Characteristic chemical probing patterns of loop motifs improve prediction accuracy of RNA secondary structures.

RNA structures play a fundamental role in nearly every aspect of cellular physiology and pathology. Gaining insights into the functions of RNA molecules requires accurate predictions of RNA secondary structures. However, the existing thermodynamic folding models remain less accurate than desired, even when chemical probing data, such as selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) reactivities, are used as restraints. Unlike most SHAPE-directed algorithms that only consider SHAPE restraints for base pairing, we extract two-dimensional structural features encoded in SHAPE data and establish robust relationships between characteristic SHAPE patterns and loop motifs of various types (hairpin, internal, and bulge) and lengths (2-11 nucleotides). Such characteristic SHAPE patterns are closely related to the sugar pucker conformations of loop residues. Based on these patterns, we propose a computational method, SHAPELoop, which refines the predicted results of the existing methods, thereby further improving their prediction accuracy. In addition, SHAPELoop can provide information about local or global structural rearrangements (including pseudoknots) and help researchers to easily test their hypothesized secondary structures.

Noncoding RNAs Serve as Diagnosis and Prognosis Biomarkers for Hepatocellular Carcinoma.

BACKGROUND: Reliable noninvasive biomarkers for hepatocellular carcinoma (HCC) diagnosis and prognosis are urgently needed. We explored the potential of not only microRNAs (miRNAs) but other types of noncoding RNAs (ncRNAs) as HCC biomarkers. METHODS: Peripheral blood samples were collected from 77 individuals; among them, 57 plasma cell-free RNA transcriptomes and 20 exosomal RNA transcriptomes were profiled. Significantly upregulated ncRNAs and published potential HCC biomarkers were validated with reverse transcription (RT)-qPCR in an independent validation cohort (60-150 samples). We particularly investigated the diagnosis and prognosis performance and biological function for 1 ncRNA biomarker, RN7SL1, and its S fragment. RESULTS: We identified certain circulating ncRNAs escaping from RNase degradation, possibly through binding with RNA-binding proteins: 899 ncRNAs were highly upregulated in HCC patients. Among them, 337 genes were fragmented long noncoding RNAs, 252 genes were small nucleolar RNAs, and 134 genes were piwi-interacting RNAs. Forty-eight candidates were selected and validated with RT-qPCR, of which, 16 ncRNAs were verified to be significantly upregulated in HCC, including RN7SL1, SNHG1, ZFAS1, and LINC01359. Particularly, the abundance of RN7SL1 S fragment discriminated HCC samples from negative controls (area under the curve, 0.87; 95% CI, 0.817-0.920). HCC patients with higher concentrations of RN7SL1 S fragment had lower survival rates. Furthermore, RN7SL1 S fragment alone promoted cancer cell proliferation and clonogenic growth. CONCLUSIONS: Our results show that various ncRNA species, not only miRNAs, identified in the small RNA sequencing of plasma are also able to serve as noninvasive biomarkers. Particularly, we identified a domain of srpRNA RN7SL1 with reliable clinical performance for HCC diagnosis and prognosis.

Neuroendocrine Regulation of Energy Metabolism Involving Different Types of Adipose Tissues.

Despite tremendous research efforts to identify regulatory factors that control energy metabolism, the prevalence of obesity has been continuously rising, with nearly 40% of US adults being obese. Interactions between secretory factors from adipose tissues and the nervous system innervating adipose tissues play key roles in maintaining energy metabolism and promoting survival in response to metabolic challenges. It is currently accepted that there are three types of adipose tissues, white (WAT), brown (BAT), and beige (BeAT), all of which play essential roles in maintaining energy homeostasis. WAT mainly stores energy under positive energy balance, while it releases fuels under negative energy balance. Thermogenic BAT and BeAT dissipate energy as heat under cold exposure to maintain body temperature. Adipose tissues require neural and endocrine communication with the brain. A number of WAT adipokines and BAT batokines interact with the neural circuits extending from the brain to cooperatively regulate whole-body lipid metabolism and energy homeostasis. We review neuroanatomical, histological, genetic, and pharmacological studies in neuroendocrine regulation of adipose function, including lipid storage and mobilization of WAT, non-shivering thermogenesis of BAT, and browning of BeAT. Recent whole-tissue imaging and transcriptome analysis of differential gene expression in WAT and BAT yield promising findings to better understand the interaction between secretory factors and neural circuits, which represents a novel opportunity to tackle obesity.

Global Transcriptome Analysis of Brown Adipose Tissue of Diet-Induced Obese Mice.

Consumption of a high-fat diet (HFD) promotes the development of obesity, a disease resulting from an imbalance between energy intake and energy expenditure. Brown adipose tissue (BAT) has thermogenic capacity that burns calories to produce heat, and it is a potential target for the treatment and prevention of obesity. There is limited information regarding the impact of HFD on the BAT transcriptome. We hypothesized that HFD-induced obesity would lead to transcriptional regulation of BAT genes. RNA sequencing was used to generate global transcriptome profiles from BAT of lean mice fed with a low-fat diet (LFD) and obese mice fed with a HFD. Gene Ontology (GO) analysis identified increased expression of genes involved in biological processes (BP) related to immune responses, which enhanced molecular function (MF) in chemokine activity; decreased expression of genes involved in BP related to ion transport and muscle structure development, which reduced MF in channel and transporter activity and structural binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathway analysis indicated that pathways associated with innate immunity were enhanced by HFD, while pathways associated with muscle contraction and calcium signaling were suppressed by HFD. Collectively, these results suggest that diet-induced obesity changes transcriptomic signatures of BAT, leading to dysfunction involving inflammation, calcium signaling, ion transport, and cell structural development.

A new flavonoid glycoside (APG) isolated from Clematis tangutica attenuates myocardial ischemia/reperfusion injury via activating PKCε signaling.

Clematis tangutica has been shown to be beneficial for the heart; however, the mechanism of this effectremains unknown. Apigenin-7-O-ß-D-(-6″-p-coumaroyl)-glucopyranoside (APG) is a new flavonoid glycoside isolated from Clematis tangutica. This study investigates the effects of APG on myocardial ischemia/reperfusion (IR) injury (IRI). An IRI model of primary myocardial cells and mice was used in this study. Compared with the IR group, APG preconditioning is protective against IRI in primary myocardial cells and in mice hearts in a dose-dependent manner. The cardioprotective mechanisms of APG may involve a significant PKCε translocation into the mitochondria and an activation of the Nrf2/HO-1 pathway, which respectively suppressesmitochondrial oxidative stress and inhibits apoptosis. In addition, PKCε-targeted siRNA and a PKCε specialized inhibitor (ε-V1-2) were used to inhibit PKCε expression and activity. The inhibition of PKCε reversed the cardioprotective effect of APG, with an inhibition of Nrf2/HO-1 activation and increased mitochondrial oxidative stress and cardiomyocyte apoptosis. In conclusion, PKCε activation plays an important role in the cardioprotective effects of APG. PKCε activation induced by APG preconditioning reduces mitochondrial oxidative stress and promotes Nrf2/HO-1-mediated anti-apoptosis signaling.

Downregulation of tNASP inhibits proliferation through regulating cell cycle-related proteins and inactive ERK/MAPK signal pathway in renal cell carcinoma cells.

Nuclear auto-antigenic sperm protein (NASP), initially described as a highly auto-immunogenic testis and sperm-specific protein, is a histone chaperone that is proved to present in all dividing cells. NASP has two splice variants: testicular NASP (tNASP) and somatic form of NASP (sNASP). Only cancer, germ, transformed, and embryonic cells have a high level of expression of the tNASP. Up to now, little has been known about tNASP in renal cell carcinoma (RCC). In the present study, the molecular mechanism of tNASP in RCC was explored. The expression level of tNASP in 16 paired human RCC specimens was determined. Downregulation of tNASP by small interfering RNA (siRNA) was transfected in RCC cell lines. The effect of downregulation of tNASP by siRNA on cell colony formation and proliferation was examined by colony formation assay and CCK-8 assay, cell cycle was analyzed by flow cytometry, and the expression of cyclin D1 and P21 were detected by Western blotting. ERK/MAPK signaling was also analyzed. tNASP has a relative high expression level in human RCC tissues. Via upregulation of P21 and downregulation of cyclinD1, silence of tNASP can inhibit cell proliferation, which induces cell cycle arrest. Furthermore, ERK signaling pathway is confirmed to mediate the regulation of cell cycle-related proteins caused by silence of tNASP. Our research demonstrates that knockdown of tNASP effectively inhibits the proliferation and causes G1 phase arrest through ERK/MAPK signal pathway.

Joint analysis of mutational and transcriptional landscapes in human cancer reveals key perturbations during cancer evolution.

BACKGROUND: Tumors are able to acquire new capabilities, including traits such as drug resistance and metastasis that are associated with unfavorable clinical outcomes. Single-cell technologies have made it possible to study both mutational and transcriptomic profiles, but as most studies have been conducted on model systems, little is known about cancer evolution in human patients. Hence, a better understanding of cancer evolution could have important implications for treatment strategies. RESULTS: Here, we analyze cancer evolution and clonal selection by jointly considering mutational and transcriptomic profiles of single cells acquired from tumor biopsies from 49 lung cancer samples and 51 samples with chronic myeloid leukemia. Comparing the two profiles, we find that each clone is associated with a preferred transcriptional state. For metastasis and drug resistance, we find that the number of mutations affecting related genes increases as the clone evolves, while changes in gene expression profiles are limited. Surprisingly, we find that mutations affecting ligand-receptor interactions with the tumor microenvironment frequently emerge as clones acquire drug resistance. CONCLUSIONS: Our results show that lung cancer and chronic myeloid leukemia maintain a high clonal and transcriptional diversity, and we find little evidence in favor of clonal sweeps. This suggests that for these cancers selection based solely on growth rate is unlikely to be the dominating driving force during cancer evolution.

Insight into coagulation/flocculation mechanisms on microalgae harvesting by ferric chloride and polyacrylamide in different growth phases.

FeCl3 and polyacrylamide (PAM) had been used to investigate the effect of coagulation, flocculation, and their combination on algae cells and extracellular organic matter (EOM) at different phases. PAM tended to aggregate particle-like substances, while FeCl3 could interact with EOM. The content of EOM kept rising during the algae growth cycle, while OD680 peaked at about 3.0. At stationary phase Ⅰ, the removal efficiencies of UV254, turbidity and OD680 of the suspension conditioned with FeCl3 + PAM reached (88.08 ± 0.89)%, (89.72 ± 0.36)% and (93.99 ± 0.05)%, respectively. Nevertheless, PAM + FeCl3 exhibited the worst efficiency because of the release of EOM caused by the turbulence. The results suggested that algal cells served as a coagulation aid to facilitate floc formation, while excessive EOM deteriorated harvesting performance. The process of FeCl3 + PAM at stationary phase Ⅰ appears to be a promising technology for microalgae harvesting.

Parathyroid hormone-related protein as a potential prostate cancer biomarker: Promoting prostate cancer progression through upregulation of c-Met expression.

Parathyroid hormone-related protein (PTHrP) plays a significant role in various tumor types, including prostate cancer. However, its specific role and underlying mechanisms in prostate cancer remain unclear. This study investigates the role of PTHrP and its interaction with the c-Met in prostate cancer. PTHrP was overexpressed and knocked down in prostate cancer cell lines to determine its effect on cell functions. Xenograft tumor models were employed to assess the impact of PTHrP overexpression on tumor growth. To delve into the interaction between PTHrP and c-Met, rescue experiments were conducted. Clinical data and tissue samples from prostate cancer patients were gathered and analyzed for PTHrP and c-Met expression. PTHrP overexpression in prostate cancer cells upregulates c-Met expression and augments cell functions. In contrast, PTHrP-knockdown diminishes c-Met expression and inhibits cell functions. In vivo experiments further demonstrated that PTHrP overexpression promoted tumor growth in xenograft models.Moreover, modulating c-Met expression in rescue experiments led to concurrent alterations in prostate cancer cell functions. Immunohistochemical analysis of clinical samples displayed a significant positive correlation between PTHrP and c-Met expression. Additionally, PTHrP expression correlated with clinical parameters like prostate-specific antigen (PSA) levels, tumor stage, lymph node involvement, distant metastasis, and Gleason score. PTHrP plays a crucial role in prostate cancer progression by upregulating c-Met expression. These insights point to PTHrP as a promising potential biomarker for prostate cancer.

A New Strategy for the High-Throughput Characterization of Materials' Mechanical Homogeneity Based on the Effect of Isostatic Pressing on Surface Microstrain.

A new strategy for the high-throughput characterization of the mechanical homogeneity of metallurgical materials is proposed. Based on the principle of hydrostatic transmission and the synergistic analysis of the composition, microstructure, defects, and surface profile of the chosen material, the microstrain characteristics and changes in surface roughness after isostatic pressing were analyzed. After isostatic pressing, two types of microstrains were produced: low microstrain (surface smoothening with decreasing roughness) and large microstrain (surface roughening with increasing roughness). Furthermore, the roughness of the roughened microregions could be further classified based on the strain degree. The phenomenon of weak-interface damage with a large microstrain (plastic deformation, cleavage fracture, and tearing near nonmetallic inclusions) indicated that the surface microstrain analysis could be a new method of high-throughput characterization for microregions with relatively poor micromechanical properties. In general, the effect of isostatic pressing on the surface microstrain of heat-resistant steel provides a promising strategy for achieving high-throughput screening and statistically characterizing microregions with poor micromechanical properties, such as microregions containing microcracks, nonmetallic inclusions, pores, and other surface defects.

Potent cancer therapy by liposome microstructure tailoring with active-to-passive targeting and shell-to-core thermosensitive features.

Liposomes have been widely studied as drug carriers for clinical application, and the key issue is how to achieve effective delivery through targeting strategies. Even though certain cell-level targeting or EPR effect designs have been developed, reaching sufficient drug concentration in intracellular regions remains a challenge due to the singularity of functionality. Herein, benefiting from the unique features of tumor from tissue to cell, a dual-thermosensitive and dual-targeting liposome (DTSL) was creatively fabricated through fine microstructure tailoring, which holds intelligent both tissue-regulated active-to-passive binding and membrane-derived homologous-fusion (HF) properties. At the micro level, DTSL can actively capture tumor cells and accompany the enhanced HF effect stimulated by self-constriction, which achieves a synergistic promotion effect targeting tissues to cells. As a result, this first active-then passive targeting process makes drug delivery more accurate and effective, and after dynamic targeting into cells, the nucleus of DTSL undergoes further thermally responsive contraction, fully releasing internal drugs. In vivo experiments showed that liposomes with dual targeting and dual thermosensitive features almost completely inhibited tumor growth. Summarized, these results provide a reference for a rational design and microstructural tailoring of the liposomal co-delivery system of drugs, suggesting that active-to-passive dual-targeting DTSL can function as a new strategy for cancer treatment.

Regulable high-contrast mechanofluorochromic enhancement behaviour based on substituent effects.

Herein, a facile strategy was established to build mechanoresponsive luminogens with high sensitivity to substituents and positional effects. Even in slightly different structures, distinct optical phenomena, including fluorescence efficiency and mechano-responsive properties, were clearly present. Outstanding mechanical-induced emission enhancement (5-100 times) properties and reversibility makes for promising applications in pressure sensors and OLEDs.

Transcatheter tricuspid valve interventions: Current devices and clinical evidence.

The tricuspid valve is known as "the forgotten valve". Tricuspid regurgitation (TR) is a highly prevalent valvular heart disease. TR is often late in the course of the disease when it becomes symptomatic, often being a marker of late-stage chronic heart failure with a poor prognosis and high mortality rate at long-term follow-up. Despite the clear correlation between TR and mortality, most TR patients are under-treated. Neither pharmacologic nor surgical treatment demonstrates a significant survival benefit. Isolated tricuspid valve surgery has the highest mortality rate of all valve surgeries. Therefore, there is an urgent clinical need for minimally invasive therapies to meet the needs of patients with TR. In recent years, a variety of transcatheter tricuspid valve interventions representing less invasive alternatives to surgery have shown promising results, which bring hope to patients with severe TR. The purpose of this review is to provide a complete and updated overview on current transcatheter tricuspid valve interventions and clinical evidence.

Pulmonary and tricuspid regurgitation after Tetralogy of Fallot repair: A case report.

BACKGROUND: Tetralogy of Fallot (TOF) is one of the most common congenital heart defects, and surgery is the primary treatment. There are no precise guidelines on the treatment protocol for tricuspid regurgitation (TR) as a common complication of TOF repair. The timing for treatment in patients presenting with valve regurgitation after TOF repair is often difficult to determine. Here, we report the first case of sequential treatment of pulmonary and TR using interventional therapy. CASE SUMMARY: We present the case of a 52-year-old female patient, who had a history of TOF repair at a young age. A few years later, the patient presented with pulmonary and tricuspid regurgitation. The symptoms persisted and TR worsened following percutaneous pulmonary valve implantation. Preoperative testing revealed that the patient's disease had advanced to an intermediate to advanced stage and that her general health was precarious. Because open-heart surgery was not an option for the patient, transcatheter tricuspid valve replacement was suggested. This procedure was successful, and the patient recovered fully without any adverse effects. This case report may serve as a useful resource for planning future treatments. CONCLUSION: Treatment of both valves should be considered in patients with tricuspid and pulmonary regurgitations following TOF repair. The interventional strategy could be an alternative for patients with poor general health.

Impact of transcatheter tricuspid valve replacement for tricuspid regurgitation on hepatic, cardiac, and venous structure.

BACKGROUND: Patients with long-term tricuspid regurgitation (TR) are mostly accompanied by hepatic, cardiac, and venous remodeling. Transcatheter tricuspid valve replacement (TTVR) device has emerged as a promising alternative to open-heart surgery for TR patients. No study has assessed the impact of TTVR on hepatic, cardiac, and venous remodeling. METHODS: Twenty-two patients with TR enrolled in this study underwent TTVR between October 2020 and January 2021. Liver, heart, and veins were reconstructed by three-dimensional computed tomography reconstruction software at baseline and 6 months follow-up. RESULTS: Twenty-two patients were enrolled in this study. The mean age was 64.8 ± 8.2 years, and all patients had severe or greater TR with multiple comorbidities. The left hepatic lobe volume decreased from 518.8 ± 171.9 ml to 470.4 ± 179.6 ml at 6 months during follow-up (p = 0.049). Evidence of a decrease in three hepatic veins parameters and splenic vein parameters was noted from baseline to 6 months. And a significant decrease in right atrial volume (317.5 ml [interquartile range: 216.1 to 497.3 ml] vs. 266.7 ml [interquartile range: 178.7 to 480.7 ml]; p = 0.003) were observed in the study. CONCLUSIONS: Six-month outcomes show that TR elimination by LuX-Valve is associated with the reverse remodeling of liver, heart, and veins. Accordingly, LuX-Valve is a promising alternative for patients presenting with severe TR.

Transjugular Transcatheter Tricuspid Valve Implantation of LuX-Valve Bioprosthesis in a Preclinical Model.

The purpose of this preclinical study in a sheep model was to confirm the feasibility and safety of the LuX-Valve transjugular tricuspid valve (TV) replacement apparatus and to optimize the implantation procedure before beginning first-in-man study. The LuX-Valve was implanted in a sheep model (n = 8) via transjugular approach. Six of eight sheep underwent successful implantation procedure on beating heart. The first two sheep died during the prostheses deployment. In the remaining 6 sheep that survived, postoperative echocardiography results showed there was no paravalvular leakage (PVL) and central tricuspid regurgitation in 5 animals, whereas 1 animal had mild PVL. The mean transvalvular gradient was 1.1 ± 0.9 mm Hg at the 4-week follow-up. No right ventricular outflow tract (RVOT) obstruction, device malposition, pericardial effusion, coronary artery compression, or arrhythmias were observed. This technology may be a promising alternative for TR patients who are at high risk for open-heart surgery. Transjugular tricuspid valved-stent implantation. a Transjugular tricuspid valve replacement in a sheep model. b and c Valved stent. d, e, and f Schematic depiction of the implantation procedure.

Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis.

In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/radiotherapy. We developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid co-culture system. Overall, this study demonstrates that characterization of the tumor microenvironment using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.

Manufacturing with pluripotent stem cells (PSConf 2021): Key issues for future research and development.

Human pluripotent stem cells (hPSC) have the capability to deliver novel cell-based medicines that could transform medical treatments for a wide range of diseases including age-related degenerative disorders and traumatic injury. In spite of significant investment in this area, due to the novel nature of these hPSC-based medicines, there are challenges in almost all aspects of their manufacturing including bioprocessing, characterization and delivery. The Chinese Academy of Sciences and the Chinese Society for Stem Cell Research have collaborated to create a new discussion forum called PSConf 2021 (Pluripotent Stem Cell Conference 2021), intended to promote exchanges in communication on cutting-edge developments and international coordination in hPSC manufacturing. The PSConf 2021 addressed crucial topics in stem cell-based manufacturing, including stem cell differentiation, culture scale-up, product formulation and release. This report summarizes the proceedings and conclusions from the discussion sessions, and it is accompanied by publication of individual papers from the speakers at the PSConf 2021. SIGNIFICANCE STATEMENT: The PSConf 2021 meeting has brought together speakers and delegates from more than 20 countries in an informal discussion forum focusing on the manufacture of cell-based medicines using hPSCs. The conference discussion sessions enabled an open exchange of information on the latest developments, ideas on key challenges and their potential solutions. It also captured the experiences and lessons learnt by professionals who had been in the field from the earliest applications of human embryonic stem cells, and presented a diverse range of new potential pluripotent stem cell-based medicines that are now under development, with some already in clinical trials.

Re-defining and tackling the emerging challenges in stem cell research and translation: A report of the 10th CSSCR annual meeting.

The 10th congress of the Chinese Society for Stem Cell Research was held from 11 to 13 October 2020 at Guiyang International Eco-Conference Center in Guizhou (Southwest China) with 700 offline participants (and 500 online participants). With a theme adopted from a poem by Mao Zedong during the long march, 'However difficult it might appear; the challenges will be overcome', the congress provided opportunities for the fast-growing field to exchange ideas among people from academia, industry and regulatory authorities, to help accelerate translation. Eight plenary lectures and six concurrent sessions on cell fate decision, stem cell metabolism, neural stem cells and neural regeneration, organoids and disease models, tissue and organ regeneration and clinical translation of stem cell research were covered, including 77 oral presentations and 75 poster presentations. The congress also included special programmes of a youth forum, a lecture award programme, a flagship journal forum and a dedicated networking session. This 3-day event will significantly boost the stem cell research in an era closing to application.

Effect of HAc on the Metastable Pitting Corrosion of 304 SS in NaCl Solution.

Stainless steels (SSs) easily suffer localized corrosion damage, such as pitting corrosion, in mixed solutions of acetic acid and sodium chloride. Currently, few works have been focused on the early stages of the pitting corrosion (metastable pitting corrosion) process of SSs in a chloride-HAc mixture solution. In this work, the effects of acetic acid (HAc) and its concentration on metastable pitting corrosion and the uniform corrosion of 304 SS in 0.6 mol/L NaCl solution were investigated by a slow-scanning potentiodynamic polarization test, scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). The results show that the uniform corrosion rate of 304 SS increases after HAc addition but, with an increase in HAc concentration, the corrosion rate decreases. In the presence of HAc, the metastable pitting potential (Em) and stable pitting potential (Eb) move negatively, but the number of metastable pits notably decreases. HAc has a promoting action on the growth rate of the metastable pits and facilitates the transition from metastable pits to stable pits. The influence of HAc is related to a decrease in solution pH and the chemical adsorption of HAc.