A panoptic segmentation dataset and deep-learning approach for explainable scoring of tumor-infiltrating lymphocytes.

Tumor-Infiltrating Lymphocytes (TILs) have strong prognostic and predictive value in breast cancer, but their visual assessment is subjective. To improve reproducibility, the International Immuno-oncology Working Group recently released recommendations for the computational assessment of TILs that build on visual scoring guidelines. However, existing resources do not adequately address these recommendations due to the lack of annotation datasets that enable joint, panoptic segmentation of tissue regions and cells. Moreover, existing deep-learning methods focus entirely on either tissue segmentation or cell nuclei detection, which complicates the process of TILs assessment by necessitating the use of multiple models and reconciling inconsistent predictions. We introduce PanopTILs, a region and cell-level annotation dataset containing 814,886 nuclei from 151 patients, openly accessible at: sites.google.com/view/panoptils . Using PanopTILs we developed MuTILs, a neural network optimized for assessing TILs in accordance with clinical recommendations. MuTILs is a concept bottleneck model designed to be interpretable and to encourage sensible predictions at multiple resolutions. Using a rigorous internal-external cross-validation procedure, MuTILs achieves an AUROC of 0.93 for lymphocyte detection and a DICE coefficient of 0.81 for tumor-associated stroma segmentation. Our computational score closely matched visual scores from 2 pathologists (Spearman R = 0.58-0.61, p < 0.001). Moreover, computational TILs scores had a higher prognostic value than visual scores, independent of TNM stage and patient age. In conclusion, we introduce a comprehensive open data resource and a modeling approach for detailed mapping of the breast tumor microenvironment.

Design, synthesis, and biological evaluation of novel discoidin domain receptor inhibitors for the treatment of lung adenocarcinoma and pulmonary fibrosis.

Discoidin domain receptors (DDR) play crucial roles in cell proliferation and differentiation. When DDRs are overexpressed, it has been associated with various diseases such as cancers, fibrotic disorders, and inflammation. This study aimed to expand on previous research by using a structure-based drug design approach to develop a series of new indole-urea derivatives as potent inhibitors of DDR1. Through biochemical analyses, it was found that these compounds effectively inhibited DDR1/2, with compound 7s demonstrating the highest activity against A549 cells (IC50 value of 1.84 µM) while maintaining selectivity for other kinases. In vivo studies showed that compound 7s exhibited stronger antitumor activity compared to dasatinib, without causing significant weight loss at a dose of 30 mg/kg. Further investigation revealed that compound 7s hindered the migration of A549 cells by targeting the ERK, Akt1, and EMT pathways. Additionally, cellular experiments demonstrated that compound 7s suppressed the activation of fibroblasts induced by TGF-ß1. In vivo experiments confirmed that compound 7s, at a dose of 30 mg/kg, effectively inhibited DDR1 activation, resulting in a reduction of lung injury and fibrosis induced by bleomycin. Overall, these findings highlight the potential of these novel DDR1 inhibitors as promising therapeutic candidates for the treatment of DDR-related diseases.

Visualizing intracellular membrane interactions and cell type-specific differentiation in ferroptosis and apoptosis with Boranil-Carbazole derivative.

Intracellular lipid systems play essential roles in various physiological functions and cell growth processes. However, our understanding of the intricate interactions within this system, especially between mitochondria and lipid droplets, is limited, particularly in the context of cancer cells' altered lipid metabolism. To address this, our study introduces an N-B-O BODIPY-hexylcarbazole derivative, named Cz-Boranil, that sets a new benchmark in visualizing these critical interactions. Cz-Boranil's unique capability lies in its ability to display distinct intracellular distribution patterns in both normal and cancer cells, offering nuanced cell type-specific differentiation. More impressively, this probe tracks the coordinated interactions of lipid droplets and mitochondria during the critical processes of ferroptosis and apoptosis. We believe that the innovative capabilities of Cz-Boranil will revolutionize our understanding of intracellular lipid interactions and prove pivotal in identifying and studying cancerous cells.

Revealing the amyloid ß-protein with zinc finger protein of micronucleus during Alzheimer's disease progress by a quaternary ammonium terpyridine probe.

Micronucleus (MN) is regarded as an abnormal structure in eukaryotic cells which can be used as a biomarker for genetic instability. However, direct observation of MN in living cells is rarely achieved due to the lack of probes that are capable of distinguishing nuclear- and MN-DNA. Herein, a water-soluble terpyridine organic small molecule (ABT) was designed and employed to recognize Zinc-finger protein (ZF) for imaging intracellular MN. The in vitro experiments suggested ABT has a high affinity towards ZF. Further live cell staining showed that ABT could selectively target MN in HeLa and NSC34 cells when combined with ZF. Importantly, we use ABT to uncover the correlation between neurotoxic amyloid ß-protein (Aß) and MN during Alzheimer's disease (AD) progression. Thus, this study provides profound insight into the relationship between Aß and genomic disorders, offering a deeper understanding for the diagnosis and treatment of AD.

Clothianidin loaded TA/Fe (III) controlled-release granules: improve pesticide bioavailability and alleviate oxidative stress.

Neonicotinoid insecticides have been widely used due to their excellent systemic activity and high insecticidal activity, but the problems of low utilization rate and environmental risk have attracted widespread attention. Controlled-release technology is an approach to realize the efficient utilization of pesticides and reduce environmental pressure. In this study, clothianidin (CLO) controlled-release granules (CLO@GR- TA (tannic acid)/Fe (III)) were prepared with TA/Fe (III) coordination chelate as the coating material. These granules exhibited the core-shell structure with 500-1200 µm of particle size, and had obvious release performance and hydrolysis behavior of coating materials. Pot experiments by root application showed that the CLO@GR-TA/Fe (III) showed balanced and lasting control efficacy to broad bean aphids. The plants have a stronger capacity for absorption and enrichment and a higher utilization rate of CLO for CLO@GR-TA/Fe (III), than those for 10% suspension concentrate (SC). One of the hydrolysates of coating materials, TA, a polyphenolic antioxidant, could improve the bioaccumulation amount and alleviating the oxidative stress response of CLO in plants. Our study illustrates that the controlled-release granules base on TA have efficient controlled-release properties and free radical scavenging performance that may eventually be used as pesticide carriers and antioxidants in the field of plant protection.

Exogenous salicylic acid alleviates the accumulation of pesticides and mitigates pesticide-induced oxidative stress in cucumber plants (Cucumis sativus L.).

Salicylic acid (SA) is an important signal molecule, regulating oxidative stress response in plants. In this study, we evaluated the influences of SA (1 mg L-1, 10 mg L-1 and 50 mg L-1) on the accumulation of clothianidin (CLO), dinotefuran (DFN) and difenoconazole (DFZ) (5 mg L-1) and pesticide-induced (CLO-10 mg L-1, DFN-20 mg L-1, and DFZ-10 mg L-1) oxidative stress in cucumber plants. Exogenous SA at 10 mg L-1 significantly reduced the half-lives of three pesticides in nutrient solution and prevented the accumulation of pesticides in roots and leaves. And the role of SA in reducing residues was related to the major accumulation sites of pesticides. By calculating the root concentration factor (RCF) and translocation factor (TF), we found that SA at 10 mg L-1 reduced the ability of roots to absorb pesticides and enhanced the translocation ability from roots to leaves. Roots exposed to high concentrations of three pesticides could reduce biomass, low chlorophyll content, increase the accumulation of reactive oxygen species (ROS) and proline, promote lipid peroxidation, and alter the activities of a range of antioxidant enzymes, respectively. Exogenous SA at low concentrations (1 mg L-1 and 10 mg L-1) significantly mitigated these negative effects. Hence, application of exogenous SA at 10 mg L-1 could effectively alleviate the accumulation of pesticides and induce stress tolerance in cucumber planting systems.

The data dimensionality reduction and bad data detection in the process of smart grid reconstruction through machine learning.

To detect false data injection attacks (FDIAs) in power grid reconstruction and solve the problem of high data dimension and bad abnormal data processing in the power system, thereby achieving safe and stable operation of the power grid system, this study introduces machine learning methods to explore the detection of FDIAs. First, through the utilization of the standard IEEE node system and the simulation of FDIAs under the condition of non-complete topology information, the construction of the attack data set is completed, and the MatPower tool is applied to simulate and analyze the data set. Second, based on the isolated Forest (iForest) abnormal score data processing algorithm combined with the Local Linear Embedding (LLE) data dimensionality reduction method, an algorithm for data feature extraction is constructed. Finally, based on the combination of the Convolutional Neural Network (CNN) and the Gated Recurrent Unit (GRU) network, an algorithm model for FDIAs detection is constructed. The results show that in the IEEE14-bus node and IEEE118-bus node systems, the overall distribution of the state estimated before and after the attack vector injection is consistent with the initial value. In the iFores algorithm, the number of iTree and the number of samples affect the extraction of abnormal score data. When the number of iTree n is determined to be 100, and the corresponding number of samples w is determined to be 10, the algorithm has the best detection effect. The FDIAs detection algorithm model based on CNN-GRU shows good detection effects under high attack intensity, with an accuracy rate of more than 95%, and its performance is better than other traditional detection algorithms. In this study, the bad data detection model based on deep learning has an active role in the realization of the safe and stable operation of the smart grid.

Exogenous salicylic acid mitigates the accumulation of some pesticides in cucumber seedlings under different cultivation methods.

Salicylic acid (SA) is a crucial signal molecule and phytohormone, regulating the biotic and abiotic stress responses as well as plant development. In this research, we comparatively examined the effects of exogenous SA on the behaviors of thiamethoxam (THIM), hymexazol (HMI) and chlorantraniliprole (CAP) in cucumber planting systems under soil pot and hydroponic cultivation. The cucumber seedlings were transplanted into soil or nutrient solution containing a target pesticide (1 mg/kg) or a target pesticide with SA (1 mg/kg) after the fourth leaf emerged. We examined the behaviors of pesticides both the SA treated and nontreated plants by analyzing cucumber root, stem and leaf samples taken on the 0-21 days following the root treatment. The root concentration factor (RCF), bioconcentration factor (BCF) and translocation factors (TFstem and TFleaf) were calculated for the comparison of the differences in the behaviors of pesticides. We found that the accumulation behaviors of pesticides in planting systems were related to the physicochemical properties of pesticides, exogenous SA and cultivation methods. Exogenous SA had a certain promoting effect on the degradation of pesticides in soil and nutrient solution, resulting in reduced half-lives. SA was able to block the accumulation of pesticides in roots and leaves and alleviated the accumulation ability of roots, the bioconcentration ability of plants, and the translocation ability from roots to leaves. Interestingly, SA had more distinct effects on the behaviors of pesticides under hydroponic experiments than under soil pot experiments. Furthermore, the behaviors of clothianidin (CLO), the main metabolite of THIM, were also assessed, indicating that THIM was mainly metabolized to CLO in leaves and stems, and SA facilitated this process. Our findings suggest that SA has a certain regulatory effect on the accumulation of pesticides in plants, and SA-blocked pesticide accumulation is practically rewarding for improving food safety.