Systematic identification and characterization of exon-intron circRNAs.

Exon-intron circRNAs (EIciRNAs) are a circRNA subclass with retained introns. Global features of EIciRNAs remain largely unexplored, mainly owing to the lack of bioinformatic tools. The regulation of intron retention (IR) in EIciRNAs and the associated functionality also require further investigation. We developed a framework, FEICP, which efficiently detected EIciRNAs from high-throughput sequencing (HTS) data. EIciRNAs are distinct from exonic circRNAs (EcircRNAs) in aspects such as with larger length, localization in the nucleus, high tissue specificity, and enrichment mostly in the brain. Deep learning analyses revealed that compared with regular introns, the retained introns of circRNAs (CIRs) are shorter in length, have weaker splice site strength, and have higher GC content. Compared with retained introns in linear RNAs (LIRs), CIRs are more likely to form secondary structures and show greater sequence conservation. CIRs are closer to the 5'-end, whereas LIRs are closer to the 3'-end of transcripts. EIciRNA-generating genes are more actively transcribed and associated with epigenetic marks of gene activation. Computational analyses and genome-wide CRISPR screening revealed that SRSF1 binds to CIRs and inhibits the biogenesis of most EIciRNAs. SRSF1 regulates the biogenesis of EIciLIMK1, which enhances the expression of LIMK1 in cis to boost neuronal differentiation, exemplifying EIciRNA physiological function. Overall, our study has developed the FEICP pipeline to identify EIciRNAs from HTS data, and reveals multiple features of CIRs and EIciRNAs. SRSF1 has been identified to regulate EIciRNA biogenesis. EIciRNAs and the regulation of EIciRNA biogenesis play critical roles in neuronal differentiation.

Tunable underwater sound absorption characteristics of 0-3 piezoelectric anechoic coating.

Piezoelectric composite materials (PCMs) with shunt damping circuits are used widely in hydroacoustics because of the flexible adjustability of their parameters. PCMs offer good underwater sound absorption, but shortcomings remain, such as poor low-frequency sound absorption, narrow bandwidth, and a single dissipation mechanism. In this paper, the tunable underwater sound absorption of a 0-3 PCM combined with a cavity structure and shunt circuit (PCMC) is studied systematically. First, the equivalent material parameters of 0-3 PCM are derived based on the Yamada model, and then a theoretical electroacoustic model is established for solving the absorption coefficient and is mutually verified with the numerical simulation method. On this basis, the tunable absorption characteristics of the structure are analyzed. The results show that coupling the energy dissipation mechanism of 0-3 PCM with the acoustic mechanism of the cavity structure not only achieves strong absorption at lower frequencies but also enriches the absorption mode in the mid-high frequencies by connecting the shunt circuits. Moreover, the influence of piezoelectric control variables and acoustic cavity morphology characteristics on structural sound absorption performance is further explored. Finally, the acoustic performance of PCMC is improved further via shape optimization and parameter optimization.

Neuroprotective effect of the traditional decoction Tian-Si-Yin against Alzheimer's disease via suppression of neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease among old adults. As a traditional Chinese medicine, the herbal decoction Tian-Si-Yin consists of Morinda officinalis How. and Cuscuta chinensis Lam., which has been widely used to nourish kidney. Interestingly, Tian-Si-Yin has also been used to treat dementia, depression and other neurological conditions. However, its therapeutic potential for neurodegenerative diseases such as AD and the underlying mechanisms remain unclear. AIM OF THE STUDY: To evaluate the therapeutic effect of the herbal formula Tian-Si-Yin against AD and to explore the underlying mechanisms. MATERIALS AND METHODS: The N2a cells treated with amyloid ß (Aß) peptide or overexpressing amyloid precursor protein (APP) were used to establish cellular models of AD. The in vivo anti-AD effects were evaluated by using Caenorhabditis elegans and 3 × Tg-AD mouse models. Tian-Si-Yin was orally administered to the mice for 8 weeks at a dose of 10, 15 or 20 mg/kg/day, respectively. Its protective role on memory deficits of mice was examined using the Morris water maze and fear conditioning tests. Network pharmacology, proteomic analysis and ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS) were used to explore the underlying molecular mechanisms, which were further investigated by Western blotting and immunohistochemistry. RESULTS: Tian-Si-Yin was shown to improve cell viability of Aß-treated N2a cells and APP-expressing N2a-APP cells. Tian-Si-Yin was also found to reduce ROS level and extend lifespan of transgenic AD-like C. elegans model. Oral administration of Tian-Si-Yin at medium dose was able to effectively rescue memory impairment in 3 × Tg mice. Tian-Si-Yin was further shown to suppress neuroinflammation by inhibition of glia cell activation and downregulation of inflammatory cytokines, diminishing tau phosphoralytion and Aß deposition in the mice. Using UHPLC-MS/MS and network pharmacology technologies, 17 phytochemicals from 68 components of Tian-Si-Yin were identified as potential anti-AD components. MAPK1, BRAF, TTR and Fyn were identified as anti-AD targets of Tian-Si-Yin from network pharmacology and mass spectrum. CONCLUSIONS: This study has established the protective effect of Tian-Si-Yin against AD and demonstrates that Tian-Si-Yin is capable of improving Aß level, tau pathology and synaptic disorder by regulating inflammatory response.

The P38MAPK/ATF2 signaling pathway is involved in PND in mice.

Accumulating evidence indicates that microglia-mediated neuroinflammation in the hippocampus contributes to the development of perioperative neurocognitive disorder (PND). P38MAPK, a point of convergence for different signaling processes involved in inflammation, can be activated by various stresses. This study aims to investigate the role of the P38MAPK/ATF2 signaling pathway in the development of PND in mice. Aged C57BL/6 mice were subjected to tibial fracture surgery under isoflurane anesthesia to establish a PND animal model. The open field test was used to evaluate the locomotor activity of the mice. Neurocognitive function was assessed with the Morris water maze (MWM) and fear conditioning test (FCT) on postoperative days 1, 3 and 7. The mice exhibited cognitive impairment accompanied by increased expression of proinflammatory factors (IL-1ß, TNF-α), proapoptotic molecules (caspase-3, bax) and microglial activation in the hippocampus 1, 3 and 7 days after surgery. Treatment with SB239063 (a P38MAPK inhibitor) decreased the expression of proinflammatory factors, proapoptotic molecules and Iba-1 in the CA1 region of the hippocampus. The number of surviving neurons was significantly increased. Inhibition of the P38MAPK/ATF2 signaling pathway attenuates hippocampal neuroinflammation and neuronal apoptosis in aged mice with PND, thus improving the perioperative cognitive function of the mice.

Friend or foe: role of pathological tau in neuronal death.

Neuronal death is one of the most common pathological hallmarks of diverse neurological diseases, which manifest varying degrees of cognitive or motor dysfunction. Neuronal death can be classified into multiple forms with complicated and unique regulatory signaling pathways. Tau is a key microtubule-associated protein that is predominantly expressed in neurons to stabilize microtubules under physiological conditions. In contrast, pathological tau always detaches from microtubules and is implicated in a series of neurological disorders that are characterized by irreversible neuronal death, such as necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent neuronal death and phagocytosis by microglia. However, recent studies have also revealed that pathological tau can facilitate neuron escape from acute apoptosis, delay necroptosis through its action on granulovacuolar degeneration bodies (GVBs), and facilitate iron export from neurons to block ferroptosis. In this review, we briefly describe the current understanding of how pathological tau exerts dual effects on neuronal death by acting as a double-edged sword in different neurological diseases. We propose that elucidating the mechanism by which pathological tau affects neuronal death is critical for exploring novel and precise therapeutic strategies for neurological disorders.

A Simple Method for the Synthesis of a Coral-like Boron Nitride Micro-/Nanostructure Catalyzed by Fe.

Catalyzed by Fe, novel a coral-like boron nitride (BN) micro-/nanostructure was synthesized from B2O3 by a ball milling and annealing process. Observations of the morphology of the product indicated that the coral-like BN micro-/nanostructure consists of a bamboo-shaped nanotube stem and dense h-BN nanoflakes growing outward on the surface of the nanotube. Experimental results showed that the morphology of the BN nanotube was greatly dependent on the anneal process parameters. With the annealing time increasing from 0.5 h to 4 h, the morphology developed from smooth BN nanotubes, with a diameter size of around 100 nm, to rough, coral-like boron nitride with a large diameter of 3.6 µm. The formation mechanism of this coral-like BN micro-/nanostructure is a two-stage growth process: bamboo-shaped BN nanotubes are first generated through a vapor-liquid-solid (VLS) mechanism and then nanoflakes grow surrounding the surface of the nanotube. Acid pickling and a hydrolysis process were carried out to remove Fe, iron nitrogen and unreacted B2O3 impurities.

Biaxial tensile test and meso damage numerical simulation of HTPB propellant.

Aiming at the shortcomings of the current research on the mechanical properties of solid propellants under complex stress conditions, an effective cross-shaped test piece configuration and variable-scale biaxial tensile test method are designed in this paper, and the meso-simulation model of propellant is constructed by Micro-CT test and random filling algorithm. Then, based on the Hook-Jeeves method and the cohesive force model, the mechanical performance parameters of each mesoscopic component were obtained, and finally the damage evolution process of the propellant was numerically simulated. The results show that the stress-strain curve of the propellant under biaxial loading is similar to that of uniaxial stretching, and has obvious rate dependence and stress state dependence. The mechanical properties of the propellant under biaxial tensile loading are significantly lower than those in uniaxial stretching, and the maximum elongation is only 45-85% of that in uniaxial stretching. The fracture process of propellant can be divided into initial linear stage, damage evolution stage and fracture stage. The dewetting phenomenon generally occurs at the interface between the large-sized AP particles and the matrix. With the loading of the load, the pores formed by the dewetting and matrix tearing continue to converge into cracks and expand in the direction perpendicular to the resultant force, and finally fracture. The propellant dehumidifies more easily under high strain rate loading, but the degree of dewetting is lower when the same strain is reached.

Continuous Analysis of Critical Incidents for 92,136 Postanesthesia Care Unit Patients of a Chinese University Hospital.

PURPOSE: To determine the spectrum of critical incidents in postanesthesia care unit (PACU) and the possible prediction and prevention of the worse scenario-associated critical incidents. DESIGN: A retrospective observational study. METHODS: The critical incidents in PACU comprising 92,136 patients were recorded. The incidents included the following disorders: delayed recovery, pain, bleeding, hypothermia, unplanned transfer to intensive care unit, shivering, agitation, nausea and vomiting, and respiratory or cardiovascular-related critical incidents. We then performed descriptive analyses and t test or χ2 test on the collected data. FINDINGS: A total of 1,760 critical incidents were recorded in 1,417 patients among 92,136 patients. Most critical incidents were associated with the patients after general anesthesia and general or gynecologic surgery. The most common critical incidents noted in the present study were pain, followed by cardiovascular-related and respiratory-related incidents. The average length of stay in PACU was 61.50 ± 44.40 minutes for the patients with critical incidents and 28.50 ± 19.40 minutes for the patients without critical incidents. CONCLUSIONS: Critical incidents lead to longer length of stay in the PACU. Regular inspection and immediate response for critical incidents in the PACU is essential for the maintenance of the quality of the immediate postoperative care.

Prediction of oxidoreductase subfamily classes based on RFE-SND-CC-PSSM and machine learning methods.

Oxidoreductase is an enzyme that widely exists in organisms. It plays an important role in cellular energy metabolism and biotransformation processes. Oxidoreductases have many subclasses with different functions, creating an important classification task in bioinformatics. In this paper, a dataset of 2640 oxidoreductase sequences was used to perform an analysis and comparison. The idea of dipeptides was introduced to process the Position Specific Score Matrix (PSSM), since each dipeptide consists of two amino acids and each column of PSSM corresponds to the information of one amino acid. Two kinds of dipeptide scores were proposed, the Standardization Normal Distribution PSSM (SND-PSSM) and the Correlation Coefficient PSSM (CC-PSSM). Recursive Feature Elimination (RFE) is used to extract features from the SND-PSSM and CC-PSSM, and the two sets of extracted features are combined to form a new feature matrix, the RFE-SND-CC-PSSM. The results show that, with the proposed method and a kernel-based nonlinear SVM classifier, the accuracy can reach 95.56% by the Jackknife test. Our method greatly improves the accuracy of oxidoreductase subclass prediction. Using this method to predict the categories of the 6 major types of enzymes effectively improves its prediction accuracy to 94.54%, indicating that this method has general applicability to other protein problems. The results show that our method is effective and universally applicable, and might be complementary to the existing methods.

Anesthetic management of radical nephrectomy in patients with renal cell carcinoma involving renal vein or inferior vena cava.

OBJECTIVE: To investigate the perioperative anesthetic management of patients diagnosed with renal cell carcinoma (RCC) metastasized into the renal vein or inferior vena cava (IVC) after undergoing radical nephrectomy to provide clinical evidence for rational anesthetic interventions. METHODS: A total of 81 patients with RCC extending into the renal vein or IVC, aged 17-73 years, undergoing radical nephrectomy were recruited. Preoperative status, intraoperative management, average operation time, average estimated blood loss, postanesthesia outcomes, and postoperative complications were retrospectively analyzed. RESULTS: The mean operation time was 288 minutes (range 146-825 minutes). The mean estimated blood loss was recorded as 1905 mL (range 200-7000 mL). Among 81 cases, 9 patients (11.1%, 1 level II, 3 level III, and 5 level IV) were switched to undergo cardiopulmonary bypass. Significant hemodynamic fluctuations were observed in 39 patients who presented with level II-IV of tumor thrombus. One patient had pulmonary embolism and died of active cardiopulmonary resuscitation. The mean postoperative hospital stay was 12.8 days. Twenty-five cases with level III-IV tumor thrombus were transferred to the intensive care unit with endotracheal intubation due to massive intraoperative blood loss. The remaining 55 cases were transferred to the postanesthesia care unit 2 hours before being transferred to the ward. One patient had postoperative acute coronary syndrome and was discharged after effective interventions. CONCLUSION: Anesthetic management and intensive postoperative care play a pivotal role in the success of complete resection of RCC that metastasize into the IVC.

Risk factors for acute kidney injury after orthotopic liver transplantation: A single-center data analysis.

Acute kidney injury (AKI) is a common complication following orthotopic liver transplantation (OLT) and is associated with increased morbidity and mortality. The aim of the current study was to determine the risk factors for AKI in patients undergoing OLT. A total of 103 patients who received OLT between January 2015 and May 2016 in Tongji Hospital, China, were retrospectively analyzed. Their demographic characteristics and perioperative parameters were collected, and AKI was diagnosed using 2012 Kidney Disease: Improving Global Outcomes (KDIGO) staging criteria. It was found that the incidence of AKI was 40.8% in this cohort and AKI was significantly associated with body mass index, urine volume, operation duration (especially > 480 min), and the postoperative use of vasopressors. It was concluded that relative low urine output, long operation duration, and the postoperative use of vasopressors are risk factors for AKI following OLT.

Blocking PAR2 attenuates oxaliplatin-induced neuropathic pain via TRPV1 and releases of substance P and CGRP in superficial dorsal horn of spinal cord.

Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, neuropathic pain is one of the main limiting complications of OXL. The purpose of this study was to examine the underlying mechanisms by which neuropathic pain is induced by OXL in a rat model. Our results demonstrated that blocking spinal proteinase-activated receptor 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) attenuated pain responses evoked by mechanical stimulation and decreased the releases of substance P and CGRP in the superficial dorsal horn of the spinal cord. The attenuating effect on mechanical pain was significantly smaller in OXL-rats than that in control rats. Blocking PAR2 also attenuated a heightened cold sensitivity evoked by OXL; whereas blocking TRPV1 had little effects on OXL-evoked hypersensitive cold response. Our data also showed that OXL increased the protein expressions of PAR2 and TRPV1 in the superficial dorsal horn. In addition, blocking PAR2 decreased TRPV1 expression in OXL-rats. Overall, our data suggest that upregulated expression of PAR2 in the superficial dorsal horn contributes to mechanical hyperalgesia and cold hypersensitivity; whereas amplified TRPV1 plays a role in regulating mechanical hyperalgesia, but not cold hypersensitivity after administration of OXL. We further suggest that TRPV1 is likely one of the signaling pathways for PAR2 to play a role in regulating OXL-induced neuropathic pain.

Role of ATP-sensitive potassium channels in modulating nociception in rat model of bone cancer pain.

Bone cancer pain is a major clinical problem and remains difficult to treat. ATP-sensitive potassium (KATP) channels may be involved in regulating nociceptive transmission at the spinal cord level. We determined the role of spinal KATP channels in the control of mechanical hypersensitivity in a rat model of bone cancer pain. The rat model of bone cancer pain was induced by implanting rat mammary gland carcinoma cells (Walker256) into the tibias. KATP modulators (pinacidil and glibenclamide) or the specific Kir6.2-siRNA were injected via an intrathecal catheter. The mechanical withdrawal threshold of rats was tested using von Frey filaments. The Kir6.2 mRNA and protein levels were measured by quantitative PCR and western blots, respectively. Intrathecal injection of pinacidil, a KATP channel opener, significantly increased the tactile withdrawal threshold of cancer cell-injected rats in a dose-dependent manner. In contrast, intrathecal delivery of glibenclamide, a KATP channel blocker, or the specific Kir6.2-siRNA significantly reduced the tactile withdrawal threshold of cancer cell-injected rats. The mRNA and protein levels of Kir6.2 in the spinal cord of cancer cell-injected rats were significantly lower than those in control rats. Our findings suggest that the KATP channel expression level in the spinal cord is reduced in bone cancer pain. Activation of KATP channels at the spinal level reduces pain hypersensitivity associated with bone cancer pain.

Non-invasive monitoring of blood pressure using the Philips Intellivue MP50 monitor cannot replace invasive blood pressure techniques in surgery patients under general anesthesia.

The Philips Intellivue MP50 monitor provides a method for non-invasive, near-continuous blood pressure (BP) monitoring and is designed to be an alternative to direct intra-arterial BP (IABP) measurement. However, no studies have specifically compared non-invasive and invasive BP measurements using the monitor. The present retrospective study observed 515 patients undergoing surgery with general anesthesia, whose invasive (intra-radial, femoral or dorsalis pedis artery) and non-invasive (oscillometric) BP (NIBP) were monitored simultaneously using the monitor. These data were analyzed using correlations, regressions and Bland-Altman plots. The patients were placed in a supine position during surgery. The correlation data for invasive BP and NIBP measurements were: for intra-radial measurements, r2=0.51 (bias and precision, 11.04±15.22 and 14.76±11.64 mmHg, respectively) for systolic BP (SBP) and r2=0.27 (6.17±11.95 and 9.77±9.25 mmHg, respectively) for diastolic BP (DBP); for intra-femoral measurements: r2=0.57 (14.79±14.55 and 17.15±11.68 mmHg, respectively) for SBP and r2=0.45 (4.12±9.70 and 7.49±7.40 mmHg, respectively) for DBP; and for intra-dorsalis pedis measurements: r2=0.33 (13.00±16.81 and 17.34±12.28 mmHg, respectively) for SBP and r2=0.30 (0.17±11.27 and 8.44±7.46 mmHg, respectively) for DBP. According to this data, the NIBP measured by the Philips Intellivue MP50 monitor showed low positive correlations and poor agreement with the IABP, as calculated by Bland-Altman analysis. Therefore, the use of oscillometric BP measured by the monitor in surgery patients under general anesthesia is not generally recommended.

Cdh1 inhibits reactive astrocyte proliferation after oxygen-glucose deprivation and reperfusion.

Anaphase-promoting complex (APC) and its co-activator Cdh1 are required for cell cycle regulation in proliferating cells. Recent studies have defined diverse functions of APC-Cdh1 in nervous system development and injury. Our previous studies have demonstrated the activity of APC-Cdh1 is down-regulated in hippocampus after global cerebral ischemia. But the detailed mechanisms of APC-Cdh1 in ischemic nervous injury are unclear. It is known that astrocyte proliferation is an important pathophysiological process following cerebral ischemia. However, the role of APC-Cdh1 in reactive astrocyte proliferation is not determined yet. In the present study, we cultured primary cerebral astrocytes and set up in vitro oxygen-glucose deprivation and reperfusion model. Our results showed that the expression of Cdh1 was decreased while Skp2 (the downstream substrate of APC-Cdh1) was increased in astrocytes after 1h oxygen-glucose deprivation and reperfusion. The down-regulation of APC-Cdh1 was coupled with reactive astrocyte proliferation. By constructing Cdh1 expressing lentivirus system, we also found exogenous Cdh1 can down-regulate Skp2 and inhibit reactive astrocyte proliferation induced by oxygen-glucose deprivation and reperfusion. Moreover, Western blot showed that other downstream proteins of APC-Cdh1, PFK-1 and SnoN, were decreased in the inhibition of reactive astrocyte proliferation with Cdh1 expressing lentivirus treatment. These results suggest that Cdh1 plays an important role in the regulation of reactive astrocyte proliferation induced by oxygen-glucose deprivation and reperfusion.

Local influence measure of zero-inflated generalized Poisson mixture regression models.

In many practical applications, count data often exhibit greater or less variability than allowed by the equality of mean and variance, referred to as overdispersion/underdispersion, and there are several reasons that may lead to the overdispersion/underdispersion such as zero inflation and mixture. Moreover, if the count data are distributed as a generalized Poisson or a negative binomial distribution that accommodates extra variation not explained by a simple Poisson or a binomial model, then the dispersion occurs too. In this paper, we deal with a class of two-component zero-inflated generalized Poisson mixture regression models to fit such data and propose a local influence measure procedure for model comparison and statistical diagnostics. At first, we formally develop a general model framework that unifies zero inflation, mixture as well as overdispersion/underdispersion simultaneously, and then we mainly investigate two types of perturbation schemes, the global and individual perturbation schemes, for perturbing various model assumptions and detecting influential observations. Also, we obtain the corresponding local influence measures. Our method is novel for count data analysis and can be used to explore these essential issues such as zero inflation, mixture, and dispersion related to zero-inflated generalized Poisson mixture models. On the basis of the results of model comparison, we could further conduct the sensitivity analysis of perturbation as well as hypothesis test with more accuracy. Finally, we employ here a simulation study and a real example to illustrate the proposed local influence measures.

Neuroprotective effects of 17ß-estradiol associate with KATP in rat brain.

Previous studies have indicated that estrogen protects the brain from ischemic damage and regulates K(ATP) channel activity; the present study was designed to address the involvement of K(ATP) channels in the neuroprotective effects of estrogen in focal cerebral ischemia: in experiment 1, K(ATP) mRNA and protein in the cortices of rats were compared among groups of ovariectomized rats (Ovx-1), Sham-operated rats (Sham-1), and ovariectomized rats administered 17ß-estradiol (Estr-1). In experiment 2, neurobehavioral scores and infarct volume of rats were evaluated after middle cerebral artery occlusion in ovariectomized rats (Ovx-2), Sham-operated rats (Sham-2), ovariectomized female rats administered 17ß-estradiol (Estr-2), and ovariectomized rats administered both 17ß-estradiol and stereotactic injections of glibenclamide (Estr+G). Our results showed that the Kir6.2 and SUR1 mRNA and protein levels in the brain cortices of female ovariectomized rats were lower than those in Sham rats. However, the expression levels of Kir6.2 and SUR1 in brain cortices of ovariectomized rats recovered after supplementation with 17ß-estradiol. The protective effects of 17ß-estradiol were abolished by glibenclamide, a K(ATP) channel blocker. This indicates that estradiol significantly upregulates the expression of K(ATP) channel subunits and channel activity in the brain cortices of ovariectomized rats. This regulation is associated with the neuroprotective effects of estradiol.