, 15 and 39 hours after intrathecal injection on dynamic contrast MRI. Additionally, imaging markers of cerebral small vessel disease, including white matter hyperintensities and enlarged perivascular spaces, were measured. Correlation analysis and linear regression were employed to verify the association of IFSH with the clearance function of mLVs. A total of 76 patients were included in the study. The visibility of IFSH was found to be associated with the percentage change of signal unite ratio in parasagittal dura from baseline to 15 and 39 hours in adjusted analyses. Furthermore, the visibility of IFSH was positively related to the age, scores of both periventricular and deep white matter hyperintensities, and the grade of enlarged perivascular spaces in centrum semiovale. These findings suggest that the visibility of IFSH on 2D FLAIR may serve as an indicator of clearance dysfunction of mLVs and may be implicated in the development of cerebral small vessel disease.

A Demographic-Conditioned Variational Autoencoder for fMRI Distribution Sampling and Removal of Confounds.

Objective: fMRI and derived measures such as functional connectivity (FC) have been used to predict brain age, general fluid intelligence, psychiatric disease status, and preclinical neurodegenerative disease. However, it is not always clear that all demographic confounds, such as age, sex, and race, have been removed from fMRI data. Additionally, many fMRI datasets are restricted to authorized researchers, making dissemination of these valuable data sources challenging. Methods: We create a variational autoencoder (VAE)-based model, DemoVAE, to decorrelate fMRI features from demographics and generate high-quality synthetic fMRI data based on user-supplied demographics. We train and validate our model using two large, widely used datasets, the Philadelphia Neurodevel-opmental Cohort (PNC) and Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP). Results: We find that DemoVAE recapitulates group differences in fMRI data while capturing the full breadth of individual variations. Significantly, we also find that most clinical and computerized battery fields that are correlated with fMRI data are not correlated with DemoVAE latents. An exception are several fields related to schizophrenia medication and symptom severity. Conclusion: Our model generates fMRI data that captures the full distribution of FC better than traditional VAE or GAN models. We also find that most prediction using fMRI data is dependent on correlation with, and prediction of, demographics. Significance: Our DemoVAE model allows for generation of high quality synthetic data conditioned on subject demographics as well as the removal of the confounding effects of demographics. We identify that FC-based prediction tasks are highly influenced by demographic confounds.

Exploration of altered miRNA expression and function in MSC-derived extracellular vesicles in response to hydatid antigen stimulation.

Background: Hydatid disease is caused by Echinococcus parasites and can affect various tissues and organs in the body. The disease is characterized by the presence of hydatid cysts, which contain specific antigens that interact with the host's immune system. Mesenchymal stem cells (MSCs) are pluripotent stem cells that can regulate immunity through the secretion of extracellular vesicles (EVs) containing microRNAs (miRNAs). Methods: In this study, hydatid antigens were isolated from sheep livers and mice peritoneal cavities. MSCs derived from mouse bone marrow were treated with different hydatid antigens, and EVs were isolated and characterized from the conditioned medium of MSCs. Small RNA library construction, miRNA target prediction, and differential expression analysis were conducted to identify differentially expressed miRNAs. Functional enrichment and network construction were performed to explore the biological functions of the target genes. Real-time PCR and Western blotting were used for miRNA and gene expression verification, while ELISA assays quantified TNF, IL-1, IL-6, IL-4, and IL-10 levels in cell supernatants. Results: The study successfully isolated hydatid antigens and characterized MSC-derived EVs, demonstrating the impact of antigen concentration on MSC viability. Key differentially expressed miRNAs, such as miR-146a and miR-9-5p, were identified, with functional analyses revealing significant pathways like Endocytosis and MAPK signaling associated with these miRNAs' target genes. The miRNA-HUB gene regulatory network identified crucial miRNAs and HUB genes, such as Traf1 and Tnf, indicating roles in immune modulation and osteogenic differentiation. Protein-protein interaction (PPI) network analysis highlighted central HUB genes like Akt1 and Bcl2. ALP activity assays confirmed the influence of antigens on osteogenic differentiation, with reduced ALP activity observed. Expression analysis validated altered miRNA and chemokine expression post-antigen stimulation, with ELISA analysis showing a significant reduction in CXCL1 expression in response to antigen exposure. Conclusion: This study provides insights into the role of MSC-derived EVs in regulating parasite immunity. The findings suggest that hydatid antigens can modulate the expression of miRNAs in MSC-derived EVs, leading to changes in chemokine expression and osteogenic capacity. These findings contribute to a better understanding of the immunomodulatory mechanisms involved in hydatid disease and provide potential therapeutic targets for the development of new treatment strategies.

Bombus terrestris Prefer Mixed-Pollen Diets for a Better Colony Performance: A Laboratory Study.

Pollen is a major source of proteins and lipids for bumblebees. The nutritional content of pollen may differ from source plants, ultimately affecting colony development. This study investigated the foraging preferences of Bombus terrestris in regard to four pollen species, i.e., oilseed rape, wild apricot, sunflower, and buckwheat, under laboratory conditions. The results show that B. terrestris diversified their preference for pollens; the bumblebees mostly preferred wild apricot pollen, whereas sunflower pollen was the least preferred. The colonies fed on a mixed four-pollen diet, with a protein-lipid ratio of 4.55-4.86, exhibited better development in terms of the number of offspring, individual body size and colony weight. The colonies fed with buckwheat and sunflower pollens produced a significantly lower number of workers and failed to produce queen and male offspring. Moreover, wild apricot pollen had the richest protein content (23.9 g/100 g) of the four pollen species, whereas oilseed rape pollen had the highest lipid content (6.7 g/100 g), as revealed by the P:L ratios of wild apricot, sunflower, buckwheat, and oilseed rape, which were 6.76, 5.52, 3.50, and 3.37, respectively. Generally, B. terrestris showed feeding preferences regarding different pollens and a mixture of pollens, which ultimately resulted in differences in colony development. The findings of this study provide important baseline information to researchers and developers of nutritive pollen diets for bumblebees.

Corrigendum: Regional myocardial work measured by echocardiography for the detection of myocardial ischemic segments: a comparative study with invasive fractional flow reserve.

[This corrects the article DOI: 10.3389/fcvm.2022.813710.].

The Distribution of Crystalline Lens Rise in High Myopia Population and Its Influence on Vault After Implanting Intraocular Collamer Lens.

INTRODUCTION: As a result of the insufficient ocular anatomical parameters used to customize implantable collamer lens (ICL), many patients still cannot achieve a suitable vault after ICL implantation surgery. This study analyzed the characteristics of a new anatomical parameter crystalline lens rise (CLR) in a population with high myopia and explored the influence of CLR on the vault after ICL implantation. METHODS: Patients (298 eyes) with high myopia who underwent ICL implantation were enrolled to study CLR characteristics. Postoperatively, patients (159 eyes) were divided into five groups according to the value of CLR (A, CLR ≤ - 150; B, - 150 < CLR ≤ 0; C, 0 < CLR < 150; D, 150 ≤ CLR < 300; E, CLR ≥ 300 µm), and to investigate the correlation between CLR and vault. RESULTS: In the 298 eyes, the CLR had a normal distribution (P = 0.35) and the mean CLR was 67.93 ± 150.66 µm. Ninety-nine eyes (33.22%) had a CLR ≤ 0 µm, of which 20 eyes (6.71%) had a CLR ≤ - 150 µm; 199 eyes (66.78%) had a CLR > 0 µm, of which 20 eyes (6.71%) had a CLR ≥ 300 µm. In 159 eyes, the CLR was negatively correlated with the vault at 1 day (R = - 0.497, P < 0.001), 3 months (R = - 0.505, P < 0.001), and 6 months (R = - 0.505, P < 0.001) postoperatively. At 6 months, the vault of group A was statistically significantly different compared to groups B-E (all P < 0.05), and that of group E was statistically significantly different compared to groups A-D (all P < 0.001). The remaining groups did not show statistically significant differences (all P > 0.05). CONCLUSION: The CLR had a normal distribution in the high myopia population, and 13.42% of the CLR values were extreme (CLR ≤ - 150 µm or CLR ≥ 300 µm). A larger ICL diameter than that recommended by the manufacturer should be considered when the CLR is ≥ 300 µm and a smaller ICL diameter should be considered when the CLR is ≤ - 150 µm.

Oleic acid-PPARγ-FABP4 loop fuels cholangiocarcinoma colonization in lymph node metastases microenvironment.

BACKGROUND AND AIMS: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing of primary tumor lesions and paired lymph node metastases from patients with cholangiocarcinoma and revealed significantly reduced intertumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer single-cell RNA sequencing analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph nodes through the oleic acid-PPARγ-fatty acid-binding protein 4 positive feedback loop by upregulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche in lymph node metastases by producing kynurenine and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response. CONCLUSIONS: Our results reveal the role of the oleic acid-PPARγ-fatty acid-binding protein 4 loop in fueling cholangiocarcinoma colonization in lymph nodes and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.

N-acetyltransferase NAT10 controls cell fates via connecting mRNA cytidine acetylation to chromatin signaling.

Cell fate transition involves dynamic changes of gene regulatory network and chromatin landscape, requiring multiple levels of regulation, yet the cross-talk between epitranscriptomic modification and chromatin signaling remains largely unknown. Here, we uncover that suppression of N-acetyltransferase 10 (NAT10), the writer for mRNA N4-acetylcytidine (ac4C) modification, can notably affect human embryonic stem cell (hESC) lineage differentiation and pluripotent reprogramming. With integrative analysis, we identify that NAT10-mediated ac4C modification regulates the protein levels of a subset of its targets, which are strongly enriched for fate-instructive chromatin regulators, and among them, histone chaperone ANP32B is experimentally verified and functionally relevant. Furthermore, NAT10-ac4C-ANP32B axis can modulate the chromatin landscape of their downstream genes (e.g., key regulators of Wnt and TGFß pathways). Collectively, we show that NAT10 is an essential regulator of cellular plasticity, and its catalyzed mRNA cytidine acetylation represents a critical layer of epitranscriptomic modulation and uncover a previously unrecognized, direct cross-talk between epitranscriptomic modification and chromatin signaling during cell fate transitions.

Detection of organic dyes using Ag NPAs/SMP SERS substrate produced via sandpaper template-assisted lithography and liquid-liquid interface self-assembly.

Surface-enhanced Raman spectroscopy (SERS) is a highly sensitive and reliable fingerprinting technique. However, its analytical capability is closely related to the quality of a SERS substrate used for the analysis. In particular, conventional colloidal substrates possess disadvantages in terms of controllability, stability, and reproducibility, which limit their application. In order to address these issues, a simple, cost-effective, and efficient SERS substrate based on silver nanoparticle arrays (Ag NPAs) and sandpaper-molded polydimethylsiloxane (SMP) was proposed in this work. Successfully prepared via template lithography and liquid-liquid interface self-assembly (LLISA), the substrate can be applied to the specific detection of organic dyes in the environment. The substrate exhibited good SERS performance, and the limit of detection (LOD) of rhodamine 6G (R6G) was shown to be 10-7 M under the optimal conditions (1000 grit sandpaper) with a relative standard deviation (RSD) of 7.76%. Moreover, the SERS signal intensity was maintained at 60% of the initial intensity after the substrate was stored for 30 days. In addition, the Ag NPAs/SMP SERS substrate was also employed to detect crystal violet (CV) and methylene blue (MB) with the LODs of 10-6 M and 10-7 M, respectively. In summary, the Ag NPAs/SMP SERS substrate prepared in this study has great potential for the detection of organic dyes in ecological environments.

Cancer-Associated Fibroblasts Promote Lymphatic Metastasis in Cholangiocarcinoma via the PDGF-BB/PDGFR-ß Mediated Paracrine Signaling Network.

Patients with cholangiocarcinoma (CCA) with lymph node metastasis (LNM) have the worst prognosis, even after complete resection; however, the underlying mechanism remains unclear. Here, we established CAF-derived PDGF-BB as a regulator of LMN in CCA. Proteomics analysis revealed upregulation of PDGF-BB in CAFs derived from patients with CCA with LMN (LN+CAFs). Clinically, the expression of CAF-PDGF-BB correlated with poor prognosis and increased LMN in patients with CCA, while CAF-secreted PDGF-BB enhanced lymphatic endothelial cell (LEC)-mediated lymphangiogenesis and promoted the trans-LEC migration ability of tumor cells. Co-injection of LN+CAFs and cancer cells increased tumor growth and LMN in vivo. Mechanistically, CAF-derived PDGF-BB activated its receptor PDGFR-ß and its downstream ERK1/2-JNK signaling pathways in LECs to promote lymphoangiogenesis, while it also upregulated the PDGFR-ß-GSK-P65-mediated tumor cell migration. Finally, targeting PDGF-BB/PDGFR-ß or the GSK-P65 signaling axis prohibited CAF-mediated popliteal lymphatic metastasis (PLM) in vivo. Overall, our findings revealed that CAFs promote tumor growth and LMN via a paracrine network, identifying a promising therapeutic target for patients with advanced CCA.

ImageNomer: Description of a functional connectivity and omics analysis tool and case study identifying a race confound.

Most packages for the analysis of fMRI-based functional connectivity (FC) and genomic data are used with a programming language interface, lacking an easy-to-navigate GUI frontend. This exacerbates two problems found in these types of data: demographic confounds and quality control in the face of high dimensionality of features. The reason is that it is too slow and cumbersome to use a programming interface to create all the necessary visualizations required to identify all correlations, confounding effects, or quality control problems in a dataset. FC in particular usually contains tens of thousands of features per subject, and can only be summarized and efficiently explored using visualizations. To remedy this situation, we have developed ImageNomer, a data visualization and analysis tool that allows inspection of both subject-level and cohort-level demographic, genomic, and imaging features. The software is Python-based, runs in a self-contained Docker image, and contains a browser-based GUI frontend. We demonstrate the usefulness of ImageNomer by identifying an unexpected race confound when predicting achievement scores in the Philadelphia Neurodevelopmental Cohort (PNC) dataset, which contains multitask fMRI and single nucleotide polymorphism (SNP) data of healthy adolescents. In the past, many studies have attempted to use FC to identify achievement-related features in fMRI. Using ImageNomer to visualize trends in achievement scores between races, we find a clear potential for confounding effects if race can be predicted using FC. Using correlation analysis in the ImageNomer software, we show that FCs correlated with Wide Range Achievement Test (WRAT) score are in fact more highly correlated with race. Investigating further, we find that whereas both FC and SNP (genomic) features can account for 10-15% of WRAT score variation, this predictive ability disappears when controlling for race. We also use ImageNomer to investigate race-FC correlation in the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) dataset. In this work, we demonstrate the advantage of our ImageNomer GUI tool in data exploration and confound detection. Additionally, this work identifies race as a strong confound in FC data and casts doubt on the possibility of finding unbiased achievement-related features in fMRI and SNP data of healthy adolescents.

Generation of Subnanometer Metal Clusters in Silicoaluminate Zeolites as Bifunctional Catalysts.

Zeolite-encapsulated subnanometer metal catalysts are an emerging class of solid catalysts with superior performances in comparison to metal catalysts supported on open-structure solid carriers. Currently, there is no general synthesis methodology for the encapsulation of subnanometer metal catalysts in different zeolite structures. In this work, we will show a general synthesis method for the encapsulation of subnanometer metal clusters (Pt, Pd, and Rh) within various silicoaluminate zeolites with different topologies (MFI, CHA, TON, MOR). The successful generation of subnanometer metal species in silicoaluminate zeolites relies on the introduction of Sn, which can suppress the migration of subnanometer metal species during high-temperature oxidation-reduction treatments according to advanced electron microscopy and spectroscopy characterizations. The advantage of encapsulated subnanometer Pt catalysts in silicoaluminate zeolites is reflected in the direct coupling of ethane and benzene for production of ethylbenzene, in which the Pt and the acid sites work in a synergistic way.