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Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMH-mediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats. We investigated whether effects of Serelaxin are mediated by its ability to activate the GMH-suppressed eNOS pathway resulting in attenuation of inflammatory marker overproduction. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U). Seven day old Sprague–Dawley rat pups (P7) were used (n = 63). GMH animals were divided in vehicle or serelaxin treated (3 µg once, 30 µg once, 30 µg multiple, i.p., starting 30 after GMH and then daily). Sham operated animals were used. We monitored the developmental profile working memory and spatial function (T-maze and open field test respectively). At day 28, all rats underwent MRI-scans for assessment of changes in cortical thickness and white matter loss. Effects of Serelaxin on eNOS pathway activation and post-GMH inflammation were evaluated. We demonstrated that Serelaxin dose-dependently attenuated GMH-induced developmental delay, protected brain and improved cognitive functions of rats after GMH. That was associated with the decreased post-GMH inflammation, mediated at least partly by amelioration of GMH-induced eNOS inhibition.

Supplemental material, sj-docx-1-psx-10.1177_0032321720964667 for Motivated Reasoning in Identity Politics: Group Status as a Moderator of Political Motivations by Ming M Boyer, Loes Aaldering and Sophie Lecheler in Political Studies

This paper seeks to gain insights into whether developing countries benefit more from the backwardness advantage for economic growth in the Information Age. The paper examines this concern through three complementary approaches. First, it derives theoretical grounds from the existing economic models to support the hypothesis that the internet, inter alia, enables developing countries to reap greater growth gains from technology acquisition and catch-up. Second, the paper uses descriptive evidence to show that the growth landscape has indeed shifted decisively in favor of developing countries in the Internet Age in comparison to the pre-internet period. Third, using rigorous econometric techniques with data of 163 countries over a 20-year period, 1996-2016, the paper evidences that developing countries on average reap significantly greater growth gains from internet adoption in comparison to the average advanced country. The paper discusses policy implications from the paper’s findings.

Malate dehydrogenase (MDH) and citrate synthase (CS) are two pacemaking enzymes involved in the tricarboxylic acid (TCA) cycle. Oxaloacetate (OAA) molecules are the intermediate substrates that are transferred from the MDH to CS to carry out sequential catalysis. It is known that, to achieve a high flux of intermediate transport and reduce the probability of substrate leaking, a MDH-CS metabolon forms to enhance the OAA substrate channeling. In this study, we aim to understand the OAA channeling within possible MDH-CS metabolons that have different structural orientations in their complexes. Three MDH-CS metabolons from native bovine, wild-type porcine, and recombinant sources, published in recent work, were selected to calculate OAA transfer efficiency by Brownian dynamics (BD) simulations and to study, through electrostatic potential calculations, a possible role of charges that drive the substrate channeling. Our results show that an electrostatic channel is formed in the metabolons of native bovine and recombinant porcine enzymes, which guides the oppositely charged OAA molecules passing through the channel and enhances the transfer efficiency. However, the channeling probability in a suggested wild-type porcine metabolon conformation is reduced due to an extended diffusion length between the MDH and CS active sites, implying that the corresponding arrangements of MDH and CS result in the decrease of electrostatic steering between substrates and protein surface and then reduce the substrate transfer efficiency from one active site to another.

Background: Inpatients hypoglycemia has adverse impacts on patient outcomes and healthcare resources use. While recurrent hypoglycemia is largely preventable, limited studies were done within the Asia-Pacific context. We sought to determine whether temporal distributions of hypoglycemia exist between insulin and/or sulfonylureas (SU) treated patients and identify predictors of recurrent hypoglycemia at a tertiary medical center in Singapore. Methods: We analyzed data of 420 hypoglycemic episodes (capillary blood glucose (CBG) ≤ 70mg/dL) in 207 diabetes patients at general medical wards over a 2-month period from 1st May 2017. This was analyzed by 4 time frames coincided with blood glucose monitoring times. Time periods associated with hypoglycemia were compared using the Chi-square test. Multivariate logistic regression estimated risk factors of recurrent hypoglycemia. Results: Most frequent hypoglycemia episodes occurred between 04:00 and 09:59 (41.7%). Greater frequency was seen in insulin- and SU-treated than insulin-treated patients between 04:00 to 09:59 (58.3% vs.37.9% of readings for respective treatments, p 7% and repeated CBG checking > 30 minutes interval emerged as predictors of recurrent hypoglycemia with odds ratio of 1.07 (95% CI 1.03-1.11), 8.07 (95% CI 2.82-23.08), 3.71 (95% CI 1.59-8.65), 3.12 (95% CI 1.26-7.74) and 3.54 (95% CI 1.59-7.91), respectively. Conclusions: Hypoglycemic episodes were more frequent in the early hours of the day in insulin and SU-treated inpatients. This may have implications for the continuing use of SU at inpatients. Recurrent hypoglycemia can be prevented by developing strategies targeting the modifiable iatrogenic risk factors. Disclosure P. Lim: None. S. Goh: None. Y. Bee: None. X. Xin: None. L. Ang: None. N.A. Salleha: None. M.M. Teh: None.

Importance Management of cystic bleb leak is difficult. It would be essential to look for a method to strengthen the original pathological conjunctiva and reverse bleb leak. Background To evaluate the long-term efficacy and safety of collagen crosslinking in patients with leaking cystic bleb. Design Prospective interventional case series at a university-based hospital. Participants Twelve eyes in 12 subjects with late-onset bleb leak from cystic bleb, without indications for prompt surgical interventions were included. Methods The subjects underwent crosslinking with 0.1% riboflavin application to bleb surface, followed by ultraviolet irradiation for 30 minutes. The subjects were followed up at baseline and at 1 week, 1 month, 3 months, 6 months post-treatment and then every 6 months afterwards. Main outcome measures Interval from treatment to cessation of bleb leak, recurrence rate of bleb leak and side effects of treatment. Results The mean follow-up after crosslinking was 29.33 ± 12.45 months. Bleb leak subsided in 11 (92%) of 12 patients after a single session of crosslinking, after 1 to 8 weeks (median 3 weeks). Time to leak cessation was significantly correlated with the number of prior glaucoma interventions (R = .71, P = .014). Bleb wall at 3 months was significantly thicker than at baseline (0.70 ± 0.67 vs 0.81 ± 0.62 mm, P = .008). None of the patients experienced any complications. Conclusions and relevance Crosslinking achieves resolution of cystic bleb leak which lasts for at least 12 months, without the need of subsequent surgical interventions. Crosslinking is a simple, non-invasive treatment for bleb leak. It aims to restore the integrity of conjunctiva.

Introduction: Studies showed dual antiplatelet therapy (DAPT) benefited TIA patients with an ABCD2 score ≥4. The present study aims to investigate whether the ABCD3-I score could be a more appropriate tool for TIA patients’ selection to use DAPT in the real-world experience. Methods: We derived data from the TIA database of the First Affiliated Hospital of Zhengzhou University. The predictive outcome was ischemic stroke at 90-day. Cox proportional hazards regression was used to examine the interaction effect between risk score and antiplatelet treatment. The Kaplan-Meier curves were plotted to present cumulative stroke rates in different risk patients with monotherapy and DAPT. Results: Among 785 patients, the mean (SD) age was 56.95 (12.73) years and 38.3% were female (n =301). A percentage of 36.9% patients used DAPT during hospitalization, and 77 patients (9.8%) had an ischemic stroke at 90-day. The Kaplan-Meier curves showed a significant difference between patients with monotherapy and DAPT in high-risk TIA patients (p= 0.021, Figure 1). After adjustment for confounding factors, DAPT only reduced 90-day stroke risk in high-risk TIA patients assessed by ABCD3-I score (HR= 0.402, 95%CI 0.189-0.859, p= 0.019, Table 1 and 2). Conclusions: High-risk TIA patients assessed by ABCD3-I score received the most pronounced clinical benefit from DAPT in the real-clinical experience.

Background: Hypercoagulability due to thrombophilia may increase the risk of paradoxic embolism. However, previous randomized controlled trials that evaluated the efficacy of PFO closure or medical therapy on the risk of recurrent stroke and/or transient ischemic attack (TIA) events, have excluded these potentially high-risk thrombophilia patients. In this study, we want to investigate the effect of PFO management on the risks of recurrent stroke and/or TIA among patients with thrombophilia. Methods: Patients with a PFO attributable ischemic stroke or TIA are prospectively recruited. Hypercoagulable tests for protein C, protein S, antithrombin III, homocysteine levels, IgG and IgM anticardiolipin antibodies, factor V Leiden and prothrombin gene variant were obtained. The primary outcome was occurrence of stroke and/or TIA after index event. Results: Thrombophilia is diagnosed in 120 PFO stroke patients who subsequently underwent PFO closure (n= 76) vs medical therapy (n= 44) ( Table 1 ). The mean duration of follow-up was 45 months in the closure group and 40 months in the medical-therapy group. The primary end point occurred in 5 patients (6.6%) in the closure group and in 14 (31.8%) in the medical therapy group (hazard ratio for medical therapy vs. closure, 5.797; 95% confidence interval [CI], 2.094 to 16.051; P = 0.001) ( Figure 1 ) with recurrent rate of 18.2% vs. 5.3% for TIA (P = 0.023) and 13.6% vs. 1.3% for stroke (P = 0.018) respectively. Conclusions: PFO stroke patients with hypercoagulable state had higher rate of recurrent stroke than those patients in clinical trials. Among patients who had cryptogenic embolism with thrombophilia, closure of a PFO was associated with a lower rate of recurrent stroke and/or TIA than medical therapy.

Background: Recent successful randomized clinical trials showed that patent foramen ovale (PFO) closure lower risk of recurrent stroke or transient ischemic attack (TIA), compared to medical therapy. However, older patients (age≥60 years old) were excluded in these trials. In this study, we investigate the effect of PFO treatment in older adults with PFO related cryptogenic embolism. Methods: We prospectively enrolled 209 patients older than 60 years of age, with cryptogenic stroke or TIA attributed to PFO from MGH Cardio-Neurology Clinic. Extensive cryptogenic stroke workup included MRI/A, echo, and MCOT. Primary end point was a composite of recurrent ischemic stroke, TIA. Results: Of the 209 PFO stroke patients, 66 patients underwent PFO closure and 143 patients received medical therapy ( Table 1 ). The mean duration of follow-up was 49 months in the closure group and 45 months in the medical-therapy group. The primary end point occurred in 4 patients (6.1%) in the closure group and in 27(18.9%) in the medical therapy group (HR for medical therapy vs. closure, 3.763; 95% CI, 1.306 to 10.840; P = 0.014) ( Figure 1 ). The respective rates were 1.5% vs 4.9% for TIA (P = 0.426) and 4.5% vs 14.0% for stroke (P = 0.043). Conclusions: Older patients with PFO related cryptogenic embolism may also derive more benefits from PFO closure compared to medical treatment.

Background: Most Aristolochiaceae plants are prohibited due to aristolochic acid nephropathy (AAN), except Xixin ( Asarum spp. ). Xixin contains trace amounts of aristolochic acid (AA) and is widely used in Traditional Chinese Medicine. Methylglyoxal and D-lactate are regarded as biomarkers for nephrotoxicity. Thus, this study aimed to evaluate tubulointerstitial injury and interstitial renal fibrosis by determining urinary methylglyoxal and D-lactate after withdrawal of low-dose AA in a chronic mouse model. Methods: C3H/He mice in the AA group ( n =24/group) were given ad libitum access to distilled water containing 3 µg/mL AA (0.5 mg/kg/day) for 56 days and drinking water from days 57 to 84. The severity of tubulointerstitial injury and fibrosis were evaluated using the tubulointerstitial histological score (TIHS) and Masson’s trichrome staining. Urinary and serum methylglyoxal were determined by high-performance liquid chromatography (HPLC); urinary D-lactate were determined by column-switching HPLC. Results: After AA withdrawal, serum methylglyoxal in the AA group increased from day 56 (429.4±48.3 μg/L) to 84 (600.2±99.9 μg/L), and peaked on day 70 (878.3±171.8 μg/L; p Conclusions: Methylglyoxal is induced after AA-induced tubulointerstitial injury, thus methylglyoxal excretion and metabolism may be a detoxification and repair strategy. A low cumulative AA dose is the key factor that limits tubulointerstitial injury and repair. Thus, AA-containing herbs, especially Xixin, should be used at low doses for short durations (less than one month).

Antibiotics in soil environments are a growing concern. Identifying transformation products is key to elucidating degradation pathways and mechanisms of antibiotics and other organic micropollutants. The primary challenge of transformation product identification is the interference of matrices. In this study, stable-isotope assisted nontarget screening was used to identify biodegradation products of florfenicol in soil. A total of 74 candidates were prioritized from thousands of mass features observed by a tiered peak filtering approach. Moreover, with the support of in silico prediction tools, the structures of 12 transformation products were elucidated, and 9 of them were reported for the first time. A biodegradation map of florfenicol consisting of amide hydrolysis, dechlorination, dehydration, defluorination, and sulfone reduction was established based on these identified products. A total of 8 products were also found in 6 field soil samples with manure application. Because of the structural similarity to florfenicol, some transformation products might still keep antimicrobial activity toward a variety of bacterial species. The strategies demonstrated in this study provide a basis for efficient identification of transformation products of other organic micropollutants in a variety of environmental matrices. The results also shed light on the degradation mechanisms, risk assessments, and regulations of these compounds.

Practical and scalable syntheses were developed that were used to prepare multikilogram batches of GSK1292263A (1) and GSK2041706A (15), two potent G protein-coupled receptor 119 (GPR119) agonists. Both syntheses employed relatively cheap and readily available starting materials, and both took advantage of an SNAr synthetic strategy.

Four new X-ray structures of tryptophan synthase (TS) crystallized with varying numbers of the amphipathic N-(4′-trifluoromethoxybenzoyl)-2-aminoethyl phosphate (F6) molecule are presented. These structures show one of the F6 ligands threaded into the tunnel from the β-site and reveal a distinct hydrophobic region. Over this expanse, the interactions between F6 and the tunnel are primarily nonpolar, while the F6 phosphoryl group fits into a polar pocket of the β-subunit active site. Further examination of TS structures reveals that one portion of the tunnel (T1) binds clusters of water molecules, whereas waters are not observed in the nonpolar F6 binding region of the tunnel (T2). MD simulation of another TS structure with an unobstructed tunnel also indicates the T2 region of the tunnel excludes water, consistent with a dewetted state that presents a significant barrier to the transfer of water into the closed β-site. We conclude that hydrophobic molecules can freely diffuse between the α- and β-sites via the tunnel, while water does not. We propose that exclusion of water serves to inhibit reaction of water with the α-aminoacrylate intermediate to form ammonium ion and pyruvate, a deleterious side reaction in the αβ-catalytic cycle. Finally, while most TS structures show βPhe280 partially blocking the tunnel between the α- and β-sites, new structures show an open tunnel, suggesting the flexibility of the βPhe280 side chain. Flexible docking studies and MD simulations confirm that the dynamic behavior of βPhe280 allows unhindered transfer of indole through the tunnel, therefore excluding a gating role for this residue.

Objective To estimate the potential value of fetal assessment for the cardiac axis (CAx) and V-sign angle (VSA) in the first trimester in the prediction of fetal major cardiac defects. Methods A cohort study was conducted from December 2015 to June 2016. Patients with singleton pregnancies and crown-rump length from 45 to 84 mm were recruited to undergo nuchal translucency sonography. The CAx on the 4-chamber view and the VSA on the 3-vessel and trachea view with Doppler mapping were measured. The estimated performance of different combinations of increased fetal nuchal translucency, CAx, and VSA in screening for major cardiac defects was examined. Results The study population of fetuses included 30 fetuses with major cardiac defects and 1538 normal fetuses. The CAx and VSA were 30° to 60° and 30° to 40°, respectively, according to the 2.5th and 97.5th percentiles in normal fetuses. When cases of isolated septal wall defects and an isolated right aortic arch were excluded, nuchal translucency above the 95th percentile, an abnormal CAx, and an abnormal VSA were observed in 63.3% (19 of 30), 63.3% (19 of 30), and 66.7% (20 of 30) of fetuses with major cardiac defects, respectively, and in 4.6% (71 of 1538), 2.0% (30 of 1538), and 5.6% (86 of 1538) of those without cardiac defects. Either an abnormal CAx or VSA was found in 93.3% (28 of 30) of the fetuses with cardiac defects and in 7.3% (113 of 1538) of those without cardiac defects. Conclusion Assessment of the CAx and VSA is helpful in defining a population at risk for major cardiac defects in the first trimester.

It is important to determine the binding pathways and mechanisms of ligand molecules to target proteins to effectively design therapeutic drugs. Molecular dynamics (MD) is a promising computational tool that allows us to simulate protein-drug binding at an atomistic level. However, the gap between the time scales of current simulations and those of many drug binding processes has limited the usage of conventional MD, which has been reflected in studies of the HIV protease. Here, we have applied a robust enhanced simulation method, Gaussian accelerated molecular dynamics (GaMD), to sample binding pathways of the XK263 ligand and associated protein conformational changes in the HIV protease. During two of 10 independent GaMD simulations performed over 500-2500 ns, the ligand was observed to successfully bind to the protein active site. Although GaMD-derived free energy profiles were not fully converged because of insufficient sampling of the complex system, the simulations still allowed us to identify relatively low-energy intermediate conformational states during binding of the ligand to the HIV protease. Relative to the X-ray crystal structure, the XK263 ligand reached a minimum root-mean-square deviation (RMSD) of 2.26 Å during 2.5 μs of GaMD simulation. In comparison, the ligand RMSD reached a minimum of only ∼5.73 Å during an earlier 14 μs conventional MD simulation. This work highlights the enhanced sampling power of the GaMD approach and demonstrates its wide applicability to studies of drug-receptor interactions for the HIV protease and by extension many other target proteins.

A large number of studies focus on the effects of news consumption on learning. However, we know surprisingly little about how the process of news consumption itself influences learning across different platforms. This experimental study (N = 149) uses eye tracking to examine to what extent news modality (i.e., whether news is presented in a printed newspaper or on a news website) affects visual attention to news, and subsequently, knowledge. Results show that differences in learning between news modalities are indeed driven by variations in attention; exposure to printed news media leads to more diverse learning through increased visual attention, while more selective visual attention to news on websites leads to learning of specific subjects only.