Pressure-Induced Topological Phase Transition and Large Rashba Effect in Halide Double Perovskite.

In general, hydrostatic pressure can suppress ferroelectric polarization and further reduce Rashba spin-splitting, considering the spin-orbit coupling effect. Here, we present the design of ferroelectric double perovskite Cs2SnSiI6, which exhibits the anomalous enhancement of Rashba spin-splitting parameters by pressure-induced ferroelectric topological order. The Rashba effect is nonlinear with the decrease in polarization under pressure and reaches a maximum at the pressure-induced Weyl semimetal (WSM) state between the transition from a normal insulator (NI) to a topological insulator (TI). Furthermore, we discover that controlling ferroelectric polarization with an electric field can also induce the topological transition with a large Rashba spin-splitting but under a lower critical pressure. These discoveries show a tunable gaint Rashba effect and pressure-induced topological phase transition for Cs2SnSiI6, which can promote future research on the interaction between the Rashba effect and topological order, and its application to new electronic and spintronic devices.

Quantifying RNA structures and interactions with a unified reduced chain representation model.

RNA is a pivotal molecule that plays critical roles in various cellular processes. Quantifying RNA structures and interactions is essential to understanding RNA function and developing RNA-based therapeutics. Using a unified five-bead model and a non-redundant database, this paper investigates the structural features and interactions of five commonly occurring RNA motifs, i.e., double-stranded helices, hairpin loops, internal/bulge loops, multi-branched junctions, and single-stranded terminal tails. Analyzing detailed distributions of RNA local structural features and base-base interactions reveals a preference for helical structures in both local backbone structures and base orientations. The interactions between adjacent bases exhibit motif-specific and sequence-dependent characteristics, reflecting the distinct topological constraints imposed by different loop-helix connection modes and the varying pairing and stacking interactions among different sequences. These findings shed light on the stability of RNA helices, emphasizing their significance in providing dominant base pairing and stacking interactions for RNA structures and stability. The four non-helix motifs encompass unpaired nucleotide loops and exhibit diverse base-base interactions, contributing to the structural diversity observed in RNA. Overall, the complexity of RNA structure arises from the intricate interplay of base-base interactions.

Neural networks prediction of the protein-ligand binding affinity with circular fingerprints.

BACKGROUND: Protein-ligand binding affinity is of significant importance in structure-based drug design. Recently, the development of machine learning techniques has provided an efficient and accurate way to predict binding affinity. However, the prediction performance largely depends on how molecules are represented. OBJECTIVE: Different molecular descriptors are designed to capture different features. The study aims to identify the optimal circular fingerprints for predicting protein-ligand binding affinity with matched neural network architectures. METHODS: Extended-connectivity fingerprints (ECFP) and protein-ligand extended connectivity fingerprints (PLEC) encode circular atomic and bonding connectivity environments with the preference for intra- and inter-molecular features, respectively. Densely-connected neural networks are employed to map the circular fingerprints of protein-ligand complexes to binding affinitiesRESULTS:The performance of neural networks is sensitive to the parameters used for ECFP and PLEC fingerprints. The R2_score of the evaluated ECFP and PLEC fingerprints reaches 0.52 and 0.49, higher than that of the improperly set ECFP and PLEC fingerprints with R2_score of 0.45 and 0.38, respectively. Additionally, compared to the predictions from the standalone fingerprints, the ECFP+PLEC conjoint ones slightly improve the prediction accuracy with R2_score of approximately 0.55. CONCLUSION: Both intra- and inter-molecular structural features encoded in the circular fingerprints contribute to the protein-ligand binding affinity. Optimizing the parameters of ECFP and PLEC can enhance performance. The conjoint fingerprint scheme can be generally extended to other molecular descriptors for enhanced feature engineering and improved predictive performance.

cRNAsp12 Web Server for the Prediction of Circular RNA Secondary Structures and Stabilities.

Circular RNAs (circRNAs) are a novel class of non-coding RNA that, unlike linear RNAs, form a covalently closed loop without the 5' and 3' ends. Growing evidence shows that circular RNAs play important roles in life processes and have great potential implications in clinical and research fields. The accurate modeling of circRNAs structure and stability has far-reaching impact on our understanding of their functions and our ability to develop RNA-based therapeutics. The cRNAsp12 server offers a user-friendly web interface to predict circular RNA secondary structures and folding stabilities from the sequence. Through the helix-based landscape partitioning strategy, the server generates distinct ensembles of structures and predicts the minimal free energy structures for each ensemble with the recursive partition function calculation and backtracking algorithms. For structure predictions in the limited structural ensemble, the server also provides users with the option to set the structural constraints of forcing the base pairs and/or forcing the unpaired bases, such that only structures that meet the criteria are enumerated recursively.

Does the board's on-site decision inhibit over-investment.

It is an effective expansion of the research on the Board of Directors to do the research based on different board meeting forms and their effects sampling A-share companies listed in 2007-2017, the article empirically tests the impact of the times of board meetings, the proportion of on-site board meetings on listed companies' over-investment. Consequently and significantly, the times of board meetings is positively correlated with over-investment, while the proportion of on-site board meetings is negatively correlated with over-investment. That is, the on-site meeting for the Board decision-making will better inhibit the enterprises' over-investment behaviors. Further research shows that when there is a controlling shareholder in the company or in a dual position, the on-site board meeting no longer has a significant inhibitory effect on over-investment. By research on the independence of the Board of Directors, it is found that when selecting on-site board decision-making, the existence of independent directors has an over-investment suppression effect, and the higher the proportion of independent directors, the more obvious the inhibitory effect is. The samples are divided into state-owned enterprises and private enterprises, the study found that when choosing on-site board meetings, state-owned enterprises have a greater inhibitory effect on over-investment than private enterprises. The findings of this study will enrich the research of the board meeting and provide a new testing method for the relevant research of the Board of Directors.

Study on the Mechanism of Periplaneta americana Extract to Accelerate Wound Healing after Diabetic Anal Fistula Operation Based on Network Pharmacology.

OBJECTIVE: Using network pharmacology research methods to explore the healing mechanism of American cockroach extract to accelerate wound healing after diabetic anal fistula surgery. METHOD: The main chemical constituents of extracts from Periplaneta americana were collected by literature retrieval. Chemical composition and targets related to diabetic anal fistula wound could be predicted based on PubChem, Swiss Target Prediction, OMIM, and GeneCards databases, and the putative targets of Periplaneta americana extraction (PAE) for diabetic anal fistula wound were obtained by Venn diagram. These common targets were predicted using the String database for protein-protein interaction (PPI) network and then screening key genes through Cytohubba. Meanwhile, the above targets were analyzed using the DAVID database for gene ontology (GO) enrichment analyses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) path enrichment analyses. RESULTS: A total of 12 chemical components of PAE were obtained by literature retrieval, and 61 therapeutic targets that may accelerate the healing of diabetic anal fistula wounds were predicted by the database. According to PPI network analysis, PAE accelerates wound healing after diabetic anal fistula surgery which may be related to proteins such as AKT1, VEGFA, EGFR, CASP3, STAT3, MAPK1, TNF, JUN, ESR1, and MMP9. GO analysis results show that targets of PAE to promote wound healing were mainly involved in biological processes such as cell proliferation, macrophage differentiation, angiogenesis, and response to hypoxia. KEGG analysis showed that the target genes were mainly concentrated in the PI3K-Akt signaling pathway, HIF-1 signaling pathway, and estrogen signaling pathway. CONCLUSION: Periplaneta americana extract regulates multiple targets and multiple pathways to promote wound healing after diabetic anal fistula surgery. PI3K-Akt signaling pathway, HIF-1 signaling pathway, and sex hormone signaling pathway may be key pathways in the process of Periplaneta americana extract promoting wound healing.

Propagation of Pathological α-Synuclein from the Urogenital Tract to the Brain Initiates MSA-like Syndrome.

The neuropathological feature of multiple system atrophy (MSA), a fatal adult-onset disorder without effective therapy, is the accumulation of pathological α-synuclein (α-Syn) in the central nervous system (CNS). Here we show that pathological α-Syn exists in nerve terminals in detrusor and external urethral sphincter (EUS) of patients with MSA. Furthermore, α-Syn-preformed fibrils (PFFs) injected in the EUS or detrusor in TgM83+/- mice initiated the transmission of pathological α-Syn from the urogenital tract to brain via micturition reflex pathways, and these mice developed widespread phosphorylated α-Syn inclusion pathology together with phenotypes. In addition, urinary dysfunction and denervation-reinnervation of external anal sphincter were detected earlier in the mouse models with α-Syn PFFs inoculation before the behavioral manifestations. These results suggest that pathological α-Syn spreading through the micturition reflex pathways retrogradely from the urogenital tract to CNS may lead to urinary dysfunction in patients with MSA, which is different from the etiology of idiopathic Parkinson disease.

SMARCB1 Gene Mutation Predisposes to Earlier Development of Glioblastoma: A Case Report of Familial GBM.

Glioblastoma (GBM) is the most aggressive adult brain tumor. While GBM typically occurs sporadically, familial GBM can be associated with certain hereditary disorders and isolated familial GBMs in the absence of syndrome are rare. Relevant hereditary factors have remained elusive in these cases. Understanding specific genetic abnormality may potentially lead to better treatment strategies in these patients. Here, we analyzed GBM tissue from our patient and 2 afflicted family members, with next generation sequencing to better understand the genetic alterations associated with this disease development. DNA was extracted and sequenced and the data were then analyzed. Results revealed 2 common mutations in afflicted family members; PDGFRA and HRAS. In addition, both siblings showed a mutation of the SMARCB1 gene. The sister of our patient exhibited a homozygous mutation, while our patient had heterozygous mutation of this gene in the tumor tissue. This result suggests that mutation of SMARCB1, either alone or in the presence of PDGFRA and HRAS mutations, is associated with earlier onset GBM.

Helix-Based RNA Landscape Partition and Alternative Secondary Structure Determination.

RNA is a versatile macromolecule with the ability to fold into and interconvert between multiple functional conformations. The elucidation of the RNA folding landscape, especially the knowledge of alternative structures, is critical to uncover the physical mechanism of RNA functions. Here, we introduce a helix-based strategy for RNA folding landscape partition and alternative secondary structure determination. The benchmark test of 27 RNAs involving alternative stable structures shows that the model has the ability to divide the whole landscape into distinct partitions at the secondary structure level and predict the representative structures for each partition. Furthermore, the predicted structures and equilibrium populations of metastable conformations for the 2'dG-sensing riboswitch reveal the allosteric conformational switch on transcript length, which is consistent with the experimental study, indicating the importance of metastable states for RNA-based gene regulation. The model delivers a starting point for the landscape-based strategy toward the RNA folding mechanism and functions.

Kinetic Mechanism of RNA Helix-Terminal Basepairing-A Kinetic Minima Network Analysis.

RNA functions are often kinetically controlled. The folding kinetics of RNAs involves global structural changes and local nucleotide movement, such as base flipping. The most elementary step in RNA folding is the closing and opening of a basepair. By integrating molecular dynamics simulation, master equation, and kinetic Monte Carlo simulation, we investigate the kinetics mechanism of RNA helix-terminal basepairing. The study reveals a six-state folding scheme with three dominant folding pathways of tens, hundreds, and thousands of nanoseconds of folding timescales, respectively. The overall kinetics is rate limited by the detrapping of a misfolded state with the overall folding time of 10-5 s. Moreover, the analysis examines the different roles of the various driving forces, such as the basepairing and stacking interactions and the ion binding/dissociation effects on structural changes. The results may provide useful insights for developing a basepair opening/closing rate model and further kinetics models of large RNAs.

CoDockPP: A Multistage Approach for Global and Site-Specific Protein-Protein Docking.

Protein-protein docking technology is an effective approach to study the molecular mechanism of essential biological processes mediated by complex protein-protein interactions. The fast Fourier transform (FFT) correlation approach makes a good balance between the exhaustive global sampling and the computational efficiency for protein-protein docking. However, it is difficult to integrate the precise knowledge-based scoring function and site constraint information into the FFT-based approach. New docking strategies with the capability of combining both global sampling and precise scoring are strongly needed. We propose a multistage protein-protein docking strategy called CoDockPP. This program takes full advantage of the sampling efficiency of the FFT-based method to choose the valid ligand protein poses with good surface complementarity. The retained poses are transformed to the real Cartesian space for the implementation of site constraints and atomic scoring. Site constraints and a rapid table lookup scoring are applied to gradually reduce the candidate poses to a tractable number. To enhance the accuracy of docking prediction, the best fast-scoring states are expanded the local sampling points and then these neighbor poses are further evaluated by the precise knowledge-based scoring function. By testing on protein-protein docking benchmark 5.0, CoDockPP remarkably improves the success rate and hit count in both ab initio docking and site-specific docking, especially in difficult cases. The server is free and open to all users with no login requirement at http://codockpp.schanglab.org.cn .

Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells.

The aim of this study is to illuminate a novel therapeutic approach by identifying a functional binding target of salinomycin, an emerging anticancer stem cell (CSC) agent, and to help dissect the underlying action mechanisms. By utilizing integrated strategies, we identify that nucleolin (NCL) is likely a salinomycin-binding target and a critical regulator involved in human neuroblastoma (NB) CSC activity. Salinomycin markedly suppresses NB CD34 expression and reduces CD34+ cell population in an NCL-dependent manner via disruption of the interaction of NCL with CD34 promoter. The elevated levels of NCL expression in NB tumors are associated with poor patient survival. Altogether, these results indicate that NCL is likely a novel functional salinomycin-binding target that exhibits the potential to be a prognostic marker for NB therapy.

Resveratrol enhances the chemotherapeutic response and reverses the stemness induced by gemcitabine in pancreatic cancer cells via targeting SREBP1.

OBJECTIVES: Gemcitabine is a standard treatment for advanced pancreatic cancer patients but can cause chemoresistance during treatment. The chemoresistant cells have features of cancer stem cells (CSCs). Resveratrol has been reported to overcome the resistance induced by gemcitabine. However, the mechanism by which resveratrol enhances chemosensitivity remains elusive. Here, we explored the mechanism by which resveratrol enhanced chemosensitivity and the role of sterol regulatory element binding protein 1 (SREBP1) in gemcitabine-induced stemness. MATERIALS AND METHODS: The pancreatic cancer cell lines MiaPaCa-2 and Panc-1 were treated under different conditions. Methyl thiazolyl tetrazolium and colony formation assays were performed to evaluate effects on proliferation. Flow cytometry was conducted to detect apoptosis. Oil red O staining was performed to examine lipid synthesis. The sphere formation assay was applied to investigate the stemness of cancer cells. Immunohistochemistry was performed on tumour tissue obtained from treated KPC mice. RESULTS: Resveratrol enhanced the sensitivity of gemcitabine and inhibited lipid synthesis via SREBP1. Knockdown of SREBP1 limited the sphere formation ability and suppressed the expression of CSC markers. Furthermore, suppression of SREBP1 induced by resveratrol reversed the gemcitabine-induced stemness. These results were validated in a KPC mouse model. CONCLUSIONS: Our data provide evidence that resveratrol reverses the stemness induced by gemcitabine by targeting SREBP1 both in vitro and in vivo. Thus, resveratrol can be an effective chemotherapy sensitizer, and SREBP1 may be a rational therapeutic target.

Hepatoprotective effects of limb ischemic post-conditioning in hepatic ischemic rat model and liver cancer patients via PI3K/ERK pathways.

The most effective way of treating liver cancer is surgical resection, which usually requires blocking the hepatic portal circulation, and may result in hepatic ischemia-reperfusion injury (HIRI). It is of paramount importance to control HIRI for liver cancer surgical resection. In this study, a 70% ischemia-reperfusion (I/R) model of rat liver was established, and the protective effect and mechanism of limb ischemic post-conditioning (LIPOC) on HIRI was investigated. We show that LIPOC has a protective effect on hepatic ischemia-reperfusion injury in rats, which reduces the elimination of superoxide dismutase, thereby increasing oxygen free radical scavenging, decreasing lipid peroxidation, inhibiting neutrophil aggregation, as well as reducing TNFα, IL1ß, and other inflammatory cytokines. In addition, LIPOC inhibited the apoptosis of hepatocytes induced by I/R injury, and decreased the Bax/Bcl-2 ratio. Furthermore, LIPOC promoted the phosphorylation of Akt and ERK1/2. The use of PI3K inhibitor LY294002 and ERK1/2 blocker PD98059 inhibited the phosphorylation of Akt and ERK1/2 caused by LIPOC and abolished the injury protection of liver I/R. Moreover, through 16 cases of hepatocellular carcinoma resections, we found that short-term LIPOC treatment significantly suppressed the elevated alanine aminotransferase, aspartic transaminase, and total bilirubin in the early post-operation of liver resection, and reduced reperfusion injury to the ischemic liver. In summary, our study demonstrates that LIPOC could be an effective method for HIRI in the clinical implementation of liver resection and uncovers the potential mechanism of LIPOC in the protective effects of HIRI.

Identification of a panel of genes as a prognostic biomarker for glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is a fatal disease without effective therapy. Identification of new biomarkers for prognosis would enable more rational selections of strategies to cure patients with GBM and prevent disease relapse. METHODS: Seven datasets derived from GBM patients using microarray or next generation sequencing in R2 online database (http://r2.amc.nl) were extracted and then analyzed using JMP software. The survival distribution was calculated according to the Kaplan-Meier method and the significance was determined using log-rank statistics. The sensitivity of a panel of GBM cell lines in response to temozolomide (TMZ), salinomycin, celastrol, and triptolide treatments was evaluated using MTS and tumor-sphere formation assay. FINDINGS: We identified that CD44, ATP binding cassette subfamily C member 3 (ABCC3), and tumor necrosis factor receptor subfamily member 1A (TNFRSF1A) as highly expressed genes in GBMs are associated with patients' poor outcomes and therapy resistance. Furthermore, these three markers combined with MGMT, a conventional GBM marker, can classify GBM patients into five new subtypes with different overall survival time in response to treatment. The four-gene signature and the therapy response of GBMs to a panel of therapeutic compounds were confirmed in a panel of GBM cell lines. INTERPRETATION: The data indicate that the four-gene panel can be used as a therapy response index for GBM patients and potential therapeutic targets. These results provide important new insights into the early diagnosis and the prognosis for GBM patients and introduce potential targets for GBM therapeutics. FUND: Baylor Scott & White Health Startup Fund (E.W.); Collaborative Faculty Research Investment Program (CFRIP) of Baylor University, Baylor Scott & White Health, and Baylor College of Medicine (E.W., T.S., J.H.H.); NIH R01 NS067435 (J.H.H.); Scott & White Plummer Foundation Grant (J.H.H.); National Natural Science Foundation of China 816280007 (J.H.H. and Fu.W.).

Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/ß-catenin pathway in pancreatic cancer cells.

The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/ß-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy.

Catalpol protects synaptic proteins from beta-amyloid induced neuron injury and improves cognitive functions in aged rats.

Synapse loss is one of the common factors contributing to cognitive disorders, such as Alzheimer's disease (AD), which is manifested by the impairment of basic cognitive functions including memory processing, perception, problem solving, and language. The current therapies for patients with cognitive disorders are mainly palliative; thus, regimens preventing and/or delaying dementia progression are urgently needed. In this study, we evaluated the effects of catalpol, isolated from traditional Chinese medicine Rehmannia glutinosa, on synaptic plasticity in aged rat models. We found that catalpol markedly improved the cognitive function of aged male Sprague-Dawley rats and simultaneously increased the expression of synaptic proteins (dynamin 1, PSD-95, and synaptophysin) in the cerebral cortex and hippocampus, respectively. In beta-amyloid (Aß) injured primary rat's cortical neuron, catalpol did not increase the viability of neuron but extended the length of microtubule-associated protein 2 (MAP-2) positive neurites and reversed the suppressive effects on expression of synaptic proteins induced by Aß. Additionally, the effects of catalpol on stimulating the growth of MAP-2 positive neurites and the expression of synaptic proteins were diminished by a PKC inhibitor, bisindolylmaleimide I, suggesting that PKC may be implicated in catalpol's function of preventing the neurodegeneration induced by Aß. Altogether, our study indicates that catalpol could be a potential disease-modifying drug for cognitive disorders such as AD.

Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression.

Emerging evidence suggests that metformin, an activator of AMP-activated protein kinase (AMPK), may be useful in preventing and treating pancreatic ductal adenocarcinoma (PDAC). However, whether metformin has an effect on the stromal reaction of PDAC remains unknown. In this study, we first evaluated the expression of AMPK and phosphorylated-AMPK (P-AMPK) in normal and PDAC tissues, our data indicate that reduced P-AMPK expression is a frequent event in PDAC and correlated with poor prognosis and the dense stromal reaction. We then determined the efficacy of metformin on PDAC growth in vitro and in vivo. We reveal that metformin reduces the production of fibrogenic cytokines from pancreatic cancer cells (PCs) and inhibits paracrine-mediated pancreatic stellate cells (PSCs) activation under PCsPSCs co-culture conditions. By using a xenograft PDAC mouse model, we show that metformin intervention prevents tumor growth and enhances the antitumor effect of gemcitabine via suppression of desmoplastic reaction. Taken together, these results suggest that induction of AMPK activation by metformin represents a novel therapeutic approach for treating advanced PDAC through reducing the desmoplastic reaction in PDAC.

Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer.

Glucose intolerance and frank diabetes mellitus (DM) can increase the risk of cancer death for pancreatic cancer (PanCa). However, the mechanism by which these factors influence cancer deaths is not clear. In this study, we established a model system to mimic the pancreatic tumor microenvironment in patients with DM to examine the biological behavior of PanCa cells and nerves in cell culture and in animals. Our in vitro studies demonstrated that hyperglycemia promoted the proliferation and invasion of PanCa cell lines and upregulated the expression of nerve growth factor in these cells. Also, the migration of Schwann cells (SCs) was inhibited by hyperglycemia and neurites exerted pathological regeneration. Furthermore, the interaction between the PanCa cells and nerves was enhanced in the tumor microenvironment. We further showed that hyperglycemia promoted the perineural invasion (PNI) of PanCa in vivo. These data suggest that DM worsens the prognosis of PanCa because of aggravated PNI. Thus, our study illustrates a novel mechanism by which hyperglycemia decreases survival in patients with PanCa.

A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma.

Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRß signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRß and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRß but not PDGFRα, is involved in PDGFRß signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFRß and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFRß and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients. Our study may resolve the controversy on the role of PDGFRs in MB and unveils JAG2 as a key downstream effector of a PDGFRß-driven signaling cascade and a potential therapeutic target.