Miracle-dz/UniFAR-FTUs huggingface dataset:
The secretome of M1 and M2 microglia differently regulate proliferation, differentiation and survival of adult neural stem/progenitor cell

Microglia has been reported to be able to regulate the proliferation, differentiation and survival of adult Neural stem/progenitor cells (NSPCs) by modulating the microenvironment, which results in different consequences of adult neurogenesis. However, whether the microglial activation is beneficial or harmful to NSPCs is still controversial because of the complexity and variability of microglial activation phenotypes. In this study, we detected the expression levels of M1 marker and M2 marker in IFN-γ- and IL-4-induced microglia at different time, respectively. The phenotypic markers of M1 and M2 microglia were stable for 24 h after removal of IFN-γ and IL-4 intervention, but exhibited different change patterns during the next 24 h. Then, the adult NSPCs were treated by the conditioned medium from IFN-γ- and IL-4-activated microglia. The conditioned medium from IFN-γ-activated microglia promoted apoptosis and astroglial differentiation of NSPCs, while suppressed proliferation and neuronal differentiation of NSPCs. However, the conditioned medium from IL-4-activated microglia exhibited opposite effects on these physiological processes. In addition, the direct treatment of IFN-γ or IL-4 alone did not significantly affect the proliferation, differentiation and survival of NSPCs. These results suggest that the secretome of pro-inflammatory (M1) and anti-inflammatory (M2) microglia differently regulated the proliferation, differentiation and survival of adult NSPCs. These findings will help further study the biological mechanism of microglia regulating neurogenesis, and provide a therapeutic strategy for neurological diseases by regulating microglial phenotypes to affect neurogenesis.
Tourmaline: A containerized workflow for rapid and iterable amplicon sequence analysis using QIIME 2 and Snakemake

Background Amplicon sequencing (metabarcoding) is a common method to survey diversity of environmental communities whereby a single genetic locus is amplified and sequenced from the DNA of whole or partial organisms, organismal traces (e.g., skin, mucus, feces), or microbes in an environmental sample. Several software packages exist for analyzing amplicon data, among which QIIME 2 has emerged as a popular option because of its broad functionality, plugin architecture, provenance tracking, and interactive visualizations. However, each new analysis requires the user to keep track of input and output file names, parameters, and commands; this lack of automation and standardization is inefficient and creates barriers to meta-analysis and sharing of results. Findings We developed Tourmaline, a Python-based workflow that implements QIIME 2 and is built using the Snakemake workflow management system. Starting from a configuration file that defines parameters and input files—a reference database, a sample metadata file, and a manifest or archive of FASTQ sequences—it uses QIIME 2 to run either the DADA2 or Deblur denoising algorithm, assigns taxonomy to the resulting representative sequences, performs analyses of taxonomic, alpha, and beta diversity, and generates an HTML report summarizing and linking to the output files. Features include support for multiple cores, automatic determination of trimming parameters using quality scores, representative sequence filtering (taxonomy, length, abundance, prevalence, or ID), support for multiple taxonomic classification and sequence alignment methods, outlier detection, and automated initialization of a new analysis using previous settings. The workflow runs natively on Linux and macOS or via a Docker container. We ran Tourmaline on a 16S rRNA amplicon dataset from Lake Erie surface water, showing its utility for parameter optimization and the ability to easily view interactive visualizations through the HTML report, QIIME 2 viewer, and R- and Python-based Jupyter notebooks. Conclusions Automated workflows like Tourmaline enable rapid analysis of environmental and biomedical amplicon data, decreasing the time from data generation to actionable results. Tourmaline is available for download at github.com/aomlomics/tourmaline.
Hippocampus maintains a flexible and coherent map under reward flavor-landmark cue conflict

Animals predominantly use salient visual cues (landmarks) for efficient navigation over other sensory modalities. When the relative position of the visual cues is altered, the hippocampal population exhibits heterogeneous responses and constructs context-specific spatial maps. Another critical factor that can strongly modulate spatial representation is the presence of reward. Reward features can drive behavior and are known to bias spatial attention. However, it is unclear whether reward flavors are used for spatial reference in the presence of distal cues and how the hippocampus population dynamics changes when the association between reward flavors and distal cues is altered. We investigated these questions by recording place cells from the CA1 while the rats ran in an environment with the conflicting association between reward flavors and distal cues. We report that the hippocampal place cells coherently and dynamically bind to reward flavors or distal cues across sessions, but not simultaneously suggesting the use of a single spatial map. We found that place cells maintained their spatial offset in the cue conflict conditions, thus showing a robust spatial coupling featuring an attractor-like property in the CA1. When the textures were added on the track, the coherency of the CA1 is degraded, as the hippocampus showed a heterogeneous response and weak spatial coupling of co-recorded cells suggesting a break away from the attractor network. These results indicate that reward flavors alone may be used for spatial reference but may not cause sufficient input difference to create context-specific spatial maps in the CA1.
DR AF T 3 D-imaging inspired improvements to hearing model in parasitoid fly Ormia ochracea

Although most binaural organisms localize sound sources using neurological structures to amplify the sounds they hear, some animals use mechanically coupled hearing organs to do so. One example, the parasitoid fly Ormia ochracea, has astoundingly accurate sound localization abilities and can locate objects in the azimuthal plane with a precision of 2°, equal to that of humans. This is accomplished despite an intertympanal distance of only 1.2 mm, which is about 1/100th of the wavelength of the sound emitted by the crickets that it parasitizes. In 1995, Miles et al. developed a model for hearing mechanics in O. Ochracea, which works well for incoming sound angles of less than ±30°, but suffers from reduced accuracy at higher angles. Despite this, it has served as the basis for multiple bio-inspired microphone designs for decades. Here, we present critical modifications to the classic O. ochracea hearing model based on information from 3D reconstructions of O. ochracea’s tympana. The 3D images reveal that the tympana have curved lateral faces in addition to the flat front-facing prosternal membranes represented in the 1995 model. To mimic these faces, we incorporated spatiallyvarying spring and damper coefficients that respond asymmetrically to incident sound waves, making a new quasi-two-dimensional (q2D) model. This q2D model has high accuracy (average errors of less than 10%) for the entire range of incoming sound angles. This improved biomechanical hearing model can inform the development of new technologies and may help to play a key role in developing improved hearing aids. 1
Why Does Rubin's Vase Differ Radically From Optical Illusions? Framing Effects Contra Cognitive Illusions

Many researchers use the term “context” loosely to denote diverse kinds of reference points. The issue is not about terminology but rather about the common conflation of one kind of reference points, such as rules of perception, which is responsible for optical illusions, with another kind, known as “context” or “frame,” as exemplified in Rubin's vase. Many researchers regard Rubin's vase as a special kind of optical illusions. This paper rather argues that the two phenomena are radically different. Optical illusions are occasional mistakes that people quickly recognize and eagerly correct, while the different figures of Rubin's vase are not mistakes but, rather, the outcomes of different perspectives that do not need correction. The competing figures in Rubin's vase can, at best, in light of more information, be more warranted or unwarranted. This paper discusses at length one ramification of the proposed distinction. The framing effects, such as loss/gain frame, are the products of contexts and, hence, resemble greatly the figures in Rubin's vase. In contrast, cognitive illusions generated occasionally by the rules of thumb (heuristics) are mistakes and, hence, resemble optical illusions. The proposed distinction carries other ramifications regarding, e.g., happiness studies, moral judgments, and the new philosophy of science.
High Proteoglycan Decorin Levels Are Associated With Acute Coronary Syndrome and Provoke an Imbalanced Inflammatory Response

Background and Aims: Acute coronary syndrome (ACS) has become one of the most common causes of disability. It is thus important to identify ACS early in the disease course of patients using novel biomarkers for prompt management. Decorin (DCN) was well-acknowledged for its effect on collagen fibrillogenesis and maintaining tissue integrity. Additionally, DCN could release as secreted proteoglycan under pathological conditions. Hence, we aimed to determine the relationship between serum DCN concentration and ACS. Methods: A total of 388 patients who underwent coronary angiography (CAG) in the cardiovascular center of Ruijin Hospital between June 2016 and December 2017 were enrolled in this study. Blood samples were drawn during CAG surgery to determine the serum DCN level of patients with ACS (n = 210) and control subjects (n = 178) using enzyme-linked immunosorbent assay. Results: We found that the serum DCN levels of ACS patients were elevated compared with those of the control subjects (13.59 ± 0.50 vs. 13.17 ± 0.38, respectively, p < 0.001). Furthermore, the serum DCN level, after being adjusted with other cardiovascular factors, was independently associated with ACS. Moreover, an increased serum DCN level was positively correlated with the number of white blood cells and the level of high-sensitivity C-reactive protein (R = 0.3 and 0.11, respectively). Mechanistically, DCN might have elicited an imbalanced inflammatory response during cardiac ischemia by suppressing the expression of anti-inflammatory genes. Conclusion: Serum DCN is a novel biomarker of ACS and contributes to the increased inflammatory response in ischemic heart disease.
SALL1 Modulates CBX4 Stability, Nuclear Bodies, and Regulation of Target Genes

Development is orchestrated through a complex interplay of multiple transcription factors. The comprehension of this interplay will help us to understand developmental processes. Here we analyze the relationship between two key transcription factors: CBX4, a member of the Polycomb Repressive Complex 1 (PRC1), and SALL1, a member of the Spalt-like family with important roles in embryogenesis and limb development. Both proteins localize to nuclear bodies and are modified by the small ubiquitin-like modifier (SUMO). Our results show that CBX4 and SALL1 interact in the nucleoplasm and that increased SALL1 expression reduces ubiquitination of CBX4, enhancing its stability. This is accompanied by an increase in the number and size of CBX4-containing Polycomb bodies, and by a greater repression of CBX4 target genes. Thus, our findings uncover a new way of SALL1-mediated regulation of Polycomb bodies through modulation of CBX4 stability, with consequences in the regulation of its target genes, which could have an impact in cell differentiation and development.
Digital Quantification of Tumor PD-L1 Predicts Outcome of PD-1-Based Immune Checkpoint Therapy in Metastatic Melanoma

Background PD-1-based immune checkpoint blockade (ICB) is a highly effective therapy in metastatic melanoma. However, 40-60% of patients are primarily resistant, with valid predictive biomarkers currently missing. This study investigated the digitally quantified tumor PD-L1 expression for ICB therapy outcome prediction. Patients and Methods Tumor tissues taken prior to PD-1-based ICB for unresectable metastatic disease were collected within the prospective multicenter Tissue Registry in Melanoma (TRIM). PD-L1 expression (clone 28-8; cut-off=5%) was determined by digital and physician quantification, and correlated with therapy outcome (best overall response, BOR; progression-free survival, PFS; overall survival, OS). Results Tissue samples from 156 patients were analyzed (anti-PD-1, n=115; anti-CTLA-4+anti-PD-1, n=41). Patients with PD-L1-positive tumors showed an improved response compared to patients with PD-L1-negative tumors, by digital (BOR 50.5% versus 32.2%; p=0.026) and physician (BOR 54.2% versus 36.6%; p=0.032) quantification. Tumor PD-L1 positivity was associated with a prolonged PFS and OS by either digital (PFS, 9.9 versus 4.6 months, p=0.021; OS, not reached versus 13.0 months, p=0.001) or physician (PFS, 10.6 versus 5.6 months, p=0.051; OS, not reached versus 15.6 months, p=0.011) quantification. Multivariable Cox regression revealed digital (PFS, HR=0.57, p=0.007; OS, HR=0.44, p=0.001) and physician (OS, HR=0.54, p=0.016) PD-L1 quantification as independent predictors of survival upon PD-1-based ICB. The combination of both methods identified a patient subgroup with particularly favorable therapy outcome (PFS, HR=0.53, p=0.011; OS, HR=0.47, p=0.008). Conclusion Pre-treatment tumor PD-L1 positivity predicted a favorable outcome of PD-1-based ICB in melanoma. Herein, digital quantification was not inferior to physician quantification, and should be further validated for clinical use.
Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.
Metabolites of Procyanidins From Litchi Chinensis Pericarp With Xanthine Oxidase Inhibitory Effect and Antioxidant Activity

Procyanidins from litchi pericarp (LPPC) has been evidenced to possess strong antioxidant activities in vivo that is possibly correlated with their intestinal metabolites. However, the xanthine oxidase inhibitory effect of LPPC and its metabolites was less concerned. In this study, three oligomeric procyanidins and eight metabolic phenolic acids were identified in the urine of rats administrated with LPPC by high performance liquid chromatography and liquid chromatography-mass spectrometry analysis. Data indicated that all the metabolites excreted were significantly increased by the treatment of 300 mg/kg body weight of LPPC (P < 0.05), revealing considerable 1, 1-Diphenyl-2-Picrylhydrazyl (DPPH) and hydroxyl radicals activities of scavenging. Moreover, phenolic metabolites involving epicatechin, A-type dimer, A-type trimer, caffeic acid, and shikimic acid exhibited greater xanthine oxidase inhibition effects compared with other metabolites, with an inhibitory rate higher than 50% at the concentration 200 μg/ml. The IC50 value of these five phenols were 58.43 ± 1.86, 68.37 ± 3.50, 74.87 ± 1.30, 95.67 ± 3.82, and 96.17 ± 1.64 μg/ml, respectively. As a whole, this work suggests that the xanthine oxidase inhibition and antioxidant activity of LPPC-derived metabolites as one of the mechanisms involved in the beneficial effects of LPPC against hyperuricemia or gout.
Reduced Expression of Erythropoietin After Intravitreal Ranibizumab in Proliferative Diabetic Retinopathy Patients—Retrospective Interventional Study

Purpose: To evaluate the expressions of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) in the vitreous and fibrovascular membranes (FVMs) of proliferative diabetic retinopathy (PDR) after the intravitreal injection of ranibizumab (IVR) and further explore the relationship between EPO and VEGF. Method: The concentrations of EPO and VEGF levels in the vitreous fluid were measured in 35 patients (24 PDR and 11 non-diabetic patients) using enzyme-linked immunosorbent assay. The patients were divided into three groups: PDR with IVR (IVR group) before par plana vitrectomy (n = 10), PDR without IVR (Non-IVR group) (n = 14) and a control group [macular holes (MHs) or epiretinal membranes (ERM), n = 11]. Fluorescence immunostaining was performed to examine the expressions of VEGF, EPO and CD 105 in the excised epiretinal membranes. Result: The PDR eyes of Non-IVR group had the highest vitreous VEGF and EPO levels (836.30 ± 899.50 pg/ml, 99.29 ± 27.77 mIU/ml, respectively) compared to the control group (10.98 ± 0.98 pg/ml and 18.96 ± 13.30 mIU/ml/ml). Both the VEGF and EPO levels in the IVR group (13.22 ± 2.72 pg/ml and 68.57 ± 41.47 mIU/ml) were significantly lower than the Non-IVR group (P = 0.004 and P = 0.04, respectively). Furthermore, no significant difference was observed for VEGF levels between the control and IVR groups (10.9 ± 0.98 pg/ml and 13.22 ± 2.72 pg/ml, respectively, P = 0.9). Yet the EPO level in the IVR group was significantly higher than that in the Non-diabetic group (68.57 ± 41.47 pg/ml and 18.96 ± 13.30 pg/ml, respectively, P = 0.001). The expressions of EPO, VEGF, and CD105 were significantly reduced in fluorescence immunostaining of FVMs in the IVR group compared with the Non-IVR group. The receiver operating characteristic (ROC) curve of the EPO and VEGF levels were 0.951 and 0.938 in the PDR group. Conclusion: Both of the VEGF and EPO level were significantly increased in PDR patients, which have equal diagnostic value in the prediction of PDR. IVR could reduce the EPO level, but not enough to the normal level.
Classification of Estrogen Receptor-Positive Breast Cancer Based on Immunogenomic Profiling and Validation at Single-Cell Resolution

Background: The aim of this paper was to identify an immunotherapy-sensitive subtype for estrogen receptor-positive breast cancer (ER+ BC) patients by exploring the relationship between cancer genetic programs and antitumor immunity via multidimensional genome-scale analyses. Methods: Multidimensional ER+ BC high-throughput data (raw count data) including gene expression profiles, copy number variation (CNV) data, single-nucleotide polymorphism mutation data, and relevant clinical information were downloaded from The Cancer Genome Atlas to explore an immune subtype sensitive to immunotherapy using the Consensus Cluster Plus algorithm based on multidimensional genome-scale analyses. One ArrayExpress dataset and eight Gene Expression Omnibus (GEO) datasets (GEO-meta dataset) as well as the Molecular Taxonomy of Breast Cancer International Consortium dataset were used as validation sets to confirm the findings regarding the immune profiles, mutational features, and survival outcomes of the three identified immune subtypes. Moreover, the development trajectory of ER+ BC patients from the single-cell resolution level was also explored. Results: Through comprehensive bioinformatics analysis, three immune subtypes of ER+ BC (C1, C2, and C3, designated the immune suppressive, activation, and neutral subtypes, respectively) were identified. C2 was associated with up-regulated immune cell signatures and immune checkpoint genes. Additionally, five tumor-related pathways (transforming growth factor, epithelial–mesenchymal transition, extracellular matrix, interferon-γ, and WNT signaling) tended to be more activated in C2 than in C1 and C3. Moreover, C2 was associated with a lower tumor mutation burden, a decreased neoantigen load, and fewer CNVs. Drug sensitivity analysis further showed that C2 may be more sensitive to immunosuppressive agents. Conclusion: C2 (the immune activation subtype) may be sensitive to immunotherapy, which provides new insights into effective treatment approaches for ER+ BC.
Prognostic Effect of Microenvironment Phenotype in Triple-Negative Breast Cancer: Biomarker Analysis of a Prospective Trial

Background: The microenvironment of triple-negative breast cancer (TNBC) can be divided into three clusters based on bioinformatics-based immunogenomic analysis: the “immune-desert” cluster, the “innate immune-inactivated” cluster, and the “immune-inflamed” cluster. The immune-inflamed cluster is considered as “hot tumor” while the other two are considered as “cold tumor”. Methods: To investigate the prognostic effect of microenvironment phenotypes on TNBC, we compared relapse-free survival (RFS) of different phenotypes in 100 patients with RNA sequencing-based expression data from the PATTERN trial (NCT01216111, published in JAMA Oncol 2020), which indicated a superior efficacy of adjuvant paclitaxel-plus-carboplatin regimen compared to the regimen of cyclophosphamide/epirubicin/fluorouracil followed by docetaxel for TNBC. We also analyzed the efficacy of the two regimens for different immune phenotypes to explore potential treatment strategies. Results: No significant difference in RFS was observed between the “hot tumor” and the “cold tumor” (hazard ratio [HR] = 0.68, 95% confidence interval [CI] 0.28–1.66, P = 0.40). However, the “hot tumor” subtype was associated with significantly longer RFS in node-positive patients (HR = 0.27, 95%CI 0.07–0.97, P = 0.03). Consistently, a similar trend to improved RFS of the “hot tumor” phenotype was detected in patients with stage pT2-3 tumors (HR = 0.29, 95%CI 0.06–1.30, P = 0.08). Furthermore, no significant difference in RFS between the two treatment arms was observed in patients with “hot tumor” (HR = 0.39, 95% CI 0.08–2.01, P = 0.24) or “cold tumor” (HR = 1.05, 95% CI 0.39–2.82, P = 0.92). Conclusion: The microenvironment phenotype in TNBC might have prognostic significance to patients with a high risk of recurrence. The association of the microenvironment phenotypes with the efficacy of adjuvant chemotherapy for TNBC remains to be further studied.