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Lead is a widespread environmental hazard that can adversely affect multiple biological functions. Blood cells are the initial targets that face lead exposure. However, a systematic assessment of lead dynamics in blood cells at single-cell resolution is still absent. Herein, C57BL/6 mice were fed with lead-contaminated food. Peripheral blood was harvested at different days. Extracted red blood cells and leukocytes were stained with 19 metal-conjugated antibodies and analyzed by mass cytometry. We quantified the time-lapse lead levels in 12 major blood cell subpopulations and established the distribution of lead heterogeneity. Our results show that the lead levels in all major blood cell subtypes follow lognormal distributions but with distinctively individual skewness. The lognormal distribution suggests a multiplicative accumulation of lead with stochastic turnover of cells, which allows us to estimate the lead lifespan of different blood cell populations by calculating the distribution skewness. These findings suggest that lead accumulation by single blood cells follows a stochastic multiplicative process.

With the growing popularity of artificial intelligence in drug discovery, many deep-learning technologies have been used to automatically predict unknown drug-target interactions (DTIs). A unique challenge in using these technologies to predict DTI is fully exploiting the knowledge diversity across different interaction types, such as drug-drug, drug-target, drug-enzyme, drug-path, and drug-structure types. Unfortunately, existing methods tend to learn the specifical knowledge on each interaction type and they usually ignore the knowledge diversity across different interaction types. Therefore, we propose a multitype perception method (MPM) for DTI prediction by exploiting knowledge diversity across different link types. The method consists of two main components: a type perceptor and a multitype predictor. The type perceptor learns distinguished edge representations by retaining the specifical features across different interaction types; this maximizes the prediction performance for each interaction type. The multitype predictor calculates the type similarity between the type perceptor and predicted interactions, and the domain gate module is reconstructed to assign an adaptive weight to each type perceptor. Extensive experiments demonstrate that our proposed MPM outperforms the state-of-the-art methods in DTI prediction.

Background: Minimally invasive liver resection of the posterosuperior region is considered a challenging procedure due to poor exposure and difficult bleeding control. A robotic approach is supposed to be advantageous in posterosuperior segmentectomy. Its benefits over laparoscopic liver resection (LLR) remain undetermined. This study compared robotic liver resection (RLR) and LLR in the posterosuperior region performed by a single surgeon. Materials and methods: We retrospectively analyzed consecutive RLR and LLR performed by a single surgeon between December 2020 and March 2022. Patient characteristics and perioperative variables were compared. A 1:1 propensity score matched (PSM) analysis was performed between both groups. Results: The analysis included 48 RLR and 57 LLR procedures in the posterosuperior region. After PSM analysis, 41 cases of both groups were retained. In pre-PSM cohort, the operative time in the RLR group was significantly shorter than in the LLR group (160 vs. 208 min, P= 0.001), especially in radical resection of malignant tumors (176 vs. 231 min, P= 0.004). The total Pringle maneuver duration was also markedly shorter (40 vs. 51 min, P= 0.047), and the estimated blood loss in the RLR group was lower (92 vs. 150 mL, P= 0.005). The postoperative hospital stay (POHS) in the RLR group was significantly shorter (5.4 vs. 7.5 days, P= 0.048). In PSM cohort, operative time in the RLR group was also significantly shorter (163 vs. 193 min, P= 0.036), and the estimated blood loss was lower (92 vs. 144 mL, P= 0.024). However, the total Pringle maneuver duration and POHS showed no significant difference. The complications were similar between two groups in both pre-PSM and PSM cohorts. Conclusion: RLR in the posterosuperior region was as safe and feasible as LLR. RLR was associated with reduced operative time and blood loss than LLR.

The benefit of combined treatment with intravenous thrombolysis before endovascular thrombectomy in patients with acute ischaemic stroke caused by large vessel occlusion remains unclear. We hypothesised that the clinical outcomes of patients with stroke with large vessel occlusion treated with direct endovascular thrombectomy within 4·5 h would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before endovascular thrombectomy).

Mass cytometry (CyTOF) is a critical cell profiling tool in acquiring multiparameter proteome data at the single-cell level. A major challenge in CyTOF analysis is sample-to-sample variance arising from the pipetting process, staining variation, and instrument sensitivity. To reduce such variations, cell barcoding strategies that enable the combination of individual samples prior to antibody staining and data acquisition on CyTOF are often utilized. The most prevalent barcoding strategy is based on a binary scheme that cross-examines the existence or nonexistence of certain mass signals; however, it is limited by low barcoding efficiency and high cost, especially for large sample size. Herein, we present a novel barcoding method for CyTOF application based on mass ratiometry. Different mass tags with specific fixed ratios are used to label CD45 antibody to achieve sample barcoding. The presented method exponentially increases the number of possible barcoded samples with the same amount of mass tags compared with conventional methods. It also reduces the overall time for the labeling process to 40 min and avoids the need for expensive commercial barcoding buffer reagents. Moreover, unlike the conventional barcoding process, this strategy does not pre-permeabilize cells before the barcoding procedure, which offers additional benefits in preserving surface biomarker signals.

Mass cytometry (CyTOF) is a critical cell profiling tool in acquiring multiparameter proteome data at the single-cell level. A major challenge in CyTOF analysis is sample-to-sample variance arising from the pipetting process, staining variation, and instrument sensitivity. To reduce such variations, cell barcoding strategies that enable the combination of individual samples prior to antibody staining and data acquisition on CyTOF are often utilized. The most prevalent barcoding strategy is based on a binary scheme that cross-examines the existence or nonexistence of certain mass signals; however, it is limited by low barcoding efficiency and high cost, especially for large sample size. Herein, we present a novel barcoding method for CyTOF application based on mass ratiometry. Different mass tags with specific fixed ratios are used to label CD45 antibody to achieve sample barcoding. The presented method exponentially increases the number of possible barcoded samples with the same amount of mass tags compared with conventional methods. It also reduces the overall time for the labeling process to 40 min and avoids the need for expensive commercial barcoding buffer reagents. Moreover, unlike the conventional barcoding process, this strategy does not pre-permeabilize cells before the barcoding procedure, which offers additional benefits in preserving surface biomarker signals.

Phenanthrenequinone (PQ) doped poly(methyl methacrylate) (PMMA) has been proven to be available material for volume polarization holographic recording. In our work, we introduced benzyl methacrylate (BzMA) into the PQ/PMMA to increase the concentration of PQ (up to 1.15 wt%) within the polymeric media. The enhancement of concentration of PQ brings a mean for improving performance of material. Compared with the pure PQ/PMMA, photoinduced birefringence and diffraction intensity were multiplied by introducing BzMA. This investigation can provide a significant foundation for improving polarization holographic characteristics of PQ/PMMA by modifying the chemical composition of the material.In our work, we introduced benzyl methacrylate (BzMA) into PQ/PMMA to increase the concentration of PQ (up to 1.15 wt%) within the polymeric media. The enhancement of concentration of PQ brings a means for improving performance of material. This is an efficient method to improve polarization holographic characteristics of PQ/PMMA.

Faithful reconstruction, the polarization state of the diffraction wave being identical to that of the signal wave, is the primary target in polarization holography. With the large crossing angle between signal and reference wave, namely, nonparaxial approximation, attaining a balance between intensity and polarization grating is generally known as a prerequisite for faithful reconstruction. However, obtaining such a balance point within polarization-sensitive material has long been known as a challenging job, due to its extremely strict exposure condition. In this paper, we report on a smart method with the well-designed reference and reading wave to faithfully reconstruct the signal wave at an arbitrary exposure energy. Moreover, when the signal is circularly polarized, the diffraction efficiency can be precisely manipulated by changing the reading wave’s polarization state, which is favorable for optical storage and functional diffractive optical elements.

We report on dual-channel recording within polarization holography written by orthogonal linear polarization waves. The null reconstruction effect (NRE) of linear polarization holography was experimentally achieved at a large cross-angle of π/2 inside the polarization-sensitive media. Based on the NRE, two polarization encoded holograms were recorded in a dual-channel recording system with negligible inter-channel crosstalk. The two polarization multiplexed holograms could then be sequentially or simultaneously readout by shifting the polarization state of reference wave with the best signal-to-noise of 18:1 obtained within the experiment.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro.Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivoand sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.

The blood–testis barrier (BTB) and apical ectoplasmic specialization (ES), which are synchronized through the crosstalk of Sertoli cells and Sertoli germ cells, are required for spermatogenesis and sperm release. Here, we show that Wnt5a, a noncanonical Wnt signaling pathway ligand, is predominately expressed in both the BTB and apical ES and has a specific expression pattern during the seminiferous epithelium cycle. We employed siRNA to knockdown Wnt5a expression in testis and Sertoli cells, and then identified elongated spermatids that lost their polarity and were embedded in the seminiferous epithelium. Moreover, phagosomes were found near the tubule lumen. These defects were due to BTB and apical ES disruption. We also verified that the expression level and/or location of BTB-associated proteins, actin binding proteins (ABPs), and F-actin was changed after Wnt5a knockdown in vivo and in vitro. Additionally, we demonstrated that Wnt5a regulated actin dynamics through Ror2-mediated mTORC1 and mTORC2. This study clarified the molecular mechanism of Wnt5a in Sertoli cell junctions through the planar cell polarity (PCP) signaling pathway. Our findings could provide an experimental basis for the clinical diagnosis and treatment of male infertility caused by Sertoli cell junction impairment.

Novel composite materials are synthesized by incorporating N-acryloylmorpholine (ACMO) in highly concentrated phenanthrenequinone (PQ) doped poly(methyl methacrylate) (PMMA). The photosensitizer concentration of PQ was increased from 0.7 wt. % to 1.8 wt. %. The doping of ACMO component results in a higher diffraction efficiency and photosensitivity than a typical PQ/PMMA system. The enhanced performance of the material may stem from the ACMO molecules, which might open a new route for improving the holographic performance of the PQ/PMMA photopolymer.