A sliding docking interaction is essential for sequential and processive phosphorylation of an SR protein by SRPK1.

The 2.9 A crystal structure of the core SRPK1:ASF/SF2 complex reveals that the N-terminal half of the basic RS domain of ASF/SF2, which is destined to be phosphorylated, is bound to an acidic docking groove of SRPK1 distal to the active site. Phosphorylation of ASF/SF2 at a single site in the C-terminal end of the RS domain generates a primed phosphoserine that binds to a basic site in the kinase. Biochemical experiments support a directional sliding of the RS peptide through the docking groove to the active site during phosphorylation, which ends with the unfolding of a beta strand of the RRM domain and binding of the unfolded region to the docking groove. We further suggest that the priming of the first serine facilitates directional substrate translocation and efficient phosphorylation.

Heptaellipside A, a rare new 2,28-bidesmosidic lupane-type saponin from the leaves of Heptapleurum ellipticum.

For the first time, phytochemical constituents of the leaves of Heptapleurum ellipticum were investigated. One rare new 2,28-bidesmosidic lupane-type saponin, named heptaellipside A (1), along with four other lupane-type analogs (2-5) were purified by combining differently chromatographic methods. All of the separated compounds (1-5) were communicated for the first time from H. ellipticum. The structures of them were definitely illustrated following extensive and comprehensive UV/VIS, FTIR, HRMS/ESI, and NMR techniques. Further, all isolated compounds were evaluated for their α-glucosidase and α-amylase inhibition. As the results, compound 3 respectively exhibited stronger in both inhibitory activities against α-glucosidase and α-amylase (IC50 values of 15.53 and 26.93 µM), than the acarbose standard (IC50 values of 214.50 and 143.48 µM).

The SRSF1 linker induces semi-conservative ESE binding by cooperating with the RRMs.

SR proteins promote spliceosome formation by recognizing exonic splicing enhancers (ESEs) during pre-mRNA splicing. Each SR protein binds diverse ESEs using strategies that are yet to be elucidated. Here, we show that the RNA-binding domain (RBD) of SRSF1 optimally binds to decameric purine rich ESE sequences although locations of purines are not stringently specified. The presence of uracils either within or outside of the recognition site is detrimental for binding with SRSF1. The entire RBD, comprised of two RRMs and a glycine-rich linker, is essential for ESE binding. Mutation within each segment reduced or nearly abolished binding, suggesting that these segments mediate cooperative binding. The linker plays a decisive role in organizing ESE binding. The flanking basic regions of the linker appear to communicate with each other in bringing the two RRMs close together to form the complex with RNA. Our study thus suggests semi-conservative adaptable interaction between ESE and SRSF1, and such binding mode is not only essential for the recognition of plethora of physiological ESE sequences but may also be essential for the interaction with various factors during the spliceosome assembly.

Adult granulosa cell tumour of the ovary incidentally discovered during caesarean section in a pregnant patient after IVF: a rare case and a review of the literature.

Adult granulosa cell tumours (AGCTs) of the ovary are very rare during pregnancy. To date, only five cases of ovarian AGCT in pregnancy have been reported in the literature and the patients all conceived spontaneously. We report a case of AGCT of the ovary that was incidentally discovered during a caesarean section in a patient undergoing In vitro fertilisation (IVF). To the authors' knowledge, this is the first case of AGCT incidentally discovered during caesarean section in a pregnant patient after IVF. A 44-year-old primigravida with 39 weeks gestation was admitted to our hospital due to premature rupture of membranes in May 2019. She was treated by in vitro fertilisation due to being an elderly mother and she was pregnant after the first cycle. She was indicated for caesarean section due to conceiving following in vitro fertilisation and being an elderly mother. She gave birth to a 3,000 g baby boy and his Apgar scores were 8/1'-9/5'. When examining the adnexa, the left ovary had a tumour with a size of 7 × 4 × 4 cm. Left oophorectomy was performed and specimen sent to for histopathology. The histopathological diagnosis was an AGCT of the ovary. A month later, the patient received chemotherapy with Carboplatin and Paclitaxel for four cycles. After 32 months of follow-up, no recurrence was detected. In conclusion, AGCTs of the ovary are very rare during pregnancy. Pre-operative diagnosis is difficult. Conservative surgery should be considered in women who wish to have children. Patients should receive adequate counselling and long-term follow-up to ensure the highest survival rates and early detection of recurrence.

Endovascular management of massive hemoptysis due to pulmonary artery pseudoaneurysm in a COVID-19 patient in Vietnam: A case report.

Pulmonary artery pseudoaneurysm with massive hemoptysis is extremely rare in patients with coronavirus disease 2019 (COVID-19)-induced pneumonia, especially in its late stage. We report a case who presented with massive hemoptysis and pulmonary artery pseudoaneurysm without pulmonary thromboembolism in their ninth week of COVID-19 infection, which was treated by endovascular embolization. The endovascular intervention was technically and clinically successful, with complete hemoptysis cessation after the procedure. This is the first case reported in Vietnam.

Endovascular management of rectus abdominis hematoma: A report of two cases.

Nontraumatic spontaneous hematoma of the rectus abdominis is frequently related to anticoagulation therapy. In most cases, this condition is spontaneously self-limited or can be controlled with conservative therapy. Nevertheless, in some patients, despite early and adequate medical therapy, continuous development of the condition requires rapid and complete hemostasis. Currently, endovascular management by selective transarterial embolization of the bleeding vessel is the most common treatment option. We report 2 cases of endovascular management of rectus abdominis hematoma using a mixture of n-butylcyanoacrylate and lipiodol to embolize the bleeding point of the superior epigastric artery. Clinical symptoms improved without noticeable complications.

Upper Gastrointestinal Bleeding Caused by Rupture of Pancreatic Pseudoaneurysms.

Pseudoaneurysm rupture in patients with pancreatitis is a rare but fatal etiology of upper gastrointestinal bleeding. We report a rare case of upper gastrointestinal bleeding in a patient who presented simultaneously with two pseudoaneurysms, a potential cause of severe gastrointestinal bleeding. Angiography was successfully performed with coil embolization of the target arteries and both pseudoaneurysmal sacs. The patient was discharged 9 days after admission without further events within a 3-month follow-up period.

Endovascular management of giant post-traumatic pseudoaneurysm in cavernous sinus: A case report.

A 20-year-old male was admitted with the history of a traumatic head injury after traffic accident. The physical examination revealed blurred vision, swelling of the right face, and minor epistaxis. CT and MRI findings revealed a giant pseudoaneurysm of cavernous carotid artery. The patient was enrolled endovascular coils embolization of the internal carotid artery. After the procedure, the patient recovered well. Endovascular treatment is an effective therapy in cavernous carotid pseudoaneurysm.

A statistical approach to boost soluble expression of E. coli-derived virus-like particles in shake-flask cultivation.

Hepatitis B core virus-like particles (HBc-VLP) have been widely used as carrier platforms to present an epitope of interest. Escherichia coli expression system is cost effective and produces high yields of recombinant protein. However major drawbacks include difficulties in obtaining soluble expression and tendency to form inclusion bodies. To boost solubility of proteins during expression of E. coli-derived HBc-VLPs carrying EBNA1 epitope, a statistical approach involving fractional factorial design and response surface methodology was used. For the first time, this approach was applied to quantitatively determine the impact of key parameters in shake-flask cultivation. Expression conditions including post-induction temperature and shaker-speed, and cell density at induction were optimized. Based on native agarose gel electrophoresis, optimized soluble protein cellular yield was 210.5 mg g-1 dry cell mass and volumetric yield was 272 mg L-1 of culture media. Findings highlight: 1) the significant interaction between post-induction temperature and shaker-speed on production, and; 2) sufficient oxygen level is required during induction. It is concluded that this statistical approach can be practically applied to optimize expression of HBc-VLP in shake-flask cultivation, and to determine key parameters for large-scale productions.

Developing a hybrid time-series artificial intelligence model to forecast energy use in buildings.

The development of a reliable energy use prediction model is still difficult due to the inherent complex pattern of energy use data. There are few studies developing a prediction model for the one-day-ahead energy use prediction in buildings and optimizing the hyperparameters of a prediction model is necessary. This study aimed to propose a hybrid artificial intelligence model for forecasting one-day ahead time-series energy consumption in buildings. The proposed model was developed based on the integration of the Seasonal Autoregressive integrated Moving average, the Firefly-inspired Optimization algorithm, and the support vector Regression (SAMFOR). A large dataset of energy consumption in 30-min intervals, temporal data, and weather data from six real-world buildings in Vietnam was used to train and test the model. Sensitivity analyses were performed to identify appropriate model inputs. Comparison results show that the SAMFOR model was more effective than the others such as the seasonal autoregressive integrated moving average (SARIMA) and support vector regression (SVR), SARIMA-SVR, and random forests (RF) models. Evaluation results on real-world building depicted that the proposed SAMFOR model achieved the highest accuracy with the root-mean-square error (RMSE) of 1.77 kWh in, mean absolute percentage error (MAPE) of 9.56%, and correlation coefficient (R) of 0.914. The comparison results confirmed that the SAMFOR model was effective for forecasting one-day-ahead energy consumption. The study contributes to (1) the knowledge domain by proposing the hybrid SAMFOR model for forecasting energy consumption in buildings; and (2) the state of practice by providing building managers or users with a powerful tool for analyzing and improving building energy performance.

Proposing a hybrid metaheuristic optimization algorithm and machine learning model for energy use forecast in non-residential buildings.

The building sector is the largest energy consumer accounting for 40% of global energy usage. An energy forecast model supports decision-makers to manage electric utility management. Identifying optimal values of hyperparameters of prediction models is challenging. Therefore, this study develops a novel time-series Wolf-Inspired Optimized Support Vector Regression (WIO-SVR) model to predict 48-step-ahead energy consumption in buildings. The proposed model integrates the support vector regression (SVR) and the grey wolf optimizer (GWO) in which the SVR model serves as a prediction engine while the GWO is used to optimize the hyperparameters of the SVR model. The 30-min energy data from various buildings in Vietnam were adopted to validate model performance. Buildings include one commercial building, one hospital building, three authority buildings, three university buildings, and four office buildings. The dataset is divided into the learning data and the test data. The performance of the WIO-SVR was superior to baseline models including the SVR, random forests (RF), M5P, and decision tree learner (REPTree). The WIO-SVR model obtained the highest value of correlation coefficient (R) with 0.90. The average root-mean-square error (RMSE) of the WIO-SVR was 2.02 kWh which was more accurate than those of the SVR model with 10.95 kWh, the RF model with 16.27 kWh, the M5P model with 17.73 kWh, and the REPTree model with 26.44 kWh. The proposed model improved 442.0-1207.9% of the predictive accuracy in RMSE. The reliable WIO-SVR model provides building managers with useful references in efficient energy management.

Severe COVID-19 during pregnancy treated with pulse corticosteroid therapy and mid-trimester termination: A case report.

BACKGROUND: At the early stage of the pandemic, severe COVID-19 was thought to be rare among pregnant women. However, cumulating data showed that gestational state is a risk factor for severe pneumonia, particularly due to the hyperinflammatory state. Recent reports suggested the efficacy of pulse corticosteroids in stopping the cytokine storm in people infected with SARS-CoV-2, but limited data exists regarding its use in pregnant women. Moreover, pregnancy termination is a treatment option in this population, but it has been reported mainly in the third trimester and rarely in the second trimester. CASE PRESENTATION: A 37-year-old woman infected with SARS-CoV-2 at 23 weeks of gestation presented with fatigue and dyspnea but soon deteriorated to severely acute respiratory failure and cytokine storm requiring mechanical ventilation combined with hemodialysis just one day after hospitalization. Low-dose corticosteroids and antibiotics were initiated, followed by antiviral therapy, anticoagulant and high-dose corticosteroid therapy. On hospital day 3, a decision to terminate her pregnancy was made; termination led to significant improvement in her clinical condition and a gradual decrease in demand for oxygen supplementation as well as the corticosteroid dose. She was discharged two weeks after admission. CONCLUSIONS: Due to the specific immune response, pregnant women with COVID-19 may differ from others in their clinical presentation, especially the probability of classic acute respiratory distress syndrome (ARDS). This report provides evidence related to the efficacy of pulse corticosteroids on this group and the influence of the mid-trimester termination on recovery.

Cellulose from the banana stem: optimization of extraction by response surface methodology (RSM) and charaterization.

Cellulose was extracted from the banana stem by chemical method and the factors affecting the extraction process such as concentration of NaOH and H2O2, as well as the assisted microwave time were investigated. Design-Expert software with Response Surface Methodology was used in the modeling and optimization of the cellulose extraction process. The results of XRD, FT-IR, SEM were also used to determine the physicochemical properties of cellulose obtained from the banana stem. The results of the modeling and optimization process of cellulose extraction showed the efficiency of the process and the high applicability of cellulose from the banana stem to create valuable industrial products.

Initial Results of Management for Acute Ischemic Stroke due to Large Vessel Occlusion by a Direct Aspiration First Pass Technique at a Vietnamese Hospital.

BACKGROUND: The development of novel revascularization devices has improved procedural and clinical outcomes in acute ischemic stroke (AIS). A direct aspiration first pass technique (ADAPT) has been introduced as a rapid simple method for achieving good recanalization and clinical outcomes using large bore aspiration catheters in the treatment of AIS due to large vessel occlusion (LVO). OBJECTIVES: The aim of this study was to assess the safety and efficacy of ADAPT in the treatment of AIS due to LVO in the Vietnamese patient population. MATERIALS AND METHODS: A retrospective analysis of a hospital database was conducted on all patients undergoing stroke therapy with the ADAPT technique at the institution from January 2017 to December 2017. Efficacy and safety were evaluated by the variables: revascularization rates (thrombolysis in cerebral infarction [TICI] score), time to revascularization, procedural complications, and clinical outcomes (modified Rankin scale [mRS] score) at the 90-day follow-up visit. RESULTS: From the database review, 37 AIS patients treated with ADAPT were identified. The mean NIHSS score at presentation was 17.3 and improved to 8.9 at discharged. The average time arterial puncture to revascularization was 32.5 min. TICI 2b/3 revascularization was achieved in 30/37 (81.1%) patients, good clinical outcomes were achieved (mRS 0-2) in 21/37 (56.7%) patients, and mortality rate was 6/37 (16.2%) during follow-up. CONCLUSIONS: ADAPT utilizing large bore aspiration catheters appears to be a fast, simple, safe, and effective method for the management of AIS in the Vietnamese patient population.

Allosteric interactions direct binding and phosphorylation of ASF/SF2 by SRPK1.

ASF/SF2, a member of the serine-arginine (SR) protein family, has two RRM domains (RRM1 and RRM2) and a C-terminal domain rich in RS dipeptides. SR protein kinase 1 (SRPK1) phosphorylates approximately 12 of these serines using a semiprocessive mechanism. The X-ray structure of the ASF/SF2-SRPK1 complex revealed several features of the complex that raised intriguing questions about how the substrate is phosphorylated by the kinase. The part of the RS domain destined to be phosphorylated at later stages of the reaction docks to a kinase groove distal to the active site while the neighboring RRM2 binds near the active site [Ngo, J. C., et al. (2008) Mol. Cell 29, 563-576]. In this study, we investigate the interplay between the RS domain and RRM2 for stable association and phosphorylation of ASF/SF2. Despite several contacts in the enzyme-substrate complex, free RRM2 does not bind efficiently to SRPK1 unless the docking groove is occupied by the RS domain. This domain cross-talk enhances the processive phosphorylation of the RS domain. The RRM-SRPK1 contact residues control the folding of a critical beta-strand in RRM2. Unfolding of this structural element may force the N-terminal serines of the RS domain into the active site for sequential phosphorylation. Thus, ASF/SF2 represents a new class of substrates that use unique primary sequence to induce allosteric binding, processive phosphorylation, and product release.

Murine Drinking Models in the Development of Pharmacotherapies for Alcoholism: Drinking in the Dark and Two-bottle Choice.

Alcohol Use Disorder (AUD) is a major problem with more than an estimated 76 million people worldwide meeting the diagnostic criteria. Current treatments are limited to three FDA-approved medications that are largely ineffective even when combined with psychosocial intervention, as is evident by the high relapse rate. As such, the search for more novel treatments represents an important public health goal. To this end, the following protocol utilizes two simple rodent drinking models to assess the preclinical efficacy of lead anti-alcohol compounds: two-bottle choice (TBC) and drinking in the dark (DID). The former allows mice to voluntary drink in moderation while the latter induces mice to voluntary consume a large amount of alcohol in a short period that mimics binge drinking. The simple and high throughput nature of both of these paradigms allow for rapid screening of pharmacological agents or for identifying strains of mice that exhibit certain voluntary drinking behavior.

Reduced expression of purinergic P2X4 receptors increases voluntary ethanol intake in C57BL/6J mice.

Purinergic P2X4 receptors (P2X4Rs) belong to the P2X superfamily of ionotropic receptors that are gated by adenosine 5'-triphosphate (ATP). Accumulating evidence indicates that P2X4Rs play an important role in regulation of ethanol intake. At the molecular level, ethanol's inhibitory effects on P2X4Rs are antagonized by ivermectin (IVM), in part, via action on P2X4Rs. Behaviorally, male mice deficient in the p2rx4 gene (P2X4R knockout [KO]) have been shown to exhibit a transient increase in ethanol intake over a period of 4 days, as demonstrated by social and binge drinking paradigms. Furthermore, IVM reduced ethanol consumption in male and female rodents, whereas male P2X4R KO mice were less sensitive to the anti-alcohol effects of IVM, compared to wildtype (WT) mice, further supporting a role for P2X4Rs as targets of IVM's action. The current investigation extends testing the hypothesis that P2X4Rs play a role in regulation of ethanol intake. First, we tested the response of P2X4R KO mice to ethanol for a period of 5 weeks. Second, to gain insights into the changes in ethanol intake, we employed a lentivirus-shRNA (LV-shRNA) methodology to selectively knockdown P2X4R expression in the nucleus accumbens (NAc) core in male C57BL/6J mice. In agreement with our previous study, male P2X4R KO mice exhibited higher ethanol intake than WT mice. Additionally, reduced expression of P2X4Rs in the NAc core significantly increased ethanol intake and preference. Collectively, the findings support the hypothesis that P2X4Rs play a role in regulation of ethanol intake and that P2X4Rs represent a novel drug target for treatment of alcohol use disorder.

Preclinical evaluation of avermectins as novel therapeutic agents for alcohol use disorders.

The deleterious effects of alcohol use disorders (AUDs) on human health have been documented worldwide. The enormous socioeconomic burden coupled with lack of efficacious pharmacotherapies underlies the need for improved treatment strategies. At present, there is a growing body of preclinical evidence that demonstrates the potential of avermectins [ivermectin (IVM), selamectin (SEL), abamectin (ABM), and moxidectin (MOX)] in treatment of AUDs. Avermectins are derived by fermentation of soil micro-organism, Streptomyces avermitilis, and have been extensively used for treatment of parasitic infections. From the mechanistic standpoint, avermectins are positive modulators of purinergic P2X4 receptors (P2X4Rs). P2X4Rs belong to P2X superfamily of cation-permeable ion channels gated by adenosine 5'-triphosphate (ATP). Building evidence has implicated a role for P2X4Rs in regulation of ethanol intake and that ethanol can inhibit ATP-gated currents in P2X4Rs. Investigations using recombinant cell models and animal models of alcohol drinking have reported that IVM, ABM, and MOX, but not SEL, were able to antagonize the inhibitory effects of ethanol on P2X4Rs in vitro and reduce ethanol intake in vivo. Furthermore, IVM was shown to reduce ethanol consumption via P2X4R potentiation in vivo, supporting the involvement of P2X4Rs in IVM's anti-alcohol effects and that P2X4Rs can be used as a platform for developing novel anti-alcohol compounds. Taken together, these findings support the utility of avermectins as a novel class of drug candidates for treatment of AUDs.

Preclinical development of moxidectin as a novel therapeutic for alcohol use disorder.

Current pharmacotherapies for alcohol used disorder (AUD) are few and relatively ineffective illustrating the need for the development of new, effective medications. Using a translational approach, our laboratory reported that ivermectin, an FDA-approved, human and animal anti-parasitic agent, can significantly reduce ethanol intake in male and female mice across different drinking paradigms. Extending this line of investigation, the current paper investigated the utility of moxidectin (MOX), an analogue of ivermectin, to reduce ethanol intake. Notably, MOX is widely held to have lower neurotoxicity potential and improved margin of safety compared to ivermectin. Using a 24-h-two-bottle choice paradigm, MOX significantly reduced ethanol intake in a dose dependent manner in both male and female C57BL/6J mice, respectively (1.25-7.5 mg/kg) and (1.25-10 mg/kg). Further, multi-day administration of MOX (2.5 mg/kg; intraperitoneal injection) for 5 consecutive days significantly reduced ethanol intake in both the 24-h-two-bottle choice and Drinking-in-the-Dark paradigms in female mice. No overt signs of behavioral toxicity were observed. Notably in both male and female mice, MOX significantly reduced ethanol intake starting approximately 4 h post-injection. Using a Xenopus oocyte expression system, we found that MOX significantly potentiated P2X4 receptor (P2X4R) function and antagonized the inhibitory effects of ethanol on ATP-gated currents in P2X4Rs. This latter finding represents the first report of MOX having activity on P2X4Rs. In addition, MOX potentiated GABAA receptors, but to a lesser degree as compared to ivermectin supporting the hypothesis that MOX would be advantageous (compared to ivermectin) with respect to reducing contraindications. Overall, the results illustrate the potential for development of MOX as a novel pharmacotherapy for the treatment of AUD.