bluuebunny/crossref_metadata_2025 huggingface dataset:
Hard Carbon Composite Electrodes for Sodium‐Ion Batteries with Nano‐Zeolite and Carbon Black Additives
Authors: Ledwoch Daniela , Robinson James B. , Gastol Dominika , Smith Katherine , Shearing Paul R. , Brett Daniel J. L. , Kendrick Emma
Published: September 2020

To enable fast charging of sodium‐ion batteries and eliminate metallic dendrite growth on the electrodes an improvement in electrode design is required. In this work, we show the benefit of a mixed composite electrode containing ionic and electronic conducting additives for a sodium‐ion battery negative electrode. Hard carbon electrodes with 5 % additive containing different proportions of zeolite and carbon black are coated. The performance of the electrodes is elucidated through electrochemical and physical characterization methods; fast sodiation, electrochemical impedance spectroscopy (EIS), galvanostatic intermittent titration techniques (GITT) and electron microscopy. The addition of zeolite improves the sodium‐ion transport diffusivity within the composite electrode by an order of magnitude at low voltages and high states of charge. EIS shows significantly lower series and solid‐electrolyte interphase (SEI) resistances in the zeolite containing electrode after cycling. The capacity retention at higher rates is improved and a significant reduction of sodium dendrite growth was observed after cycling. SEM images confirm that porosity is still present in the zeolite containing electrode samples, enabling a pore network for sodium ion transport. These results emphasize the importance and limitations of ionic transport within hard carbon electrodes, and the required optimisation between electronic and ionic conductivity for sodium ion transport in these electrodes.
The Sound of Batteries: An Operando Acoustic Emission Study of the LiNiO2 Cathode in Li–Ion Cells
Authors: Schweidler Simon , Bianchini Matteo , Hartmann Pascal , Brezesinski Torsten , Janek Jürgen
Published: September 2020

Invited for this month's cover picture is the group of Jürgen Janek at KIT. The cover picture shows that acoustic emission is a promising technique that allows degradation of battery materials such as particle fracture to be probed in a non‐destructive manner. Read the full text of the Article at 10.1002/batt.202000099.
A detailed model and Monte Carlo simulation for predicting DIP genome length distribution in baculovirus infection of insect cells
Authors: Das Ashok , Dutta Soumajit , Sen Moumita , Saxena Abha , Kumar Jitendra , Giri Lopamudra , Murhammer David W. , Chakraborty Jayanta
Published: September 2020

Baculoviruses have enormous potential for use as biopesticides to control insect pest populations without the adverse environmental effects posed by the widespread use of chemical pesticides. However, continuous baculovirus production is susceptible to DNA mutation and the subsequent production of defective interfering particles (DIPs). The amount of DIPs produced and their genome length distribution are of great interest not only for baculoviruses but for many other DNA and RNA viruses. In this study, we elucidate this aspect of virus replication using baculovirus as an example system and both experimental and modeling studies. The existing mathematical models for the virus replication process consider DIPs as a lumped quantity and do not consider the genome length distribution of the DIPs. In this study, a detailed population balance model for the cell‐virus culture is presented, which predicts the genome length distribution of the DIP population along with their relative proportion. The model is simulated using the kinetic Monte Carlo algorithm, and the results agree well with the experimental results. Using this model, a practical strategy to maintain the DIP fraction to near to its maximum and minimum limits has been demonstrated.
Altered long‐ and short‐range functional connectivity density associated with poor sleep quality in patients with chronic insomnia disorder: A resting‐state fMRI study
Authors: Zhou Fuqing , Zhu Yanyan , Zhu Yujun , Huang Muhua , Jiang Jian , He Laichang , Huang Suhua , Zeng Xianjun , Gong Honghan
Published: September 2020

Introduction

Previous neuroimaging studies have suggested that brain functional impairment and hyperarousal occur during the daytime among patients with chronic insomnia disorder (CID); however, alterations to the brain's intrinsic functional architecture and their association with sleep quality have not yet been documented.

Methods

In this study, our aim was to investigate the insomnia‐related alterations to the intrinsic connectome in patients with CID (n = 27) at resting state, with a data‐driven approach based on graph theory assessment and functional connectivity density (FCD), which can be interpreted as short‐range (intraregional) or long‐range (interregional) mapping.

Results

Compared with healthy controls with good sleep, CID patients showed significantly decreased long‐range FCD in the dorsolateral prefrontal cortices and the putamen. These patients also showed decreased short‐range FCD in their multimodal‐processing regions, executive control network, and supplementary motor‐related areas. Furthermore, several regions showed increased short‐range FCD in patients with CID, implying hyper‐homogeneity of local activity.

Conclusions

Together, these findings suggest that insufficient sleep during chronic insomnia widely affects cortical functional activities, including disrupted FCD and increased short‐range FCD, which is associated with poor sleep quality.
Gemcitabine and doxorubicin in immunostimulatory monophosphoryl lipid A liposomes for treating breast cancer
Authors: Wu Debra , Zhao Zongmin , Kim Jayoung , Razmi Amaya , Wang Lily Li‐Wen , Kapate Neha , Gao Yongsheng , Peng Kevin , Ukidve Anvay , Mitragotri Samir
Published: September 2020

Cancer therapy is increasingly shifting toward targeting the tumor immune microenvironment and influencing populations of tumor infiltrating lymphocytes. Breast cancer presents a unique challenge as tumors of the triple‐negative breast cancer subtype employ a multitude of immunosilencing mechanisms that promote immune evasion and rapid growth. Treatment of breast cancer with chemotherapeutics has been shown to induce underlying immunostimulatory responses that can be further amplified with the addition of immune‐modulating agents. Here, we investigate the effects of combining doxorubicin (DOX) and gemcitabine (GEM), two commonly used chemotherapeutics, with monophosphoryl lipid A (MPLA), a clinically used TLR4 adjuvant derived from liposaccharides. MPLA was incorporated into the lipid bilayer of liposomes loaded with a 1:1 molar ratio of DOX and GEM to create an intravenously administered treatment. In vivo studies indicated excellent efficacy of both GEM‐DOX liposomes and GEM‐DOX‐MPLA liposomes against 4T1 tumors. In vitro and in vivo results showed increased dendritic cell expression of CD86 in the presence of liposomes containing chemotherapeutics and MPLA. Despite this, a tumor rechallenge study indicated little effect on tumor growth upon rechallenge, indicating the lack of a long‐term immune response. GEM/DOX/MPLA‐L displayed remarkable control of the primary tumor growth and can be further explored for the treatment of triple‐negative breast cancer with other forms of immunotherapy.
Investigating the role of mechanics in lignocellulosic biomass degradation during hydrolysis: Part II
Authors: Digaitis Ramūnas , Thybring Emil Engelund , Thygesen Lisbeth Garbrecht
Published: September 2020

Lignocellulose breakdown in biorefineries is facilitated by enzymes and physical forces. Enzymes degrade and solubilize accessible lignocellulosic polymers, primarily on fiber surfaces, and make fibers physically weaker. Meanwhile physical forces acting during mechanical agitation induce tearing and cause rupture and attrition of the fibers, leading to liquefaction, that is, a less viscous hydrolysate that can be further processed in industrial settings. This study aims at understanding how mechanical agitation during enzymatic saccharification can be used to promote fiber attrition. The effects of reaction conditions, such as substrate and enzyme concentration on fiber attrition rate and hydrolysis yield were investigated. To gain insight into the fiber attrition mechanism, enzymatic hydrolysis was compared to hydrolysis by use of hydrochloric acid. Results show that fiber attrition depends on several factors concerning reactor design and operation including drum diameter, rotational speed, mixing schedule, and concentrations of fibers and enzymes. Surprisingly, different fiber attrition patterns during enzymatic and acid hydrolysis were found for similar mixing schedules. Specifically, for tumbling mixing, slow continuous mixing appears to function better than faster, intermittent mixing even for the same total number of drum revolutions. The findings indicate that reactor design and operation as well as hydrolysis conditions are key to process optimization and that detailed insights are needed to obtain fast liquefaction without sacrificing saccharification yields.
RETRACTED: GANT61 plays antitumor effects by inducing oxidative stress through the miRNA‐1286/RAB31 axis in osteosarcoma
Authors: Zhang Kuai‐qiang , Chu Xiang‐dong
Published: September 2020

Osteosarcoma (OS) is a rare malignancy of bone associated with poor clinical outcomes. The antitumor effects of GANT61 on OS is unclear. To investigate antitumor effects and mechanism of GANT61 in OS cells and xenograft model. Effects of GANT61 on cell viability, clone formation, cell cycle, apoptosis, migration, and invasion ability of OS cells were assessed. Reactive oxygen species (ROS) levels measured by dichlorofluorescein fluorescence were used to evaluate oxidative stress. The Xenograft model was constructed to investigate the antitumor effects of GANT61 in vivo. The microRNA (miRNA)‐1286 was downregulated, while RAB31 upregulated in OS tissues and cells. GANT61 inhibited viability, migration, and invasion ability of OS cells (SaOS‐2 and U2OS), and induced apoptosis and the ROS production, along with miRNA‐1286 upregulation and RAB13 downregulation. After knockdown of miRNA‐1286, GANT6‐induced cell inhibition was attenuated, along with RAB31 upregulation. Inversely, miRNA‐1286 overexpression downregulated RAB31. Dual‐luciferase reporter assay verified that miR‐1286 negatively targeted RAB13. Moreover, the knockdown of RAB31 stimulated apoptosis and ROS production while inhibited viability, migration, and invasion of GANT61‐treated cells. In vivo experiments further confirmed that GANT61 inhibited tumor growth and RAB13 expression, but enhanced miRNA‐1286. The study demonstrated that GANT61 inhibited cell aggressive phenotype and tumor growth by inducing oxidative stress through the miRNA‐1286/RAB31 axis. Our findings provided a potential antitumor agent for the OS clinical treatment.
A new perspective in CTO PCI
Authors: Rodriguez‐Paz Enrique , Heuser Richard R.
Published: September 2020

Key Points

Comparative studies of CTO PCI versus medical therapy have not shown consistent benefits of intervention.

Interventional treatment of CTO takes more time, manual dexterity, device utilization, and results in a potential of increase in complications compared to non‐CTO PCI.

As experience and equipment evolve, PCI of CTO has dramatically improved.
Applied pharmacology in percutaneous coronary intervention: You can't fight mother nature
Authors: Bengaluru Jayanna Manju , Gray William A.
Published: September 2020

Key Points

Differential outcomes based on target vessel diameter persist in the era of second generation drug eluting stents.

These differences are mainly driven by need for target vessel revascularization without appreciable differences in hard atherosclerotic cardiovascular disease outcomes that is, mortality and myocardial infarction.

Future non mechanistic treatment options based on patient characteristics maybe needed.
Left atrial function, the cherrie on top in understanding clinical outcomes in functional mitral regurgitation
Authors: Zahr Firas , Cigaarroa Joaquin E.
Published: September 2020

Key Points

Left atrial function, as assessed by global longitudinal strain (GLS), is an important predictor of mortality and morbidity.

In patients with severe mitral regurgitation (MR) with reduced left ventricular systolic function (LVEF), effective treatment of the MR by mitral clip did not result in favorable left atrial or LV remodeling.

Despite effective and sustained treatment of MR, left ventricular diastolic pressure continued to increase during the follow‐up period.
Intravascular lithotripsy in calcified‐coronary lesions: A real‐world observational, European multicenter study
Authors: Aziz Amir , Bhatia Gurbir , Pitt Michael , Choudhury Anirban , Hailan Ahmed , Upadhyaya Subramanya , Lee Leong , Testa Luca , Casenghi Matteo , Ielasi Alfonso , Cortese Bernardo , Rides Hannah , Basavarajaiah Sandeep
Published: September 2020

Background

The recently introduced intravascular lithotripsy (IVL) appears promising and relatively safer than conventional approaches when dealing with calcified lesions. Although there are published reports on this novel technology, data from the real world are limited. In this study, we aim to report on the experience of IVL from a real‐world population derived from six European centers that undertake high‐volume complex coronary interventions.

Methods and results

We enrolled all patients treated with IVL between November 2018 and February 2020 at six centers. Procedural success and complications were assessed along with clinical outcomes, which included: cardiac death, target vessel myocardial infarction (TVMI), target lesion revascularisation (TLR), and major adverse cardiac event (MACE) (composite of cardiac death, TVMI, and TLR).

Hundred and ninety patients (200 lesions) with a mean age of 72 years were treated using IVL. Diabetes and chronic kidney disease were present in 50% (n = 95) and 16% (n = 30) of cases, respectively. Acute‐coronary syndromes accounted for 91 (48%) of the cases. Most were de‐novo lesions (77%; n = 154). Upfront use of IVL occurred in 26% of cases, while the rest were bail‐out procedures due to inadequate predilatation with conventional balloons. Adjuvant rotational atherectomy was needed in 17% of cases. Procedural success was achieved in 99% of cases with a complication rate of 3%. During the median follow‐up of 222 days, there was two cardiac deaths (1%), one case of TVMI (0.5%), 3 TLR (1.5%) taking the MACE rate to 2.6%.

Conclusion

Use of IVL appears to be safe and effective in dealing with calcified‐coronary lesions. A high success rate was observed with low procedural complications and event rates.
Looking Back: A Short History of the Discovery of Enzymes and How They Became Powerful Chemical Tools
Authors: Heckmann Christian M. , Paradisi Francesca
Published: September 2020

Enzymatic approaches to challenges in chemical synthesis are increasingly popular and very attractive to industry given their green nature and high efficiency compared to traditional methods. In this historical review we highlight the developments across several fields that were necessary to create the modern field of biocatalysis, with enzyme engineering and directed evolution at its core. We exemplify the modular, incremental, and highly unpredictable nature of scientific discovery, driven by curiosity, and showcase the resulting examples of cutting‐edge enzymatic applications in industry.
Mechanistic Insights into Fe Catalyzed α‐C−H Oxidations of Tertiary Amines
Authors: Legacy Christopher J. , Hope Taylor O. , Gagné Yohann , Greenaway Frederick T. , Frenette Mathieu , Emmert Marion H.
Published: September 2020

We report detailed mechanistic investigations of an iron‐based catalyst system, which allows the α‐C−H oxidation of a wide variety of amines. In contrast to other catalysts that effect α‐C−H oxidations of tertiary amines, the system under investigation exclusively employs peroxy esters as oxidants. More common oxidants (e. g. tBuOOH) previously reported to affect amine oxidations via free radical pathways do not provide amine α‐C−H oxidation products in combination with the described catalyst system. The investigations described herein employ initial rate kinetics, kinetic profiling, DFT calculations as well as Eyring, kinetic isotope effect, Hammett, ligand coordination, and EPR studies to shed light on the Fe catalyst system. The obtained data suggest that the catalytic mechanism proceeds through C−H abstraction at a coordinated substrate molecule. This rate‐determining step occurs either through an Fe(IV) oxo pathway or a 2‐electron pathway at an Fe(II) intermediate with bound oxidant. DFT calculations indicate that the Fe(IV) oxo mechanism will be the preferred route of these two possibilities. We further show via kinetic profiling and EPR studies that catalyst activation follows a radical pathway, which is initiated by hydrolysis of PhCO3tBu to tBuOOH. Overall, the obtained mechanistic data support a non‐classical, Fe catalyzed pathway that requires substrate binding, inducing selectivity for α‐C−H functionalization.
Si/SiOx Nanoparticles Embedded in a Conductive and Durable Carbon Nanoflake Matrix as an Efficient Anode for Lithium‐Ion Batteries
Authors: Nulu Arunakumari , Nulu Venugopal , Sohn Keun Y.
Published: September 2020

In this study, a route to synthesize a Si@SiOx/carbon nanoflake nanocomposite is proposed using ecological and polar solvent‐soluble ethyl cellulose as a promising new carbon source for obtaining silicon composites. Equal proportions of ethylcellulose and commercial nanosilicon powders are used to prepare the silicon/organic hybrid through an in situ chemical process, and the subsequent carbonization affords the Si@SiOx/C composite. The SiOx layer is partially formed using the employed method and air drying processes. As an anode electrode for lithium‐ion batteries (LIBs), the composite provides excellent reversible capacity (1830 mAh g−1 at 200 mA g−1 after 60 cycles) with 92 % capacity retention and superior rate performance (1464 mAh g−1 at 3.2 A g−1). The electrode with a high mass loading of 3.42 mg cm−2 delivered discharge capacities of 753 and 387 mAh g−1 at high current densities of 2 A g−1 and 4 A g−1, respectively. These results show that the coupling of silicon nanoparticles with an oxide layer and a conductive carbon framework is an effective design to retain the inherent properties of the silicon‐based anode, exhibiting its potential for use as a low‐cost anode for practical applications.
Overweight and obesity as protective factors against mortality in nonischemic cardiomyopathy patients with an implantable cardioverter defibrillator
Authors: Zhou Bin , Zhao Shuang , Tang Min , Chen Keping , Hua Wei , Su Yangang , Chen Silin , Liang Zhaoguang , Xu Wei , Li Xiaoyao , Xue Xiaodi , Sun Xuerong , Zhang Shu
Published: September 2020

Background

Previous studies have reported inconsistent results on the relationship between body mass index (BMI) and clinical outcomes in implantable cardioverter defibrillator (ICD) patients. Additionally, research on ICD patients with nonischemic cardiomyopathy (NICM) is lacking.

Hypothesis

This study aimed to investigate the impact of BMI on mortality and ventricular arrhythmias (VAs) in NICM patients with an ICD.

Methods

This study retrospectively analyzed the data from the Study of Home Monitoring System Safety and Efficacy in Cardiac Implantable Electronic Device‐implanted patients (SUMMIT) in China. Four hundred and eighty NICM patients with an ICD having BMI data were enrolled. Patients were divided into two groups: underweight and normal range group (BMI < 24 kg/m2), overweight and obese group (BMI≥24 kg/m2). The primary endpoint was all‐cause mortality. The secondary endpoint was the first occurrence of VAs requiring appropriate ICD therapy or shock.

Results

During a median follow‐up of 61 (1‐95) months, 70 patients (14.6%) died, 173 patients (36%) experienced VAs requiring appropriate ICD therapy, and 112 patients (23.3%) were treated with ICD shock. Multivariate Cox regression modeling indicated a decreased mortality risk in the overweight and obese group compared with the underweight and normal range group (hazard ratio = 0.44, 95% confidence interval 0.26‐0.77, P = .003). However, the risk of VAs was similar in both groups in univariate and multivariate Cox models.

Conclusions

Compared with underweight and normal weight, overweight and obesity are protective against mortality but have only a neutral impact on VAs risk in NICM patients with an ICD.
Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2
Authors: Welker Armin , Kersten Christian , Müller Christin , Madhugiri Ramakanth , Zimmer Collin , Müller Patrick , Zimmermann Robert , Hammerschmidt Stefan , Maus Hannah , Ziebuhr John , Sotriffer Christoph , Schirmeister Tanja
Published: September 2020

Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PLpro are valuable starting points for the development of new pan‐coronaviral inhibitors.
Synthesis and Structure‐Activity Relationships of 3‐Arylisoquinolone Analogues as Highly Specific hCES2A Inhibitors
Authors: Zhao Yitian , Xiong Yuan , Dong Sanfeng , Guan Xiaoqing , Song Yunqing , Yang Yanqing , Zou Kun , Li Zhao , Zhang Yong , Fang Shengquan , Li Bo , Zhu Weiliang , Chen Kaixian , Jia Qi , Ge Guangbo
Published: September 2020

Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3‐arylisoquinolones 3 h [3‐(4‐(benzyloxy)‐3‐methoxyphenyl)‐7,8‐dimethoxyisoquinolin‐1(2H)‐one] and 4 a [3‐(4‐(benzyloxy)‐3‐methoxyphenyl)‐4‐bromo‐7,8‐dimethoxyisoquinolin‐1(2H)‐one] were found to have potent inhibitory effects on hCES2A (IC50=0.68 μΜ, Ki=0.36 μΜ) and excellent specificity (more than 147.05‐fold over hCES1 A). Moreover, 4 a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3 h, with an IC50 value of 0.41 μΜ. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3 h and 4 a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure−activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity.
Morphological and physiological properties of Rohon‐Beard neurons along the zebrafish spinal cord
Authors: Katz Hilary R. , Menelaou Evdokia , Hale Melina E.
Published: September 2020

Primary mechanosensory neurons play an important role in converting mechanical forces into the sense of touch. In zebrafish, Rohon‐Beard (RB) neurons serve this role at embryonic and larval stages of development. Here we examine the morphology and physiology of RBs in larval zebrafish to better understand how mechanosensory stimuli are represented along the spinal cord. We report that the morphology of RB neurons differs along the rostrocaudal body axis. Rostral RB neurons arborize in the skin near the cell body whereas caudal cells arborize at a distance posterior to their cell body. Using a novel electrophysiological approach, we also found longitudinal differences in the mechanosensitivity and physiological properties of RB neurons. Rostral RB neurons respond to mechanical stimulations close to the soma and produce up to three spikes with increasing stimulus intensity, whereas caudal cells respond at more distal locations and can produce four or more spikes when the intensity of the mechanical stimulus increases. The mechanosensory properties of RB neurons are consistent with those of rapidly adapting mechanoreceptors and can signal the onset, offset and intensity of mechanical stimulation. This is the first report of the intensity encoding properties of RB neurons, where an increase in spike number and a decrease in spike latency are observed with increasing stimulation intensity. This study reveals an unappreciated complexity of the larval zebrafish mechanosensory system and demonstrates how differences in the morphological and physiological properties of RBs related to their rostrocaudal location can influence the signals that enter the spinal cord.
Small Particle Fluorescence and Light Scatter Calibration Using FCMPASSSoftware
Authors: Welsh Joshua A. , Jones Jennifer C.
Published: September 2020

Use of flow cytometry to analyze small particles has been implemented for several decades. More recently, small particle analysis has become increasingly utilized owing to the increased sensitivity of conventional and commercially available flow cytometers along with growing interest in small particles such as extracellular vesicles (EVs). Despite an increase in small particle flow cytometry utilization, a lack of standardization in data reporting has resulted in a growing body of literature regarding EVs that cannot be easily interpreted, validated, or reproduced. Methods for fluorescence and light scatter standardization are well established, and the reagents to perform these analyses are commercially available. Here, we describe FCMPASS, a software package for performing fluorescence and light scatter calibration of small particles while generating standard reports conforming to the MIFlowCyt‐EV standard reporting framework. This article covers the workflow of implementing calibration using FCMPASSas follows: acquisition of fluorescence and light scatter calibration materials, cataloguing the reference materials for use in the software, creating cytometer databases and datasets to associate calibration data and fcs files, importing fcs files for calibration, inputting fluorescence calibration parameters, inputting light scatter calibration parameters, and applying the calibration to fcs files. Published 2020. U.S. Government.

Basic Protocol 1: Acquisition and gating of light scatter calibration materials

Basic Protocol 2: Acquisition and gating of fluorescence calibration materials

Alternate Protocol: Cross‐calibration of fluorescence reference materials

Basic Protocol 3: Cataloguing light scatter calibration materials

Basic Protocol 4: Cataloguing fluorescence calibration materials

Basic Protocol 5: Creating cytometer databases and datasets

Basic Protocol 6: Importing fcs files

Basic Protocol 7: Fluorescence calibration

Basic Protocol 8: Light scatter calibration

Basic Protocol 9: Performing and reporting fcs file calibration
Bioequivalence and Pharmacokinetic Evaluation of Two Metformin Hydrochloride Tablets Under Fasting and Fed Conditions in Healthy Chinese Volunteers
Authors: Huang Xiao‐mei , Wang Gong‐zhu , He Bin‐bin , Gao Ting , Long Ping , Zhang Bi‐kui
Published: September 2020

This article aims to assess the bioequivalence of the test and the reference metformin hydrochloride tablets in healthy Chinese volunteers under fasting and fed conditions and to explore the effect of food on the pharmacokinetic (PK) profiles of both formulations. In total, 56 healthy Chinese subjects (28 in each group) were enrolled in this randomized, open, single‐center, single‐dose, 2‐treatment, 2‐sequence, 2‐cycle cross clinical trial. The subjects were administrated a single dose of the test and the reference tablets at 0.25 g with a 7‐day washout. Venous blood samples of all subjects were taken from predose 0 hour to postdose 24 hours according to the planned times. PK parameters for metformin were analyzed and calculated with noncompartmental methods. There were no significant differences in the PK parameters between the 2 formulations under both the fasting and the fed states. The 90% confidence intervals of 2 formulations were within 80.00%‐125.00% based on Cmax, AUC0‐t, and AUC0‐∞ under both conditions. High‐fat and high‐calorie diets delayed the Tmax and reduced the AUC0‐t and AUC0‐∞. No severe adverse events occurred in this study. Two metformin hydrochloride tablets were bioequivalent under both fasting and fed states; the high‐fat and high‐calorie diet could lower the rate and extent of absorption of metformin in healthy Chinese volunteers.
Linked Pharmacometric‐Pharmacoeconomic Modeling and Simulation in Clinical Drug Development
Authors: Hill‐McManus Daniel , Marshall Scott , Liu Jing , Willke Richard J. , Hughes Dyfrig A.
Published: September 2020

Market access and pricing of pharmaceuticals are increasingly contingent on the ability to demonstrate comparative effectiveness and cost‐effectiveness. As such, it is widely recognized that predictions of the economic potential of drug candidates in development could inform decisions across the product life cycle. This may be challenging when safety and efficacy profiles in terms of the relevant clinical outcomes are unknown or highly uncertain early in product development. Linking pharmacometrics and pharmacoeconomics, such that outputs from pharmacometric models serve as inputs to pharmacoeconomic models, may provide a framework for extrapolating from early‐phase studies to predict economic outcomes and characterize decision uncertainty. This article reviews the published studies that have implemented this methodology and used simulation to inform drug development decisions and/or to optimize the use of drug treatments. Some of the key practical issues involved in linking pharmacometrics and pharmacoeconomics, including the choice of final outcome measures, methods of incorporating evidence on comparator treatments, approaches to handling multiple intermediate end points, approaches to quantifying uncertainty, and issues of model validation are also discussed. Finally, we have considered the potential barriers that may have limited the adoption of this methodology and suggest that closer alignment between the disciplines of clinical pharmacology, pharmacometrics, and pharmacoeconomics, may help to realize the potential benefits associated with linked pharmacometric‐pharmacoeconomic modeling and simulation.
Antidepressant treatment in patients following acute coronary syndromes: a systematic review and Bayesian meta‐analysis
Authors: Sweda Romy , Siontis George C.M. , Nikolakopoulou Adriani , Windecker Stephan , Pilgrim Thomas
Published: September 2020

Aims

The aim of this study is to investigate the effect of antidepressant therapy on mortality and cardiovascular outcomes in patients with acute coronary syndrome (ACS).

Methods and results

We systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials and performed a Bayesian random‐effects meta‐analysis of randomized controlled trials that investigated antidepressant pharmacotherapy in patients following ACS. The primary outcome was all‐cause mortality. Secondary outcomes were repeat hospitalizations and recurrent myocardial infarctions (MIs). Ten randomized controlled trials with a total of 1935 patients qualified for inclusion. Selective serotonin reuptake inhibitors were investigated in six, bupropion in three, and mirtazapine in one trial. Placebo was used as control in eight trials. There was no difference in all‐cause mortality [odds ratio (OR) 0.97, 95% credible interval (CrI) 0.66–1.42] and recurrent MI (OR 0.64, 95% CrI 0.40–1.02) between patients receiving antidepressants compared with controls, whereas antidepressant therapy was associated with less repeat hospitalizations (OR 0.62, 95% CrI 0.40–0.94). In patients with ACS and concomitant depression, antidepressants reduced the odds of recurrent MI compared with usual care/placebo (OR 0.45, 95% CrI 0.25–0.81). Extended funnel plots suggest robustness of the observations.

Conclusions

Antidepressants in patients following ACS have no effect on mortality but reduce repeat hospitalizations; in patients with depression, there is a reduced risk of recurrent MI with antidepressant therapy.
Predictive value of heart failure with reduced versus preserved ejection fraction for outcome in pulmonary embolism
Authors: Obradovic Slobodan , Dzudovic Boris , Subotic Bojana , Matijasevic Jovan , Mladenovic Zorica , Bokan Aleksandar , Trobok Jadranka , Pekovic Sandra , Salinger‐Martinovic Sonja , Jovanovic Ljiljana , Kos Ljiljana , Kovacevic‐Preradovic Tamara , Nikolic Maja , Miloradovic Vladimir , Kovacevic‐Kuzmanovic Ana , Zec Nenad , Markovic‐Nikolic Natasa , Srdanovic Ilija , Gluvic Zoran , Kafedzic Srdjan , Pancevacki Sasa , Neskovic Aleksandar , Konstantinides Stavros
Published: September 2020

Aims

This study aimed to investigate whether the risk of short‐term mortality is different in pulmonary embolism (PE) patients who have heart failure with reduced ejection fraction (HFrEF) as compared with those with heart failure with preserved ejection fraction (HFpEF).

Methods and results

Predictive value of HFrEF or HFpEF for 7‐day (intrahospital) and 30‐day all‐cause mortality was determined in the cohort of 1055 out of 1201 consecutive acute PE patients from the Serbian multicentre PE registry. Patients were classified into either HFrEF or HFpEF group, according to guideline‐proposed criteria. A 7‐day (intrahospital) and 30‐day all‐cause mortality was 18.5% vs. 7.3% vs. 4.5% (P < 0.001) and 22.2% vs. 16.3% vs. 7.9% (P < 0.001) for patients with the history of HFrEF, HFpEF, and without HF, respectively. Multivariable analysis adjusted to age, gender, history of chronic obstructive pulmonary disease, diabetes mellitus, arterial hypertension, presence of atrial fibrillation, and mortality risk assessment at admission has shown that only HFrEF, but not HFpEF, was an independent predictor for 7‐day mortality (hazard ratio 2.22, 95% confidence interval 1.25‐4,38.41, P = 0.021) and neither HFrEF or HFpEF was an independent predictor for 30‐day mortality. Among various admission parameters associated to PE outcome, only systolic pressure in HFrEF patients (P < 0.001), heart rate (P = 0.01), and right ventricle systolic pressure (P = 0.039) in HFpEF patients were significantly different in patients who died compared with those who survived at 7 days.

Conclusions

Our study has shown that the presence of previous history of HFrEF, but not HFpEF, in acute PE is an independent risk factor for mortality at 7 days.
Fibroblast‐growth‐factor‐23 in heart failure with preserved ejection fraction: relation to exercise capacity and outcomes
Authors: Kanagala Prathap , Arnold Jayanth R. , Khan Jamal N. , Singh Anvesha , Gulsin Gaurav S. , Eltayeb Mohamed , Gupta Pankaj , Squire Iain B. , McCann Gerry P. , Ng Leong L.
Published: September 2020

Aims

This study aimed to assess plasma fibroblast growth factor 23 (FGF23) in patients with heart failure with preserved ejection fraction (HFpEF) and its relation to inflammation, renal function, clinical and imaging characteristics, exercise capacity, and prognosis.

Methods and results

We performed a prospective, observational study of 172 age‐matched and sex‐matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, female 50%) who underwent plasma biomarker sampling, echocardiography, cardiac magnetic resonance imaging, and 6 min walk testing (6MWT). The primary endpoint was the composite of all‐cause death or HF hospitalization. FGF23 was higher in HFpEF compared with controls (62 [42–105] vs. 34 [22–41] pg/mL, P < 0.0001). In HFpEF, FGF23 correlated with greater symptom burden (New York Heart Association class: r = 0.308), poorer exercise capacity (6MWT distance: r = −0.345), and plasma biomarkers reflecting inflammation (highly sensitive C‐reactive protein: r = 0.207, myeloperoxidase: r = 0.311), bone metabolism (osteoprotegerin: r = 0.446), renal dysfunction (urea: r = 0.267, creatinine: r = 0.351, estimated glomerular filtration rate: r = −0.367), and echocardiographic E/e′ (r = 0.298); P < 0.05. Following multivariable linear regression modelling, FGF23 remained independently associated with shorter 6MWT distance (P = 0.012) in addition to age, body mass index, and lower haemoglobin. During follow‐up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations) in patients with HFpEF. In multivariable Cox regression analysis, FGF23 [adjusted hazard ratio (HR) 1.665; 95% confidence interval (CI) (1.284–2.160; P < 0.0001)], B‐type natriuretic peptide (HR 1.433; CI 1.053–1.951; P = 0.022), and prior HF hospitalization (HR 2.058; CI 1.074–3.942; P = 0.030) were independent predictors of the composite endpoint.

Conclusions

Plasma FGF23 is higher in HFpEF compared with age‐matched and sex‐matched controls and is strongly associated with exercise incapacity and prognosis. FGF23 correlates with plasma markers of inflammation and renal impairment.
Boiling Heat Transfer Enhancement by Self‐Assembled Graphene/Silver Hybrid Film for the Thermal Management of Concentrated Photovoltaics
Authors: Sezer Nurettin , Khan Shoukat Alim , Koç Muammer
Published: September 2020

Graphene nanosheets have attracted appreciable interest in heat transfer augmentation due to the unique deposition characteristics. The porous morphology of the graphene deposited on the heating surface via self‐assembly is reported to retard the transition boiling significantly. However, less attention has been paid to ameliorate the heat transfer coefficient (HTC) of graphene‐dispersed solutions. Herein, silver ions are introduced into graphene nanofluids to ameliorate its HTC. During boiling, graphene nanosheets and silver nanoparticles simultaneously deposit on the heating surface to form a well‐structured porous graphene/silver hybrid coating. The newly formed surface is characterized for surface morphology, wettability, and roughness. The new surface coating enhances the HTC by up to 109% and maintains the retarded critical heat flux of graphene‐only nanofluids. The application of the enhanced boiling heat transfer for the thermal management of concentrated photovoltaics is studied. It is demonstrated that enhanced boiling allows for cogeneration of electricity and heat from concentrated photovoltaics at approximately fourfold increased production rate while maintaining efficient, safe, and reliable operation.
Transfer and dissipation of strain energy in surrounding rock of deep roadway considering strain softening and dilatancy
Authors: Yi Kang , Liu Zhenghe , Lu Zhiguo , Zhang Junwen , Sun Zhuoyue
Published: September 2020

In this study, the transfer and dissipation of strain energy in the surrounding rock of a deep roadway were analyzed, considering the objective strain softening and dilatancy behaviors. The strain energy increment was decomposed, and its variation was analyzed based on the incremental plastic flow theory; then, a numerical simulation was conducted for verification and further analysis. The results were verified by the field monitoring data of a coal mine gateway. The results show that in the elastic stage, the volumetric elastic strain energy density Uev decreases, while the shear elastic strain energy density Ues increases. In the plastic stage, both Uev and Ues decrease. The volumetric plastic strain energy density Upv is negative, and its absolute value increases, leading to strain energy accumulation. In contrast, the shear plastic strain energy density Ups is positive and increases, leading to strain energy dissipation. Considering strain softening, the elastic strain energy decreases, the plastic strain energy increases, and the region of strain energy dissipation expands. Considering dilatancy, the plastic strain energy varies more significantly, and the effect of strain softening is amplified. The strain energy is transferred from the deep part to the shallow part of the elastic zone and then to the plastic zone. The preexisting and input strain energies in the plastic zone are transformed into considerable amounts of plastic strain energy and then dissipated. Thereafter, a significant plastic strain appears, leading to the large deformation of the surrounding rock.
Natural levee evolution in vegetated fluvial‐tidal environments
Authors: Boechat Albernaz Marcio , Roelofs Lonneke , Pierik Harm Jan , Kleinhans Maarten G.
Published: September 2020

Natural levees are common features in river, delta and tidal landscapes. They are elevated near‐channel morphological features that determine the connection between channel and floodbasin, and consequently affect long‐term evolution up to delta‐scales. Despite their relevance in shaping fluvial‐tidal systems, research on levees is sparse and often limited to fluvial or non‐tidal case studies. There is also a general lack of understanding of the role of vegetation in shaping these geomorphic units, and how levee morphology and dimensions vary in the transition from fluvial to coastal environments, where tides are increasingly important. Our goal is to unravel the effects of fluvial‐tidal boundary conditions, sediment supply and vegetation on levee characteristics and floodbasin evolution. These conditions were systematically explored by 60 large‐scale idealized morphodynamic simulations in Delft3D which self‐developed levees over the course of one century. We compared our results to a global levee dataset compilation of natural levee dimensions. We found that levee height is determined by the maximum water level, provided sufficient levee building sediments are available. Discharge fluctuations increased levee width and triggered more levee breaches, i.e. crevasses, that effectively filled the fluvio‐tidal floodbasin. The presence of wood‐type (sparse) vegetation further increased the number of crevasses in comparison with the non‐vegetated scenarios. Conversely, reed‐type (dense) vegetation strongly dampened tidal amplitude and reduced the accommodation space and sedimentation further into the floodbasin, resulting in narrower levees, no crevasses and limited floodbasin accretion. However, dense vegetation reduced tidal forces which allowed levee growth further downstream. Ultimately, the levees merged with the coastal barrier, eliminating the floodbasin tides entirely. Our results elucidate the mechanisms by which levee and crevasse formation, and vegetation may fill fluvio‐tidal wetlands and affect estuary evolution. This brings new insights for geological reconstructions as well as for the future management of deltas and estuaries under sea‐level rise. © 2020 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Ltd
Enhanced dynamic team access control for collaborative Internet of Things using context
Authors: Djilali Hadjer Benhadj , Tandjaoui Djamel , Khemissa Hamza
Published: September 2020

The development of the Internet of Things (IoT) aims to overcome security issues especially in critical areas that require integrity, confidentiality and a high level of privacy of the data. Among security challenges, the access control model should be well defined and adapted to the characteristics and security requirements of IoT applications. The work presented here proposes big enforcement of security for dynamic team access control using context information in order to provide granular and secure authorizations with different access control levels related to collaborative IoT. The enhanced dynamic team access control (EDTMAC) model introduces a formal theoretical model which relies on the top of the role‐based access control model. The use of different context information with a global context information security policy and security rules raised the model strength against unauthorized access and avoided security breaches such as the leak of information by providing the least privileges for the users. The result of EDTMAC analysis shows that the model is well adapted to IoT dynamic nature and collaborative IoT activities for teams. Moreover, the model is flexible and scalable, user‐driven, reliable, and secure against unauthorized access requests. The developed model supports the well‐known least‐privilege principle and separation of duties for the team members. In addition, it allows easy management of the teams, provides fine‐grained access control authorizations and supports delegation.
Over expression of brain and acute leukemia, cytoplasmic and ETS‐related gene is associated with poor outcome in acute myeloid leukemia
Authors: Hasan Syed Khizer , Patkar Nikhil V. , Rajamanickam Deepan , Gokarn Anant , Lucena‐Araujo Antonio R. , Tembhare Prashant , Bagal Bhausaheb , Kadam Amare Pratibha , Jain Hasmukh , Gujral Sumeet , Sengar Manju , Subramanian Papagudi Ganesan , Khattry Navin
Published: September 2020

The high expression of brain and acute leukemia, cytoplasmic (BAALC) and ETS‐related gene (ERG) has been reported to influence the outcome in acute myeloid leukemia (AML), but due to limited prospective studies, their role as prognostic factors is unclear. At diagnosis, the prognostic value of BAALC and ERG expression with respect to other cytogenetic and molecular markers was analyzed in 149 AML patients. Patients were divided into quartiles which resulted in the formation of four groups (G1–G4) based on expression values of BAALC and ERG and clinical response defined across groups. Groups with similar survival probabilities were merged together and categorized subsequently as high versus low expressers. Patients with high BAALC and ERG expression had significantly lower overall survival (OS; BAALC: p = 0.001 at 5 years 29.4% vs. 69.8%; ERG: p < 0.0001 at 5 years 4% vs. 50.4%) and disease‐free survival (BAALC: p = 0.001 at 5 years 19.5% vs. 69.8%; ERG: p < 0.0001 at 5 years 4.2% vs. 47%). Patients were further stratified combining BAALC and ERG expression in an integrative prognostic risk score (IPRS). After a median follow‐up of 54 months (95% CI 45–63 months) among survivors, IPRS for high versus low expressers was a significant predictor for OS (BAALC + ERG: 4% vs. 71.6%, p < 0.0001) and DFS (BAALC + ERG: 4.5% vs. 74.1%, p < 0.0001). In a multivariate model, IPRS of BAALC + ERG expression retained prognostic significance for OS (hazard ratio [HR] 2.96, 95%CI 1.91–4.59, p < 0.001) and DFS (HR 3.61, 95%CI 2.26–5.76, p < 0.001).
How do economic policy uncertainties affect stock market volatility? Evidence from G7 countries
Authors: Ma Yaming , Wang Ziwei , He Feng
Published: September 2020

This study explores the dynamic and frequency spillover characteristics between economic policy uncertainty (EPU) and stock market realized volatility (RV) in G7 countries. We apply the monthly data of country‐specific economic policy uncertainty indices and realized volatility to calculate the directional spillover indicator. Then we use a Fourier transformation to calculate the frequency of spillovers to study the duration of the spillover effect. We find that the spillover effect of EPU on stock market volatility is relatively large in the U.S., Japan and Canada, and has certain regional similarities. EPU has longer spillover effects on the stock markets of France, Germany and Italy, which is strongest over 3–18 months. Finally, important economic events such as the financial crisis and the Brexit, increased EPU spillover level and lasting time. We provide the dynamic and frequency spillover characteristics between EPU and the stock market in G7 countries, making this study useful for international asset allocation and risk management.