zDHHC20-driven S-palmitoylation of CD80 is required for its costimulatory function.

CD80 is a transmembrane glycoprotein belonging to the B7 family, which has emerged as a crucial molecule in T cell modulation via the CD28 or CTLA4 axes. CD80-involved regulation of immune balance is a finely tuned process and it is important to elucidate the underlying mechanism for regulating CD80 function. In this study we investigated the post-translational modification of CD80 and its biological relevance. By using a metabolic labeling strategy, we found that CD80 was S-palmitoylated on multiple cysteine residues (Cys261/262/266/271) in both the transmembrane and the cytoplasmic regions. We further identified zDHHC20 as a bona fide palmitoyl-transferase determining the S-palmitoylation level of CD80. We demonstrated that S-palmitoylation protected CD80 protein from ubiquitination degradation, regulating the protein stability, and ensured its accurate plasma membrane localization. The palmitoylation-deficient mutant (4CS) CD80 disrupted these functions, ultimately resulting in the loss of its costimulatory function upon T cell activation. Taken together, our results describe a new post-translational modification of CD80 by S-palmitoylation as a novel mechanism for the regulation of CD80 upon T cell activation.

Malignant arrhythmias detection using a synthesis-by-analysis modeling method of arterial blood pressure signal.

Extreme bradycardia, extreme tachycardia, ventricular flutter fib, and ventricular tachycardia are four malignant arrhythmias (MAs) that lead to sudden cardiac death. It is very important to detect them in daily life. The arterial blood pressure (ABP) signal contains abundant pathological information about four MAs and is easy to be recorded under domestic conditions. Thus, a synthesis-by-analysis (SA) modeling method for ABP signal was proposed to detect the four MAs in this study. The average models of MAs and healthy subjects were obtained by SA modeling, and the change of each ABP wave was quantitively described by twelve parameters of wave models. Then, the probabilistic neural network (PNN) and random forest (RF) are trained to detect the MAs. The experimental data were employed from Fantasia and the 2015 PhysioNet/CinC Challenge databases. The SA modeling results show that some pathological and physiological changes could be extracted from the average models. The two-sample ks-test results between different groups are markedly different (h = 1, p < 0.05). The detection results show that the performances of PPN classifiers are less than that of RF. The kappa coefficients (KC) for the RF classifiers are 97.167 ± 1.46 %, 97.888 ± 0.808 %, 99.895 ± 0.545 %, 98.575 ± 1.683 % and 92.241 ± 1.517 %, respectively. The mean KC is 97.083 ± 0.67 %. Compared to the performance of some existing studies, the proposed method has better performance and is potential to diagnose MAs in m-health.

Digestion characteristics of polysaccharides from Gracilaria lemaneiformis and its interaction with the human gut microbiota.

The health effects of polysaccharides have attracted lots of attention, but the exact mechanism remains unclear. This study indicated that polysaccharides from Gracilaria lemaneiformis (GLPs) tolerated the conditions of mouth, stomach, and small intestine, and it reached the colon integrally, where it increased the production of short chain fatty acids, altered the gut microbiota, and especially increased the level of Bacteroides. To explore the underlying mechanism, hundreds of Bacteroides strains were isolated from the human feces and identified by MALDI-TOF/MS. It showed that Bacteroides species profile was different between individuals, revealing an inherent difference in the human gut microbiota. The use of Bacteroides on GLPs was species-dependent, and various small molecular GLPs fragments can be liberated from growth of Bacteroides species. On the other hand, Bacteroides species that unable to grow with GLPs can live in GLPs-derived fragments, forming a GLPs utilization network. It should be noted that small molecular GLPs fragments can be easier to be metabolized by intestinal microbes and have better effect on cellular response. It suggested that the effect of polysaccharides cannot only be attributed to modulation of the gut microbiota, but also associated with the effect of microbial degradation on GLPs own activities.

HEDGEHOG/GLI Modulates the PRR11-SKA2 Bidirectional Transcription Unit in Lung Squamous Cell Carcinomas.

We previously demonstrated that proline-rich protein 11 (PRR11) and spindle and kinetochore associated 2 (SKA2) constituted a head-to-head gene pair driven by a prototypical bidirectional promoter. This gene pair synergistically promoted the development of non-small cell lung cancer. However, the signaling pathways leading to the ectopic expression of this gene pair remains obscure. In the present study, we first analyzed the lung squamous cell carcinoma (LSCC) relevant RNA sequencing data from The Cancer Genome Atlas (TCGA) database using the correlation analysis of gene expression and gene set enrichment analysis (GSEA), which revealed that the PRR11-SKA2 correlated gene list highly resembled the Hedgehog (Hh) pathway activation-related gene set. Subsequently, GLI1/2 inhibitor GANT-61 or GLI1/2-siRNA inhibited the Hh pathway of LSCC cells, concomitantly decreasing the expression levels of PRR11 and SKA2. Furthermore, the mRNA expression profile of LSCC cells treated with GANT-61 was detected using RNA sequencing, displaying 397 differentially expressed genes (203 upregulated genes and 194 downregulated genes). Out of them, one gene set, including BIRC5, NCAPG, CCNB2, and BUB1, was involved in cell division and interacted with both PRR11 and SKA2. These genes were verified as the downregulated genes via RT-PCR and their high expression significantly correlated with the shorter overall survival of LSCC patients. Taken together, our results indicate that GLI1/2 mediates the expression of the PRR11-SKA2-centric gene set that serves as an unfavorable prognostic indicator for LSCC patients, potentializing new combinatorial diagnostic and therapeutic strategies in LSCC.

99mTc-conjugated manganese-based mesoporous silica nanoparticles for SPECT, pH-responsive MRI and anti-cancer drug delivery.

In recent decades, hybrid imaging techniques that exploit the advantages of multiple imaging technologies have aroused extensive attention due to the deficiencies of single imaging modes. Along with the development of single photon emission computed tomography-magnetic resonance imaging (SPECT-MRI), it is currently necessary to develop a series of dual probes that can combine the outstanding sensitivity of SPECT with the high spatial resolution of MRI. Herein, the commonly used technetium-99 (99mTc) was labelled on the surface of manganese oxide-based mesoporous silica nanoparticles (MnOx-MSNs) for use in SPECT-MRI dual-modal imaging. The radiolabelling yield was as high as 99.1 ± 0.6%, and the r1 value of the nanoprobes was able to reach 6.60 mM-1 s-1 due to the pH-responsive properties of the MnOx-MSNs. The high-performance SPECT-MRI dual-modal imaging was confirmed in vivo in tumour-bearing mice, which could also provide semi-quantitative information for tumour detection. Importantly, these nanoprobes can deliver anti-cancer drugs in cancer therapy due to their unique mesoporous structures. Thus, nanotheranostics combining dual-modal imaging with anti-cancer therapeutic properties were achieved.