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Additional file 1: Figure S1. Reporter gene assays validated the regulatory effect of the identified TF binding-disrupting SNPs. Figure S2. CTCF, RAD21, and SMC3 knockdown resulted in significant changes of CRHR1-IT1, DND1P1, LRRC37A4P, MAPT expression in SH-SY5Y cell lines, indicating that these genes are regulated by the CTCF, RAD21 and SMC3 TFs. Figure S3. Boxplots of the eQTL analyses in the LIBD and CMC brain eQTL datasets. Figure S4. AMT gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S5. ARL17A gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S6. DALRD3 gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S7. GPX1 gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S8. KAT8 gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S9. NCKIPSD gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S10. NUPL2 gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S11. P4HTM gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S12. PDLIM2 gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S13. STX4 gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Figure S14. WDR6 gene expression in single-cell dataset of developing human neocortex ( http://solo.bmap.ucla.edu/shiny/webapp/ ). Table S1. 44 PD index SNPs used in this study. Table S2. PCR primers used to construct DNA fragments for reporter gene assays. Table S3: shRNAs used to knockdown of TFs. Table S4: RT-qPCR primers used in this study. Table S6. Identification of 44 TF binding-disrupting SNPs from the 44 PD risk loci. Table S7. 15 TF binding-disrupting SNPs for reporter gene assays. Table S8. Summary of the reporter gene assays. Table S14. Identification of differentially expressed genes in the prefrontal cortex of PD patients using RNA-Seq.

Anti-roll hydraulically interconnected suspension (HIS) due to its roll-vibration stiffness and damping performance has been studied and applied in passenger vehicles, buses, and tri-axle straight ...

Distracted driving has become a major cause of road traffic accidents. There are generally four different types of distractions: manual, visual, auditory, and cognitive. Manual distractions are the most common. Previous studies have used physiological indicators, vehicle behavior parameters, or machine-visual features to support research. However, these technologies are not suitable for an in-vehicle environment. To address this need, this study examined a non-intrusive method for detecting in-transit manual distractions. Wrist kinematics data from 20 drivers were collected using wearable inertial measurement units (IMU) to detect four common gestures made while driving: dialing a hand-held cellular phone, adjusting the audio or climate controls, reaching for an object in the back seat, and maneuvering the steering wheel to stay in the lane. The study proposed a progressive classification model for gesture recognition, including two major time-based sequencing components and a Hidden Markov Model (HMM). Results show that the accuracy for detecting disturbances was 95.52%. The accuracy associated with recognizing manual distractions reached 96.63%, using the proposed model. The overall model has the advantages of being sensitive to perceptions of motion, effectively solving the problem of a fall-off in recognition performance due to excessive disturbances in motion samples.

Additional file 1: Figure S1. The flowchart of our quality control steps. Figure S2. The PCA results of the GSA group (831 cases and 1,700 controls). Figure S3. The PCA results of our samples (genotyped with ASA SNP array) and subjects from the 1000 Genome project (including CHB, CHS, JPT, CEU and YRI). Figure S4. The PCA results of our samples (genotyped with GSA SNP array) and subjects from the 1000 Genome project (including CHB, CHS, JPT, CEU and YRI). Figure S5. The Quantile-Quantile plots of our Han Chinese samples. Figure S6. The allelic frequency of rs57016637 in global populations from the 1000 Genome project. Figure S7. The Manhattan plot of meta-analysis result of our Han Chinese samples and East Asian samples (26,271 cases and 40,071 controls). Figure S8. The locuszoom plot of rs3845188 (P = 6.50 × 10-8, OR = 0.91). Figure S9. Tissue and cell-type enrichment results. Table S1. The detail association result of the new genome wide significant loci identified in this study in different meta-analysis datasets. Table S2. Genes associated with the 17 newly identified lead SNPs in the human brain tissues. Table S3. Expression analysis of the potential eQTL target genes (of the newly identified lead SNPs) in schizophrenia cases and controls. Table S4. The MAGMA gene set enrichment analysis result (items with FDR < 0.10 were listed). Table S5. The TWAS result. Significant genes (after Bonferroni correction) were listed.

Photoactivatable fluorescent probes are ideal tools for organelle study with a significant advantage of high spatiotemporal resolution., Photoactivatable fluorescent probes are ideal tools for organelle study with a significant advantage of high spatiotemporal resolution. However, conventional photo-caged fluorophores for organelle-specific imaging suffer from several drawbacks, such as aggregation-caused quenching (ACQ), instability under ambient light, low photoactivation efficiency, and toxic photo-cleavage byproducts. Herein, we propose a strategy for in situ generation of photoactivatable aggregation-induced emission (AIE) probes of 2-(2-hydroxyphenyl)-benzothiazolines from easily available disulfide and thiol substrates through tandem S–S bond reduction and intramolecular cyclization reaction. Because the photoactivatable AIE probes can be in situ generated in a quantitative yield, they can be directly used for bio-imaging without complicated separation steps. Under both one- and NIR two-photon irradiation, excellent spatiotemporal resolution and high photoactivation efficiency were achieved for specific imaging of lipid droplets and lysosomes, respectively. Based on their in situ generation and adjustable organelle-targeting ability, the photoactivatable AIE probes could become an easy-to-use imaging tool in the study of the biological functions of organelles.

PIP–TPE’s fluorescence turns on blue due to the large viscosity of lysosomes which restricts intramolecular motions but it red-shifts in the bulk., Lysosomes are involved in a multitude of cellular processes and their dysfunction is associated with various diseases. They are the most acidic organelles (pH 3.8–6.6, size 0.1–1.2 μm) with the highest viscosity (47–190 cP at 25 °C) in the cell. Because of their acidity, pH dependent non-AIE active fluorescent lysosomal probes have been developed that rely on protonation inhibited photoinduced electron transfer (PET). In this work, an acidic pH independent lysosome targetable piperazine–TPE (PIP–TPE) AIEgen has been designed with unique photophysical properties making it a suitable probe for quantifying viscosity. In a non-aggregated state PIP–TPE shows deep-blue emission as opposed to its yellowish-green emission in the bulk. It possesses high specificity for lysosomes with negligible cytotoxicity and good tracing ability due to its better photostability compared to LysoTracker Red. In contrast to most known lysosome probes that rely solely on PET, restriction of intramolecular motion (RIM) due to the larger viscosity inside the lysosomes is the mechanism responsible for PIP–TPE’s fluorescence. PIP–TPE’s high selectivity is attributed to its unique molecular design that features piperazine fragments providing a perfect balance between lipophilicity and polarity.

Photoactivatable probes for lipid droplets (LDs)-specific live-cell imaging are powerful tools for investigating their biological functions through precise spatial and temporal control., Photoactivatable probes for lipid droplets (LDs)-specific live-cell imaging are powerful tools for investigating their biological functions through precise spatial and temporal control. Ideal photoactivatable probes for LDs imaging require high concentration accumulation of fluorophores in LDs, simple synthetic procedures, and excellent photoactivation efficiency. However, it is difficult to overcome these challenges by conventional fluorophores due to aggregation-caused quenching (ACQ). In this study, a new class of photoactivatable and LDs-specific fluorescent probes was developed based on dihydro-2-azafluorenones, which can easily undergo photooxidative dehydrogenation reaction to afford 2-azafluorenones with aggregation-induced emission (AIE) properties. Dihydro-2-azafluorenones as photoactivatable and LDs-specific probes display significant advantages of excellent photoactivation efficiency and lack of self-quenching in the aggregated state, and are expected to have broad applications in study of biological functions of LDs' through light-controlled spatiotemporal imaging.

Qian Mu,1,2,* Miao Jiang,1,* Yuzhu Zhang,1 Fei Wu,1 Hui Li,1 Wen Zhang,1 Fang Wang,1 Jiang Liu,1 Liang Li,1 Dongshan Wang,3 Wenjuan Wang,1 Shiwu Li,1 Haibo Song,4 Dongqi Tang1 1Gene and Immunotherapy Center, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Health Management Center, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 4Central Research Laboratory, Zibo Maternal and Child Health Hospital, Affiliated to Shandong Academy of Medical Science, Zibo, People’s Republic of China *These authors contributed equally to this work Background: CD19-chimericantigen receptor (CAR) modified T cells (CD19-CAR T cells) have been well documented to possess potent anti-tumor properties against CD19-expressingleukemia cells. As a traditional medicine, metformin has been widely used to treat type II diabetes mellitus and more recently has become a candidate for the treatment of cancer. However, no report has revealed the direct effect of metformin on CD19-CAR T cell biological function and its underling mechanisms. Purpose: The purpose of this research was to explore the effect of metformin on CD19-CAR T cell biological function and the mechanisms involved. Methods: CD19-CAR T cells proliferation, apoptosis and cytotoxicity were mainly tested by CCK-8 assay, flow cytometry and ELISA. The detection of mechanism primarily used western blot. Bioluminescence imaging is the main application technology of animal studies. Results: In the current study, it was found that metformin inhibited CD19-CAR T cell proliferation and cytotoxicity and induced apoptosis. Furthermore, our study revealed that metformin activated AMPK and suppressed mTOR and HIF1α expression. By using an AMPK inhibitor, compound C, we demonstrated the crucial roles of AMPK in CD19-CAR T cells when they were treated with metformin. Finally, we verified that metformin suppressed the cytotoxicity of CD19-CAR T cell in vivo. Conclusion: Taken together, these results indicated that metformin may play an important role in modulating CD19-CAR T cell biological functions in an AMPK-dependent and mTOR/HIF1α-independent manner. Keywords: Chimeric antigen receptor, metformin, proliferation, apoptosis, cytotoxicity, AMPK