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Supplementary Methods, Figures 1-5 from Nuclear ErbB2 Enhances Translation and Cell Growth by Activating Transcription of Ribosomal RNA Genes

4-Isoxazolines are important motifs in various biologically interesting molecules and versatile synthons for the preparation of various cyclic and acyclic compounds. Herein, two green and facile protocols were reported for...

We conducted a multi-institutional study in Taiwan and a systematic review of the literature for reports of Guillain-​Barré syndrome after coronavirus disease vaccination. This condition, mostly the classic form and the acute inflammatory demyelinating polyneuropathy subtype, has been reported in 39 cases and has occurred within 2 weeks of vaccine administration.

This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.

A one-pot catalyst-free synthetic method of benzopyrroxazine derivatives is reported, which relies on an efficient self-catalyzed [3 + 2] cycloaddition process.

The nonlinear optical response of soft chiral crystal system-blue-phase (BP) liquid crystals was studied experimentally using a second-harmonic-generation (SHG) microscope. With the aid of the SHG microscope (SHM), the internal coupling between the polarization and structural deformation was visualized in a short time. In this study, a fringing field, formed at the electrode edges, causes lattice deformation of the cubic BPs, which contributes to the flexoelectric-optic response and field-induced SHG at low frequencies. Using the SHM, we can observe the spatial distribution of the induced polarization in the BPs, and the mean SHG intensity of the cubic BP depends quadratically on the strength of the electric field at a lower value. As the applied electric field increases, the structure of the BPs transfers to the chiral nematic phase (N*), and then the SHG intensity remains constant. Compared to the mean intensities of the SHG signal in N* and the different BPs in the low electric field, the SHG signal caused by the lattice deformation in BPs is weaker in N* and depends on the cubic structure of the BPs. The experimental results demonstrate that through the SHM, the influence of the inhomogeneous electric field on the BPs can be exhibited clearly because the response of the SHG signal in BPs is sensitive to field-induced lattice deformation and phase transitions between the BPs and chiral nematic. This will help us elucidate the mechanism of the secondary electro-optical response in BPs and for further improvement and development of high-performance photonic devices using BPs.

Background: Concurrent use of valproate and carbapenem antibiotics may decrease serum valproate concentration (SVC). This study evaluated the effects of carbapenem–valproate drug interactions. Rese...

Gestational maternal immune activation (MIA) in mice induces persistent brain microglial activation and a range of neuropathologies in the adult offspring. Although long-term phenotypes are well documented, how MIA in utero leads to persistent brain inflammation is not well understood. Here, we found that offspring of mothers treated with polyriboinosinic–polyribocytidylic acid [poly(I:C)] to induce MIA at gestational day 13 exhibit blood–brain barrier (BBB) dysfunction throughout life. Live MRI in utero revealed fetal BBB hyperpermeability 2 d after MIA. Decreased pericyte–endothelium coupling in cerebral blood vessels and increased microglial activation were found in fetal and 1- and 6-mo-old offspring brains. The long-lasting disruptions result from abnormal prenatal BBB formation, driven by increased proliferation of cyclooxygenase-2 (COX2; Ptgs2)-expressing microglia in fetal brain parenchyma and perivascular spaces. Targeted deletion of the Ptgs2 gene in fetal myeloid cells or treatment with the inhibitor celecoxib 24 h after immune activation prevented microglial proliferation and disruption of BBB formation and function, showing that prenatal COX2 activation is a causal pathway of MIA effects. Thus, gestational MIA disrupts fetal BBB formation, inducing persistent BBB dysfunction, which promotes microglial overactivation and behavioral alterations across the offspring life span. Taken together, the data suggest that gestational MIA disruption of BBB formation could be an etiological contributor to neuropsychiatric disorders.

Increasing nitrogen use efficiency (NUE) is critical to improve crop yield, reduce N fertilizer demand and alleviate environmental pollution. N remobilization is a key component of NUE. The nitrate transporter NRT1.7 is responsible for loading excess nitrate stored in source leaves into phloem and facilitates nitrate allocation to sink leaves. Under N starvation, the nrt1.7 mutant exhibits growth retardation, indicating that NRT1.7-mediated source-to-sink remobilization of stored nitrate is important for sustaining growth in plants. To energize NRT1.7-mediated nitrate recycling, we introduced a hyperactive chimeric nitrate transporter NC4N driven by the NRT1.7 promoter into the nrt1.7 mutant. NRT1.7p::NC4N::3′ transgenic plants accumulated more nitrate in younger leaves, and 15NO3− tracing analysis revealed that more 15N was remobilized into sink tissues. Consistently, transgenic Arabidopsis, tobacco and rice plants showed improved growth or yield. Our study suggests that enhancing source-to-sink nitrate remobilization represents a new strategy for enhancing NUE and crop production. One important direction to reduce the application of nitrogen fertilizer is to improve nitrogen use efficiency (NUE) of crops. Now an interesting strategy that engineers the transporter responsible for source-to-sink nitrate remobilization is employed to generate transgenic Arabidopsis, tobacco and rice lines with enhanced NUE and plant yield.

In this paper, we present experimental results on electrically tunable reflected wavelength in the full visible spectral range from 460 nm to 620 nm in one simple cubic blue-phase cell due to the s...

The emergence of carbapenem-resistant Enterobacteriaceae (CRE) is a threat to public health worldwide. This study aimed to determine the risk factors and outcomes for CRE colonization and infection in infants.Children aged1 year hospitalized with CRE pathogens isolated from January 2016 to June 2019 were retrospectively analyzed. Demographic and clinical data were examined.A total of 48 infections were identified in 70 infants aged1 year, and 66.7% (32/48) of these infants were born preterm. The infection rate in infants aged1 month was higher than that of others (P = 0.005). The most commonly isolated CRE was Klebsiella pneumoniae (60.4%, 29/48), followed by Enterobacter cloacae complex (18.8%, 9/48). Sputum (37.5%, 18/48), blood (27.1%, 13/48), and urine (25.0%, 12/48) were the most common clinical samples. Urinary tract infection was common in infants aged 6-12 months. CRE infection was associated with mechanical ventilation (P = 0.037), central venous catheter (CVC) insertion (P = 0.034), and congenital heart disease (P = 0.027). The hospital stay of patients with CRE infection was longer (median, 75 days; SD, 66.4 days), and their all-cause mortality (6.4%) was higher than those with colonization.CRE infection was common in infants aged1 month, and patients usually had longer hospitalization. Carbapenemase production was not common. Mechanical ventilation, CVC insertion, and congenital heart disease were associated with a higher risk of CRE acquisition in infants aged1 year.

This work uses surface acoustic waves (SAWs) that are generated by a piezoelectric substrate containing an interdigital transducer (IDT) to which a low voltage of 2 mV was applied at a frequency of 1 kHz to fabricate a polymer-stabilized blue phase liquid crystal (PS-BPLC) layer. The PS-BPLC layer has a more uniform optical microscope (OM) image at a voltage of 2 mV than at zero voltage, and its reflective spectrum exhibits a smaller full width at half maximum (FWHM) at the former than at the latter. The uniform OM image and small FWHM reveal that the lattices in the PS-BPLC layer have monodomain structure. The monodomain PS-BPLC layer is formed because the SAWs cause longitudinal and transverse vibrations of the PS-BPLC lattices in the vertical plane along their traveling direction. The proposed method for fabricating the monodomain PS-BPLC layer using the SAWs has potential for the development of reflective optical devices that consume low power during their fabrication.

BackgroundTo compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin.MethodsWe conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications.ResultsWe identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95).ConclusionThe risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.

The T cell Ig and mucin domain (TIM) proteins inhibit release of HIV-1 and other enveloped viruses by interacting with cell- and virion-associated phosphatidylserine (PS). Here, we show that the Nef proteins of HIV-1 and other lentiviruses antagonize TIM-mediated restriction. TIM-1 more potently inhibits the release of Nef-deficient relative to Nef-expressing HIV-1, and ectopic expression of Nef relieves restriction. HIV-1 Nef does not down-regulate the overall level of TIM-1 expression, but promotes its internalization from the plasma membrane and sequesters its expression in intracellular compartments. Notably, Nef mutants defective in modulating membrane protein endocytic trafficking are incapable of antagonizing TIM-mediated inhibition of HIV-1 release. Intriguingly, depletion of SERINC3 or SERINC5 proteins in human peripheral blood mononuclear cells (PBMCs) attenuates TIM-1 restriction of HIV-1 release, in particular that of Nef-deficient viruses. In contrast, coexpression of SERINC3 or SERINC5 increases the expression of TIM-1 on the plasma membrane and potentiates TIM-mediated inhibition of HIV-1 production. Pulse-chase metabolic labeling reveals that the half-life of TIM-1 is extended by SERINC5 from

Background and importance Clinical decision support systems (CDSSs) are frequently adopted in hospitals to increase prescription accuracy in patients with renal impairment, but the alerts from CDSSs are usually overridden in clinical practice. Therefore, an intensified CDSS with more detailed information should be developed and its effectiveness with regard to prescribing errors determined. Aim and objectives To evaluate the effectiveness of an intensified CDSS with regard to prescribing errors for inappropriate drugs in cases of renal dysfunction. Material and methods We conducted a pre- and post-intervention study in an inpatient setting in the largest medical centre in Taiwan in 2019. Previously, the CDSS only reminded clinicians to adjust drugs according to the patient’s renal function. After May 2019, we initiated an intensified CDSS directly providing clinicians with the precise drug dosage or alternative drug recommendations for patients with renal impairment. The study outcome was the rate of prescribing errors, as identified by pharmacists after prescribing by clinicians. We used interrupted time series analysis to estimate the trend in prescribing error rate before (January 2019 to May 2019) and after (June 2019 to December 2019) implementing the intensified CDSS. As a control, we conducted similar analyses in another hospital with the same healthcare systems but without an intensified CDSS. We hypothesised there would be a reduction in the rate of prescribing errors for inappropriate drugs in cases of renal dysfunction after the intensification of CDSS in the study hospital, compared with the control hospital. Results The mean prescribing error rates due to inappropriate drugs in patients with renal dysfunction were 1.70 and 1.59 per 1000 inpatient beds before and after the introduction of the intensified CDSS, respectively, which did not constitute a significant change between the pre- and post- intervention (β=0.01; 95% CI −0.32 to 0.35). However, we observed a non-significantly increased prescribing error rate between the study hospital and the control hospital (β=0.04; 95% CI −0.51 to 0.59) after the introduction of the intensified CDSS. Conclusion and relevance The deployment of an intensified CDSS providing detailed information on how to prescribe drugs for patients with renal impairment may inhibit the increase in prescribing error rate due to inappropriate drugs in patients with renal dysfunction. References and/or acknowledgements Conflict of interest No conflict of interest

Compared with root development regulated by external nutrients, less is known about how internal nutrients are monitored to control plasticity of shoot development. In this study, we characterize an Arabidopsis thaliana transceptor, NRT1.13 (NPF4.4), of the NRT1/PTR/NPF family. Different from most NRT1 transporters, NRT1.13 does not have the conserved proline residue between transmembrane domains 10 and 11; an essential residue for nitrate transport activity in CHL1/NRT1.1/NPF6.3. As expected, when expressed in oocytes, NRT1.13 showed no nitrate transport activity. However, when Ser 487 at the corresponding position was converted back to proline, NRT1.13 S487P regained nitrate uptake activity, suggesting that wild-type NRT1.13 cannot transport nitrate but can bind it. Subcellular localization and β-glucuronidase reporter analyses indicated that NRT1.13 is a plasma membrane protein expressed at the parenchyma cells next to xylem in the petioles and the stem nodes. When plants were grown with a normal concentration of nitrate, nrt1.13 showed no severe growth phenotype. However, when grown under low-nitrate conditions, nrt1.13 showed delayed flowering, increased node number, retarded branch outgrowth, and reduced lateral nitrate allocation to nodes. Our results suggest that NRT1.13 is required for low-nitrate acclimation and that internal nitrate is monitored near the xylem by NRT1.13 to regulate shoot architecture and flowering time.

Background Ammonium (NH4+), a key nitrogen form, becomes toxic when it accumulates to high levels. Ammonium transporters (AMTs) are the key transporters responsible for NH4+ uptake. AMT activity is under allosteric feedback control, mediated by phosphorylation of a threonine in the cytosolic C-terminus (CCT). However, the kinases responsible for the NH4+-triggered phosphorylation remain unknown. Results In this study, a functional screen identified protein kinase CBL-Interacting Protein Kinase15 (CIPK15) as a negative regulator of AMT1;1 activity. CIPK15 was able to interact with several AMT1 paralogs at the plasma membrane. Analysis of AmTryoshka, an NH4+ transporter activity sensor for AMT1;3 in yeast, and a two-electrode-voltage-clamp (TEVC) of AMT1;1 in Xenopus oocytes showed that CIPK15 inhibits AMT activity. CIPK15 transcript levels increased when seedlings were exposed to elevated NH4+ levels. Notably, cipk15 knockout mutants showed higher 15NH4+ uptake and accumulated higher amounts of NH4+ compared to the wild-type. Consistently, cipk15 was hypersensitive to both NH4+ and methylammonium but not nitrate (NO3−). Conclusion Taken together, our data indicate that feedback inhibition of AMT1 activity is mediated by the protein kinase CIPK15 via phosphorylation of residues in the CCT to reduce NH4+-accumulation.

SUMMARYAmmonium (NH4+), a key nitrogen form, becomes toxic when it accumulates to high levels. Ammonium transporters (AMTs) are the key transporters responsible for NH4+ uptake. AMT activity is under allosteric feedback control, mediated by phosphorylation of a threonine in the cytosolic C-terminus (CCT). However, the kinases responsible for the NH4+-triggered phosphorylation remain unknown. In this study, a functional screen identified protein kinase CBL-Interacting Protein Kinase15 (CIPK15) as a negative regulator of AMT1;1 activity. CIPK15 was able to interact with several AMT1 paralogs at the plasma membrane. Analysis of AmTryoshka, an NH4+ transporter activity sensor for AMT1;3 in yeast, and a two-electrode-voltage-clamp (TEVC) of AMT1;1 in Xenopus oocytes showed that CIPK15 inhibits AMT activity. CIPK15 transcript levels increased when seedlings were exposed to elevated NH4+ levels. Notably, cipk15 knockout mutants showed higher 15NH4+ uptake and accumulated higher amounts of NH4+ compared to the wild-type. Consistently, cipk15 was hypersensitive to both NH4+ and methylammonium but not nitrate (NO3−). Taken together, our data indicate that feedback inhibition of AMT1 activity is mediated by the protein kinase CIPK15 via phosphorylation of residues in the CCT to reduce NH4+-accumulation.

Objective To assess the effectiveness and safety of Kuntai capsules (KTC) in treatment of premature ovarian failure (POF). Method A systematic review and meta-analysis of randomized controlled trials studied KTC alone or combined with hormone therapy (HT) used for treating POF. PubMed, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, Chinese Scientific Journal and Wanfang database were searched until July 2019. The Cochrane risk of bias method was used to assess the quality of the included studies, a meta-analysis was conducted with Review Manager 5.3 software and the level of evidence was rated by using GRAEDpro 3.6 software. Results A total of 14 RCTs (1257 participants) were included. Meta-analysis indicated that KTC can significantly improve the total clinical effective rate (P Conclusion KTC may be effective for POF treatment, and lower risk of side effects. More high-quality articles are needed to provide more reliable sources and data to evaluate the clinical efficacy of KTC in the future.

BackgroundHead-to-head comparison of clinical effectiveness between dulaglutide and liraglutide in Asia is limited. This study was aimed to assess the real-world comparative effectiveness of dulaglutide versus liraglutide.MethodsWe conducted a retrospective cohort study by utilizing multi-institutional electronic medical records to identify real-world type 2 diabetes patients treated with dulaglutide or liraglutide during 2016–2018 in Taiwan and followed up until 2019. Effectiveness outcomes were assessed at every 3 months in the 1-year follow-up. Propensity score techniques were applied to enhance between-group comparability. Significant differences in changes of effectiveness outcomes between treatment groups during the follow-up were examined and further analyzed using mixed-model repeated-measures approaches.ResultsA total of 1512 subjects receiving dulaglutide and 1513 subjects receiving liraglutide were identified. At 12 months, significant HbA1c changes from baseline were found in both treatments (dulaglutide: − 1.06%,p p p 2,p 2,p p ConclusionsIn real-world T2D patients, dulaglutide versus liraglutide was associated with better glycemic control and comparable effects on changes of weight, blood pressure, and liver and renal functions.

ObjectiveTo evaluate the influence of pharmacists' dispensing workload (PDW) on pharmacy services as measured by prescription suggestion rate (PSR) and dispensing error rate (DER).MethodThis was an observational study in northern and southern Taiwan's two largest medical centers, from 2012 to 2018. We calculated monthly PDW as number of prescriptions divided by number of pharmacist working days. We used monthly PSR and DER as outcome indicators for pharmacists' review and dispensing services, respectively. We used Poisson regression model with generalized estimation equation methods to evaluate the influence of PDW on PSR and DER.ResultsThe monthly mean of 463,587 (SD 32,898) prescriptions yielded mean PDW, PSR and DER of 52 (SD 3) prescriptions per pharmacist working days, 30 (SD 7) and 8 (SD 2) per 10,000 prescriptions monthly, respectively. There was significant negative impact of PDW on PSR (adjusted rate ratio, aRR: 0.9786; 95%CI: 0.9744-0.9829) and DER (aRR: 0.9567; 95%CI: 0.9477-0.9658). Stratified analyses by time periods (2012-2015 and 2016-2018) revealed the impact of PDW on PSR to be similar in both periods; but with positive association between PDW and DER in the more recent one (aRR: 1.0086, 95%CI: 1.0003-1.0169).ConclusionsReduced pharmacist workload was associated with re-allocation of pharmacy time to provide prescription suggestions and, more recently, decrease dispensing errors. Continuous efforts to maintain appropriate workload for pharmacists are recommended to ensure prescription quality.

The decarboxylative aldol reaction of α,α-difluoro-β-keto acids and unprotected isatins under catalyst- and base-free conditions has been developed. This method is operationally convenient under simple conditions using low-cost readily available raw materials, and therefore could serve as an attractive strategy for the synthesis of 3-difluoroalkyl-3-hydroxy-2-oxindole derivatives with potential biological activities in moderate to excellent yields.