Poricoic acid A (PAA) inhibits T-cell acute lymphoblastic leukemia through inducing autophagic cell death and ferroptosis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with poor clinical outcome. Poricoic acid A (PAA) is the main chemical constituent on the surface layer of the mushroom Poria cocos, and exerts protective effects against various diseases. In the study, its effects on T-ALL progression were investigated both in vitro and in vivo. Our results showed that PAA strongly reduced the cell viability of T-ALL cell lines, and induced cell G2 cycle arrest and apoptosis in vitro. Mitochondrial dysfunction was also elevated by PAA, along with enhanced cellular reactive oxygen species (ROS) production. Importantly, PAA-suppressed cell viability and -triggered apoptosis were ROS-dependent. Additionally, autophagy was significantly induced by PAA in T-ALL cells through regulating AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and LC3 signaling pathways. PAA treatments also provoked ferroptosis in T-ALL cells with reduced glutathione (GSH) levels and elevated malonaldehyde (MDA) contents. Suppressing autophagy and ferroptosis almost abrogated the capacity of PAA to restrain T-ALL proliferation and growth. The effects of PAA to suppress T-ALL tumor growth were also confirmed in vivo with undetectable toxicity. Therefore, the present study highlighted the potential of PAA for T-ALL treatment mainly through inducing autophagic cell death and ferroptosis.

Nowhere to Hide: Online Rumor Detection Based on Retweeting Graph Neural Networks.

Online rumor detection is crucial for a healthier online environment. Traditional methods mainly rely on content understanding. However, these contents can be easily adjusted to avoid such supervision and are insufficient to improve the detection result. Compared with the content, information propagation patterns are more informative to support further performance promotion. Unfortunately, learning the propagation patterns is difficult, since the retweeting tree is more topologically complicated than linear sequences or binary trees. In light of this, we propose a novel rumor detection framework based on structure-aware retweeting graph neural networks. To capture the propagation patterns, we first design a novel conversion method to transform the complex retweeting tree as more tractable binary tree without losing the reconstruction information. Then, we serialize the retweeting tree as a corpus of meta-tree paths, where each meta-tree can preserve a basic substructure. A deep neural network is then designed to integrate all meta-trees and to generate the global structural embeddings. Furthermore, we propose to integrate content, users, and propagation patterns to enhance more reliable performance. To this end, we propose a novel self-attention-based retweeting neural network to learn individual features from both content and users. We then fuse the node-level features with our global structural embeddings via a mutual attention unit. In this way, we can generate more comprehensive representations for rumor detection. Extensive evaluations on two real-world datasets show remarkable superiorities of our model compared with existing methods.

Significance changes in the levels of myocardial enzyme in the child patients with Mycoplasma Pneumoniae Pneumonia.

Mycoplasma is a gram-negative with thin wall bacterium that in humans, Mycoplasma pneumoniae causes pneumonia. This experiment was designed to explore the changes of myocardial enzymes in the mycoplasma pneumoniae pneumonia (MPP) child patients, and analyze the clinical value of these changes, in combination with the relevant indicators, symptoms and signs, in the evaluation of the pneumonia mycoplasma infection. For this aim, a total of 120 child patients with MPP in the acute phase,120 child patients with MPP in the recovery phase and 120 healthy children were simultaneously enrolled into this study to detect the levels of aspartate aminotransferase (AST), creatine kinase (CK), Creatine Kinase Isoenzyme (CK-MB) and lactic dehydrogenase (LDH) in blood. Results showed that MPP patients in the acute phase had higher levels of LDH, CK, CK-MB, AST, PCt, CRP, MPV, PDW, PCt, percentage of neutrophils, WBC count in the peripheral blood and ESR than those of the patients in the recovery patients and healthy children, while the level of PLT was lower (all P<0.05). In the acute phase, the level of CK-MB correlated to the fever, fever duration, extrapulmonary organ damage (except for the myocardial damage) and the antibody titer of MP (all P<0.05). It was concluded that in the acute phase of MMP, the level of CK-MB could not only reflect the myocardial damage readily but also the infection of MP as well as the resultant inflammation and disease progression, which could effectively guide the diagnosis and treatment of MPP.

SOX21-AS1 is associated with clinical stage and regulates cell proliferation in nephroblastoma.

LncRNA SOX21 antisense RNA 1 (SOX21-AS1) dysregulated in many types of human cancer, and functioned as tumor suppressor or promoter depending on tumor types. However, there was no report about the role of SOX21-AS1 in nephroblastoma. In the present study, we first found that SOX21-AS1 expression was elevated in nephroblastoma tissues and cell lines compared with adjacent normal tissues and normal human embryonic kidney cell line, respectively. Moreover, we observed nephroblastoma patients with large tumor size, advanced National Wilms Tumor Study (NWTS) stage or unfavorable histopathological type, and patients that had higher SOX21-AS1 expression levels than nephroblastoma patients with small tumor size, early NWTS stage or favorable histopathological type. The in vitro studies suggested that knockdown of SOX21-AS1 suppressed nephroblastoma cell proliferation and colony formation, and induced cell-cycle arrest through up-regulating p57 expression. In conclusion, our study suggests that SOX21-AS1 functions as oncogenic lncRNA in nephroblastoma, which may provide a novel insight for nephroblastoma carcinogenesis.

Molecular design of sequence-minimized, structure-optimized, and hydrocarbon-stapled helix-helix interactions in the trimer-of-hairpins motif of pediatric pneumonia RSV-F protein.

The respiratory syncytial virus fusion (RSV-F) protein is a primary target for vaccine and drug development against respiratory infection and pediatric pneumonia. The RSV-F core forms a trimer-of-hairpins (TOH) motif in postfusion conformation, which is characterized by a six-helix bundle (6HB) where the three N-terminal HRn helices define a central coiled-coil, while three C-terminal HRc helices pack on the coiled-coil surface in an antiparallel manner. Here, one tightly packed HRn-HRc helix-helix interaction is stripped from the 6HB, which represents the minimum unit of RSV-F TOH motif. The helix-helix interaction sequence can be truncated to derive a core binding region (CBR) that covers intense nonbonded interactions across the interaction interface. Dynamics simulation and energetics analysis reveal that the CBR HRc peptide has a large flexibility and intrinsic disorder in unbound free state, which would incur a considerable entropy penalty upon its binding to CBR NRn peptide. Two strategies are described to constrain the HRc peptide conformation. First, the four non-interfacial residues of HRc peptide are artificially substituted with new amino acid combinations of high helical propensity and, second, the helical conformation of wild-type and mutant HRc peptides is stabilized by adding an all-hydrocarbon bridge across two spatially vicinal, non-interfacial residues 503 (i) and 507 (i + 4). Free energy calculation and fluorescence-based assay confirm that the substitution and stapling can effectively improve the binding affinity of CBR HRn-HRc interaction.

Effect of calcium channels blockers and inhibitors of the renin-angiotensin system on renal outcomes and mortality in patients suffering from chronic kidney disease: systematic review and meta-analysis.

BACKGROUND: The renoprotective effect of inhibitors of renin-angiotensin system (RAS) has been identified through placebo-controlled trials. However, the effect of calcium-channel blockers (CCBs) on renal system is still controversial. Our current meta-analysis includes available evidences to compare the effect of dihydropyridine CCBs and ACEIs or ARBs on renal outcomes and mortality. We also further investigate whether CCBs can be used in combination with inhibitors of RAS to improve the prognosis of patients with chronic kidney disease (CKD). METHODS AND RESULTS: Electronic databases were searched up to July 2012, for clinical randomized controlled trials, assessing the effect of dihydropyridine CCBs on the incidence of end-stage renal disease (ESRD) and all-cause mortality in contrast to ACEIs or ARBs. Eight clinical trials were included containing 25,647 participants. ESRD showed significantly higher frequency with CCBs therapy compared with ACEIs or ARBs therapy, though blood pressure was decreased similarly in both groups in every trial (OR, 1.25; 95% CI, 1.05-1.48; p = 0.01). In contrast, there was no significant difference in the incidence of all-cause mortality between these two groups, though ACEIs or ARBs exhibited better renoprotective effect compared to CCBs (OR, 0.96; 95% CI, 0.89-1.03; p = 0.24). CONCLUSIONS: CCBs did not increase all-cause mortality incidence in patients with CKD though they displayed weaker renoprotective, compared to ACEIs or ARBs therapy. Our results suggest the combination of a CCB and an ACEI or ARB should be a preferable antihypertensive therapy in patients with CKD, considering their higher effect in decreasing blood pressure and fewer adverse metabolic problems caused.