bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small‐Molecule Inhibition of the uPAR ⋅ uPA Interaction by Conformational Selection
Authors: Xu David , Bum‐Erdene Khuchtumur , Leth Julie M. , Ghozayel Mona K. , Ploug Michael , Meroueh Samy O. 
Published: October 2020

AbstractThe urokinase receptor (uPAR) is a cell surface receptor that binds to the serine protease urokinase‐type plasminogen activator (uPA) with high affinity. This interaction is beneficial for extravascular fibrin clearance, but it has also been associated with a broad range of pathological conditions including cancer, atherosclerosis, and kidney disease. Here, starting with a small molecule that we previously discovered by virtual screening and cheminformatics analysis, we design and synthesize several derivatives that were tested for binding and inhibition of the uPAR ⋅ uPA interaction. To confirm the binding site and establish a binding mode of the compounds, we carried out biophysical studies using uPAR mutants, among them uPARH47C−N259C, a mutant previously developed to mimic the structure of uPA‐bound uPAR. Remarkably, a substantial increase in potency is observed for inhibition of uPARH47C−N259C binding to uPA compared to wild‐type uPAR, consistent with our use of the structure of uPAR in its uPA‐bound state to design small‐molecule uPAR ⋅ uPA antagonists. Combined with the biophysical studies, molecular docking followed by extensive explicit‐solvent molecular dynamics simulations and MM‐GBSA free energy calculations yielded the most favorable binding pose of the compound. Collectively, these results suggest that potent inhibition of uPAR binding to uPA with small molecules will likely only be achieved by developing small molecules that exhibit high‐affinity to solution apo structures of uPAR, rather than uPA‐bound structures of the receptor.
Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T‐cell acute lymphoblastic leukemia and lymphoma
Authors: Borthakur Gautam , Martinelli Giovanni , Raffoux Emmanuel , Chevallier Patrice , Chromik Jörg , Lithio Andrew , Smith Claire L. , Yuen Eunice , Oakley Gerard Joseph , Benhadji Karim A. , DeAngelo Daniel J. 
Published: October 2020

BackgroundDeregulated Notch signaling is implicated in T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (T‐LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T‐ALL/T‐LBL.MethodsJJCB was a multicenter, nonrandomized, open‐label, dose‐escalation, phase 1 study in adult patients with relapsed/refractory T‐ALL/T‐LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28‐day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose‐limiting toxicity (DLT) at the recommended dose level.ResultsIn total, 36 patients with T‐ALL (n = 31 [86.1%]) or T‐LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75‐mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100‐mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125‐mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty‐eight patients (77.8%) experienced 1 or more treatment‐emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event‐free survival was 1.18 months (95% confidence interval, 0.76‐2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels.ConclusionsCrenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T‐ALL/T‐LBL.
Methods for Expression of Recombinant Proteins Using a Pichia pastoris Cell‐Free System
Authors: Aw Rochelle , Spice Alex J. , Polizzi Karen M. 
Published: October 2020

AbstractCell‐free protein synthesis is a powerful tool for engineering biology and has been utilized in many diverse applications, from biosensing and protein prototyping to biomanufacturing and the design of metabolic pathways. By exploiting host cellular machinery decoupled from cellular growth, proteins can be produced in vitro both on demand and rapidly. Eukaryotic cell‐free platforms are often neglected due to perceived complexity and low yields relative to their prokaryotic counterparts, despite providing a number of advantageous properties. The yeast Pichia pastoris (also known as Komagataella phaffii) is a particularly attractive eukaryotic host from which to generate cell‐free extracts, due to its ability to grow to high cell densities with high volumetric productivity, genetic tractability for strain engineering, and ability to perform post‐translational modifications. Here, we describe methods for conducting cell‐free protein synthesis using P. pastoris as the host, from preparing the cell lysates to protocols for both coupled and linked transcription‐translation reactions. By providing these methodologies, we hope to encourage the adoption of the platform by new and experienced users alike. © 2020 The Authors.Basic Protocol 1: Preparation of Pichia pastoris cell lysateBasic Protocol 2: Coupled in vitro transcription and translationBasic Protocol 3: Determining luciferase production from cell‐free protein synthesis reactionsAlternate Protocol 1: Linked in vitro transcription and translationAlternate Protocol 2: Quantifying HSA protein concentrationSupport Protocol 1: Preparation of mRNA by in vitro transcription for linked transcription and translation
Development and evaluation of an interdisciplinary teaching model via 3D printing
Authors: Reymus Marcel , Liebermann Anja , Diegritz Christian , Keßler Andreas 
Published: October 2020

AbstractThe investigation aimed to assess the feasibility of creating an interdisciplinary training model simulating endodontic, restorative as well as implantologic treatment procedures by using 3D printing technology. A CBCT scan of the mandible of a real patient was initially taken. The generated DICOM‐data were converted to a STL‐file, which was further processed to design spaces for exchangeable replica teeth, a bone segment and an adapter to fix the model in a mannequin's head. After the manufacturing process, the model was evaluated by dental students performing a root canal treatment, the insertion of a glass fibre post and the insertion of an implant. The workflow allowed a simple and cost‐effective way of manufacturing a single model, which is suitable for several training scenarios in the fields of endodontics, prosthodontics and implantology. The model was rated as being comparable to the real patient situation and offers repetitive treatment simulations. The present workflow is a feasible way of using DICOM‐data and 3D printing for an interdisciplinary training model. The dental schools can design models according to their own curriculum and put the focus on a patient centered education.
Transition Metal‐Free Synthesis of Carbamates Using CO2 as the Carbon Source
Authors: Schilling Waldemar , Das Shoubhik 
Published: October 2020

AbstractUtilization of carbon dioxide as a C1 synthon is highly attractive for the synthesis of valuable chemicals. However, activation of CO2 is highly challenging, owing to its thermodynamic stability and kinetic inertness. With this in mind, several strategies have been developed for the generation of carbon–heteroatom bonds. Among these, formation of C−N bonds is highly attractive, especially, when carbamates can be synthesized directly from CO2. This Minireview focuses on transition metal‐free approaches for the fixation of CO2 to generate carbamates for the production of fine chemicals and pharmaceuticals. Within the past decade, transition metal‐free approaches have gained increasing attention, but traditional reviews have rarely focused on these approaches. Direct comparisons between such methods have been even more scarce. This Minireview seeks to address this discrepancy.
Multilevel governance in environmental policy integration: A content analysis of regional and urban nested hierarchies in China
Authors: Sheng Rong 
Published: October 2020

AbstractThis study attempts to identify the different priorities of environmental policy integration under a multilevel governance background in China. The subjects for analysis included the four‐level hierarchies of China's central government, the Yangtze River Delta, Shanghai, and Chongming eco‐island. NVivo 12 Plus software aided the content analysis of regional and urban nested hierarchy planning documents. The results represent environmental policy integration (EPI) priorities in different hierarchical levels and sectors, as well as the sectoral elaboration on prioritized policy instruments. In addition, the implications of the results in the process toward co‐work in multilevel governance of EPI are discussed. Though inconsistencies exist in EPI priorities, it is advised to design the coordinative vertical framework and approach these policy instruments cooperatively across multilevel governance. In the strategic co‐work relations, the four levels follow the same blueprint in their EPI. Regarding the interactions among multilevel ranks, the results show an inclination of being fueled by the central authority. However, how the local governmental levels will embody and enforce higher levels' priorities could depend on the different natural and societal conditions at each level.
Spatial hierarchical modeling of threshold exceedances using rate mixtures
Authors: Yadav Rishikesh , Huser Raphaël , Opitz Thomas 
Published: October 2020

AbstractWe develop new flexible univariate models for light‐tailed and heavy‐tailed data, which extend a hierarchical representation of the generalized Pareto (GP) limit for threshold exceedances. These models can accommodate departure from asymptotic threshold stability in finite samples while keeping the asymptotic GP distribution as a special (or boundary) case and can capture the tails and the bulk jointly without losing much flexibility. Spatial dependence is modeled through a latent process, while the data are assumed to be conditionally independent. Focusing on a gamma–gamma model construction, we design penalized complexity priors for crucial model parameters, shrinking our proposed spatial Bayesian hierarchical model toward a simpler reference whose marginal distributions are GP with moderately heavy tails. Our model can be fitted in fairly high dimensions using Markov chain Monte Carlo by exploiting the Metropolis‐adjusted Langevin algorithm (MALA), which guarantees fast convergence of Markov chains with efficient block proposals for the latent variables. We also develop an adaptive scheme to calibrate the MALA tuning parameters. Moreover, our model avoids the expensive numerical evaluations of multifold integrals in censored likelihood expressions. We demonstrate our new methodology by simulation and application to a dataset of extreme rainfall events that occurred in Germany. Our fitted gamma–gamma model provides a satisfactory performance and can be successfully used to predict rainfall extremes at unobserved locations.
Alteration of lipid profile and value of lipids in the prediction of the length of hospital stay in COVID‐19 pneumonia patients
Authors: Qin Chen , Minghan Huang , Ziwen Zhao , Yukun Luo 
Published: October 2020

AbstractTo observe lipid profiles and their alterations in hospitalized patients with COVID‐19 pneumonia (NCP) and evaluate the value of lipids for the prediction of the length of hospital stay (LOS), a total of 248 patients aged 18 years or older were enrolled in this retrospective study. At admission, the median levels of triglyceride (TG), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C), and low‐density lipoprotein cholesterol (LDL‐C) in all patients were 1.11, 4.00, 0.89, and 2.11 mmol/L, respectively. Compared with common cases (n = 174), severe cases (n = 74) exhibited higher TG and HDL‐C, and lower LDL‐C. Levels of TC and LDL‐C were negatively correlated with LOS. In 68 severe cases, serum lipids were followed up during hospitalization, and the median LOS was 29 days. The average levels of serum lipids were lowest at admission and gradually increased during hospitalization. Compared with the LOS ≤ 29 days group, serum levels of TC, HDL‐C, and LDL‐C were significantly lower in the LOS > 29 days group at admission; this lower trend was found in the subsequent tests for TC and LDL‐C but not for HDL‐C or TG. Multiple‐variant COX regression showed that levels of TC or LDL‐C at admission were independent risk of LOS prolongation. Together, these findings suggest that in patients with NCP, levels of TC and LDL‐C at admission were negatively correlated with LOS. In severe cases, the gradual increase in TC, LDL‐C, and HDL‐C during hospitalization might indicate gradual recovery. TC < 3.75 mmol/L or LDL‐C < 1.7 mmol/L at admission may act as an independent predictor of prolonged LOS.
111 m, 74 m und 37 m lange Probepfähle für den Elbtower in Hamburg
Authors: Kaya‐Sandt Hatice , Borchert Kurt‐Michael , von Quillfeldt Michael , Wedenig Andreas 
Published: October 2020

AbstractAm östlichen Ende der HafenCity in Hamburg wird der Elbtower mit einer Höhe von rund 245 m geplant. Der Turm mit der angrenzenden Sockelbebauung wird mit zwei bis drei Untergeschossen auf einer Fläche von ca. 15 000 m2 ab voraussichtlich 2020 errichtet. Bei den Baugrunderkundungen stellte sich heraus, dass der Neubau im Bereich eines Kreuzungsbereichs von eiszeitlichen Rinnen zu gründen ist, in dem eine heterogene Baugrundschichtung bis wahrscheinlich rund 200 m unter Gelände vorzufinden ist. Im Bereich des geplanten Turms ist eine für Hamburger Verhältnisse typische Absetztiefe der Pfähle in die bis zu 30 m unter Gelände reichenden Sande, insbesondere mit Blick auf die Setzungen des Bauwerks, nicht realisierbar. Ziel ist es, die Bauwerkslasten aus dem Turm bis in die tiefliegenden Schichten unterhalb der anstehenden, setzungsrelevanten Tone und Schluffe zu leiten und die Setzungen hiermit in einem verträglichen Maß zu halten. Zur Ermittlung der Baugrundverhältnisse und ‐kennwerte wurden umfangreiche Erkundungen im Feld sowie im Labor durchgeführt. Zur Ermittlung von Pfahlsetzungen und ‐tragfähigkeiten erfolgten Probebelastungen mit Bohrpfählen unterschiedlicher Längen. An jedem Pfahl wurden ca. 5 m über dem Pfahlfuß Osterberg‐Zellen angeordnet. Die Probepfähle wurden im August 2019 durch die Bauer Spezialtiefbau GmbH im Kelly‐Bohrverfahren hergestellt. Der Einbau der Belastungs‐ und Messtechnik sowie die Durchführung der Probebelastungen wurden von der Firma Fugro/Loadtest ausgeführt. Die Probebelastungen erfolgten im Oktober 2019. Es konnten für die langen Pfähle Tragfähigkeiten von über 60 MN nachgewiesen werden.
Nodal disease burden and outcome of medullary thyroid carcinoma
Authors: Moses Lindsey E. , Oliver Jamie R. , Rotsides Janine M. , Shao Qianhui , Patel Kepal N. , Morris Luc G. T. , Givi Babak 
Published: October 2020

AbstractBackgroundMedullary thyroid carcinoma (MTC) is a rare malignancy with high incidence of cervical lymph node (CLN) metastasis. We investigated the impact of nodal disease burden on survival.MethodsWe searched the National Cancer Database for MTC patients treated surgically. Impact of nodal metastasis on survival was analyzed using Cox univariable and multivariable regression.ResultsWe identified 2627 patients from 2004 to 2015. Positive CLNs were identified in 1433 (54.5%), and 542 (20.6%) had >10 CLN+. Overall survival was 94.5% and 89.6% at 3 and 5 years. Patients with 11 to 20 CLN+ had significantly worse survival than patients with 1 to 10 CLN+ in univariable and multivariable analyses (HR = 3.56 (2.31‐5.50) vs 2.26 (1.60‐3.20); P < .0001). The ratio of positive to dissected CLN was associated with overall survival.ConclusionsHigher burden of nodal disease is associated with worse survival in MTC. The number of positive nodes could be a valuable prognosticator in addition to the current staging system.
A double‐blind randomized trial on subendometrial injection of vasopressin to control bleeding in postpartum hysterectomy due to abnormally invasive placenta
Authors: Ghotbizadeh Vhdani Fahimeh , Nasiri Khormoji Najmeh , Eftekhar Negar , Deldar Pasikhani Maryam , Hantoushzadeh Sedigheh , Ghamari Azin , Panahi Zahra 
Published: October 2020

AbstractObjectiveTo investigate the effect of subendometrial vasopressin injection in patients with abnormally invasive placenta (AIP), who underwent cesarean section and hysterectomy.MethodsThis randomized double‐blinded clinical trial was conducted on pregnant women diagnosed with AIP grade 4 and 5 by ultrasonography during cesarean section. Women were randomly divided into two equal groups including group 1 (vasopressin) and group 2 (control) who underwent 20 units of vasopressin and 20 cc normal saline injection, respectively. Vasopressin and placebo were injected subendometrially 1 cm medial to the uterine vessels into the lower uterine segment. The exclusion criteria include presence of myocardial infarction, cardiomyopathy, congestive heart failure, uncontrolled hypertension, chronic obstructive pulmonary disease, pelvic malignancy. The outcome of the study was total quantitative blood loss during the cesarean section. We estimated blood loss by measuring the blood volume in one of the suction bottles with addition for weight changes of mops, pads, and soaked linen savers.ResultsSixty patients were recruited into the study, 30 as the vasopressin group and 30 as the controls; with no excluded case. The amount of bleeding in the vasopressin group was significantly lower compared with that in the control group (P < 0.001). In the vasopressin group, 83.4% of patients had bleeding of less than 1.5 L, while only 3.3% of the control women had bleeding of less than 1.5 L (relative risk = 5). In addition, the number of injected packed cells was lower in the vasopressin group (P < 0.001).ConclusionIt was shown that vasopressin injection can help prevent excess hemorrhage and the subsequent risks of anemia or blood transfusions during abdominal hysterectomy in women with AIP.
Male partner involvement and successful completion of the prevention of mother‐to‐child transmission continuum of care in Kenya
Authors: Hampanda Karen , Helova Anna , Odwar Tobias , Odeny Thomas , Onono Maricianah , Bukusi Elizabeth , Turan Janet , Abuogi Lisa 
Published: October 2020

AbstractObjectiveTo examine the relationship between male partner involvement (MPI) in prevention of mother‐to‐child transmission (PMTCT) activities and successful completion of the PMTCT continuum of care, which remains sub‐optimal in settings with high prevalence of HIV.MethodsA cross‐sectional survey was administered in June–August 2017 to a sample of 200 postpartum Kenyan women with HIV enrolled in a parent trial. Composite PMTCT and MPI variables were created. Descriptive, simple and multivariable regression, and mediation analyses were performed.ResultsOf the women, 54% reported successful completion of PMTCT. Depression and internalized HIV stigma were independently associated with lower likelihood of successful completion of PMTCT (adjusted risk ratio [aRR] 0.97; 95% confidence interval [CI] 0.94–0.99; aRR 0.92; 95% CI 0.88–0.98, respectively). Each MPI activity was associated with 10% greater likelihood of successful completion of PMTCT (P < 0.05). The relationship between MPI and the successful completion of PMTCT was partially mediated through women's reduced internalized HIV stigma (β −0.03; 95%CI −0.06 to −0.00).ConclusionGreater MPI in PMTCT activities has direct and indirect effects on women's successful completion of all necessary steps across the PMTCT continuum. Reduced internalized HIV stigma is likely a key mechanism in the relationship.
In vitro copper oxide nanoparticle toxicity on intestinal barrier
Authors: Bertero Alessia , Colombo Graziano , Cortinovis Cristina , Bassi Virginia , Moschini Elisa , Bellitto Nicholas , Perego Maria Chiara , Albonico Marco , Astori Emanuela , Dalle‐Donne Isabella , Gedanken Aharon , Perelshtein Ilana , Mantecca Paride , Caloni Francesca 
Published: October 2020

AbstractThe use of CuO nanoparticles (NPs) has increased greatly and their potential effects on human health need to be investigated. Differentiated Caco‐2 cells were treated from the apical (Ap) and the basolateral (Bl) compartment with different concentrations (0, 10, 50 and 100 μg/mL) of commercial or sonochemically synthesized (sono) CuO NPs. Sono NPs were prepared in ethanol (CuOe) or in water (CuOw), obtaining CuO NPs differing in size and shape. The effects on the Caco‐2 cell barrier were assessed via transepithelial electrical resistance (TEER) evaluation just before and after 1, 2 and 24 hours of exposure and through the analysis of cytokine release and biomarkers of oxidative damage to proteins after 24 hours. Sono CuOe and CuOw NPs induced a TEER decrease with a dose‐dependent pattern after Bl exposure. Conversely, TEER values were not affected by the Ap exposure to commercial CuO NPs and, concerning the Bl exposure, only the lowest concentration tested (10 μg/mL) caused a TEER decrease after 24 hours of exposure. An increased release of interleukin‐8 was induced by sono CuO NPs after the Ap exposure to 100 μg/mL and by sono and commercial CuO after the Bl exposure to all the concentrations. No effects of commercial and sono CuO NPs on interleukin‐6 (with the only exception of 100 μg/mL Bl commercial CuO) and tumor necrosis factor‐α release were observed. Ap treatment with commercial and CuOw NPs was able to induce significant alterations on specific biomarkers of protein oxidative damage (protein sulfhydryl group oxidation and protein carbonylation).
Development of tantalum with highly hydrophilic surface and antimicrobial properties obtained by micro‐arc oxidation process
Authors: Sopata Mateusz , Karpiński Tomasz M. , Jakubowicz Jaroslaw , Sopata Maciej 
Published: October 2020

AbstractTantalum (Ta) and its application in biomaterials has been attracting more and more attention recently. It can be considered as a material for hard tissue implants. This study focuses on antimicrobial and surface characterization of micro‐arc oxidized (MAO) nanocrystalline Ta compared with its microcrystalline equivalent. For the purposes of the investigation, x‐ray diffractometry (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), wetting analysis, optical profilometry, corrosion resistance measurement, and antimicrobial tests were performed. Nanocrystalline Ta was fabricated using high‐energy ball milling (HEBM) and pulse plasma sintering (PPS). The MAO process done at 250 V results in the formation of a porous oxide surface. An XRD analysis confirmed the presence of a Ta2O5 oxide layer. Based on the SEM pictures, the obtained oxide layer was approximately 3–4 μm thick for nanocrystalline Ta substrate. For microcrystalline Ta, the oxide layer was thinner, in the range of 0.3–0.6 μm. The analysis of polarization curves showed a significant improvement of corrosion resistance for MAO nanocrystalline Ta (2.62 × 10−8 A/cm2) versus not oxidized nanocrystalline Ta (1.20 × 10−5 A/cm2). The surface roughness of MAO nanocrystalline Ta proved to be several times higher than that of unoxidized Ta. Wetting analysis showed that the oxide layer on the nanocrystalline substrate is hydrophilic. This research provides detailed information about MAO microcrystalline and MAO nanocrystalline Ta antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa. A significant decrease of S. aureus for MAO nanocrystalline Ta (control 10,435 ± 981 vs. sample 3,453 ± 130) was noticed. No significant difference was noticed for MAO microcrystalline and nanocrystalline Ta tested for P. aeruginosa.