Lung metastasis-Harnessed in-Situ adherent porous organic nanosponge-mediated antigen capture for A self-cascaded detained dendritic cells and T cell infiltration.

The infiltration of cytotoxic T lymphocytes promises to suppress the most irresistible metastatic tumor for immunotherapy, yet immune privilege and low immunogenic responses in these aggressive clusters often restrict lymphocyte recruitment. Here, an in situ adherent porous organic nanosponge (APON) doubles as organ selection agent and antigen captor to overcome immune privilege is developed. With selective organ targeting, the geometric effect of APON composed of disc catechol-functionalized covalent organic framework (COF) boosts the drug delivery to lung metastases. Along with a self-cascaded immune therapy, the therapeutic agents promote tumor release of damage-associated molecular patterns (DAMPs), and then, in situ deposition of gels to capture these antigens. Furthermore, APON with catechol analogs functions as a reservoir of antigens and delivers autologous DAMPs to detain dendritic cells, resulting in a sustained enhancement of immunity. This disc sponges (APON) at lung metastasis as antigen reservoirs and immune modulators effectively suppress the tumor in 60 days and enhanced the survival rate.

Exploring fNIRS-Based Brain State Recognition and Visualization through the use of Explainable Convolutional Neural Networks.

Functional near infrared spectroscopy (fNIRS) is a neuroimaging technique that has grown vigorously in recent years. With noticeable attention, machine learning methods have also been applied to fNIRS. However, the current approach lacks interpretability of the results. In recent years, the utilization and investigation of fNIRS have experienced significant growth and are now being utilized in clinical research. However, the collection of clinical fNIRS data is limited in sample size. Therefore, our aim is to utilize the collected fNIRS data from all channels and achieve interpretable analysis results with minimal human manipulation, channel selection or feature extraction. We developed an fNIRS-based interpretable model and used class-specific gradient information to visualize the biomarkers captured by the model via locating the important region. The accuracy of our model's classification was 6% higher than that of the conventional SVM method under within-subject classification. The model focuses on signals from the left brain in the classification of right-hand finger tapping task, while in the task of classifying left-handed movements, the model relies on signals from the right brain. These results were consistent with current understanding of physiology.Clinical Relevance- The machine learning-based fNIRS model has the potential to be used for the diagnosis and prediction of therapeutic efficacy in clinical settings.

Transcriptome-wide association study coupled with eQTL analysis reveals the genetic connection between gene expression and flowering time in Arabidopsis.

Genome-wide association study (GWAS) has improved our understanding of complex traits, but challenges exist in distinguishing causation versus association caused by linkage disequilibrium. Instead, transcriptome-wide association studies (TWAS) detect direct associations between expression levels and phenotypic variations, providing an opportunity to better prioritize candidate genes. To assess the feasibility of TWAS, we investigated the association between transcriptomes, genomes, and various traits in Arabidopsis, including flowering time. The associated genes formerly known to regulate growth allometry or metabolite production were first identified by TWAS. Next, for flowering time, six TWAS-newly identified genes were functionally validated. Analysis of the expression quantitative trait locus (eQTL) further revealed a trans-regulatory hotspot affecting the expression of several TWAS-identified genes. The hotspot covers the FRIGIDA (FRI) gene body, which possesses multiple haplotypes differentially affecting the expression of downstream genes, such as FLOWERING LOCUS C (FLC) and SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1). We also revealed multiple independent paths towards the loss of function of FRI in natural accessions. Altogether, this study demonstrates the potential of combining TWAS with eQTL analysis to identify important regulatory modules of FRI-FLC-SOC1 for quantitative traits in natural populations.

Preoperative CT parameters to predict tibiofibular syndesmosis injury associated with ankle fracture: a propensity score-matched analysis.

BACKGROUND: Untreated ankle fractures with concomitant tibiofibular syndesmosis injury often lead to postoperative pain and early traumatic arthritis. CT has advantages in the preoperative diagnosis of combined ankle injuries. However, a few studies have investigated the best preoperative CT parameters to predict tibiofibular syndesmosis injuries associated with ankle fractures. This study aimed to identify and evaluate the optimal preoperative CT parameters for predicting tibiofibular syndesmosis injuries associated with ankle fractures. METHODS: We retrospectively analyzed 129 patients who underwent preoperative CT of an ankle fracture treated between January 2016 and April 2022 at a tertiary A hospital. All patients underwent open reduction and internal fixation and intraoperative stability testing. Based on the Cotton test, the patients were divided into the stable group (n = 83, 64.3%) and unstable group (n = 46, 35.7%). After 1:1 propensity score matching, the general conditions, anterior tibiofibular distance (TFD), posterior TFD, maximum TFD, tibiofibular syndesmosis area, sagittal fracture angle, Angle-A, and Angle-B were compared between the stable and unstable groups. RESULTS: The propensity score-matched cohort comprised 82 patients. There were no significant differences between the stable and unstable groups in sex, age, affected side, operation interval, injury mechanism, Lauge-Hansen classification, sagittal fracture angle, and Angle-A (all P > 0.05). Compared with the stable group, the unstable group had a significantly greater aTFD, pTFD, maxTFD, and area (all P < 0.05). PTFD, maxTFD, and area were positively correlated with joint instability. Angle-B was smaller in the unstable group (57.13°) than the stable group (65.56°). ROC analysis showed that Area (AUC 0.711) and maxTFD (AUC 0.707) had the highest diagnostic efficacy. CONCLUSION: MaxTFD and Area were the best predictive parameters; a larger Area was associated with a higher likelihood of instability of the tibiofibular syndesmosis after ankle fracture fixation.

Programmed Catalytic Therapy-Mediated ROS Generation and T-Cell Infiltration in Lung Metastasis by a Dual Metal-Organic Framework (MOF) Nanoagent.

Nano-catalytic agents actuating Fenton-like reaction in cancer cells cause intratumoral generation of reactive oxygen species (ROS), allowing the potential for immune therapy of tumor metastasis via the recognition of tumor-associated antigens. However, the self-defense mechanism of cancer cells, known as autophagy, and unsustained ROS generation often restricts efficiency, lowering the immune attack, especially in invading metastatic clusters. Here, a functional core-shell metal-organic framework nanocube (dual MOF) doubling as a catalytic agent and T cell infiltration inducer that programs ROS and inhibits autophagy is reported. The dual MOF integrated a Prussian blue (PB)-coated iron (Fe2+)-containing metal-organic framework (MOF, MIL88) as a programmed peroxide mimic in the cancer cells, facilitating the sustained ROS generation. With the assistance of Chloroquine (CQ), the inhibition of autophagy through lysosomal deacidification breaks off the self-defense mechanism and further improves the cytotoxicity. The purpose of this material design was to inhibit autophagy and ROS efficacy of the tumor, and eventually improve T cell recruitment for immune therapy of lung metastasis. The margination and internalization-mediated cancer cell uptake improve the accumulation of dual MOF of metastatic tumors in vivo. The effective catalytic dual MOF integrated dysfunctional autophagy at the metastasis elicits the ~3-fold recruitment of T lymphocytes. Such synergy of T cell recruitment and ROS generation transported by dual MOF during the metastases successfully suppresses more than 90% of tumor foci in the lung.

S-Allylcysteine Ameliorates Aging Features via Regulating Mitochondrial Dynamics in Naturally Aged C57BL/6J Mice.

SCOPE: S-Allylcysteine (SAC) is the most abundant organosulfur molecule derived from aged garlic. The effects ofSAC on improving Aging in naturally aged C57BL/6J male mice and mitochondrial dynamics in Caenorhabditis elegans and its underlying mechanisms is evaluated. METHODS AND RESULTS: When mice have attained reproductive senescence at 60 weeks of age, SAC is supplemented to 0.05% and 0.2% into their normal diet for 12 weeks. The results show that SAC could significantly improve the level of hepatic optic atrophy 1 (OPA1) mRNA, which is a key factor for mitochondrial fusion, and consequently elevated the mitochondrial biogenesis-related proteins sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), thus ameliorating oxidative stress, such as malondialdehyde (MDA) in the liver and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine. Among the biochemical markers of aging, SAC significantly reduces liver galactosidase ß1 (GLB1) and senescence-associated ß-galactosidase (SA-ßgal), which are induced by replicative senescence. The mitochondria with green fluorescent protein (GFP)-tagged transgenic strain SJ4103 C. elegans is incubated with 5 or 50 µM SAC, and SAC treated groups maintain the linear morphology of mitochondria. CONCLUSION: SAC regulates mitochondrial dynamics and ameliorated aging to a significant degree. This study also confirms that mitochondrial dynamics are a promising target for screening materials to combat aging and as a direction for anti-aging product development.

Functional analysis of a nonsyndromic hearing loss-associated mutation in the transmembrane II domain of the GJC3 gene.

In a previous study, we identified a novel missense mutation, p.W77S, in the GJC3 gene encoding connexin30.2/connexin31.3 (CX30.2/CX31.3) from patients with hearing loss. The functional alteration of CX30.2/CX31.3 caused by the p.W77S mutant of GJC3 gene, however, remains unclear. In the current study, our result indicated that the p.W77 is localized at the second membrane-spanning segments (TM2) and near border of the E1 domain of the CX30.2/CX31.3 protein and highly conserved (Conseq score = 8~9) in all species. The p.W77S missense mutation proteins in the intracellular distribution are different CX30.2/CX31.3WT and an accumulation of the mutant protein in the endoplasmic reticulum (ER) of the HeLa cell. Furthermore, co-expression of WT and p.W77S mutant chimerae proteins showed that the heteromeric connexon accumulated in the cytoplasm, thereby impairing the WT proteins' expression in the cell membranes. In addition, we found that CX30.2/CX31.3W77S missense mutant proteins were degraded by lysosomes and proteosomes in the transfected HeLa cell. Based on these findings, we suggest that p.W77S mutant has a dominant negative effect on the formation and function of the gap junction. These results give a novel molecular elucidation for the mutation of GJC3 in the development of hearing loss.