bluuebunny/crossref_metadata_2025 huggingface dataset:
JAK
Family Inhibitors for Autoimmune Diseases
Authors: Borzilleri Robert M. , Hart Amy C. , Moslin Ryan , Tokarski John S. , Wrobleski Stephen T.
Published: April 2021

The JAK family of non‐receptor tyrosine kinases mediates the signaling of proinflammatory cytokines that contribute to the pathogenesis of numerous autoimmune diseases. While cytokine‐directed therapies are available to treat immune‐driven diseases, oral small‐molecule inhibitors of the JAK family (Jakinibs) have been approved as viable alternatives for the treatment of RA, PsA, and IBD. These first‐generation pan‐JAK inhibitors target the highly conserved catalytically active kinase domains in a reversible, ATP‐competitive manner, albeit in a nonselective fashion. Novel approaches to target alternative binding modes through, for example irreversible or allosteric kinase inhibition, have led to the identification of the next generation of agents, which demonstrate improved JAK family selectivity. This improved selectivity offers the potential for greater and perhaps broader efficacy by allowing for higher dosing, while avoiding undesired side effects. This article provides an overview of the JAK‐STAT signaling pathway and outlines the challenges associated with the discovery of selective JAK inhibitors while highlighting a unique allosteric TYK2 inhibitor. For each of the agents discussed, a synopsis of the medicinal chemistry efforts leading to a particular molecule is provided along with a brief summary of available preclinical and clinical efficacy and safety data.
Toxicology and Nonclinical Safety Assessment in Pharmaceutical Discovery and Development
Authors: Reynolds Vincent L. , Abernathy Matthew M. , Baracani Ronee B. , Bhalli Javed A. , Morford LaRonda , Steeves Meredith A. , Wang Wei
Published: April 2021

Nonclinical safety assessment is an essential component of drug discovery and development. Early in the drug discovery/development continuum, there are no regulatory guidelines and sponsors typically harness a range of
in silico
,
in vitro
, and short‐term
in vivo
toxicology screens and pilot studies to develop comparative toxicity profiles for compounds under consideration. Results from these early evaluations can be used to terminate the development of compounds with undesirable toxicity liabilities as well as to prioritize other compounds for further evaluation. As drug candidate molecules approach entry into clinical trials, regulatory expectations regarding nonclinical safety assessment become more explicit. Scientists in the pharmaceutical industry have worked with their regulatory counterparts to establish an organizational structure – the International Conference on Harmonisation (ICH) – to develop internationally accepted guidelines that specify requirements for nonclinical safety assessment activities in a phase‐specific manner. The ICH guidelines cover the need for repeat‐dose toxicology studies of increasing duration in rodents and nonrodents, safety pharmacology studies, genetic toxicity tests, immunotoxicity and immunogenicity evaluations, phototoxicity assessments, developmental and reproductive toxicity studies, and carcinogenicity assessments. In planning, conducting, and reporting these studies, the toxicologist must ensure that a fully integrated assessment of potential safety liabilities associated with the test drug is communicated to the development team so that potential safety concerns can be properly addressed.
Antifungal Drugs
Authors: Seyedmousavi Seyedmojtaba
Published: April 2021

Invasive fungal infections are considered an expanding public health threat, worldwide. Annually, over one billion people are estimated to suffer from fungal infections and/or allergies originating from opportunistic and pathogenic fungi. Fungal diseases also kill more than 1.5 million each year.

Antifungal therapy is a central component in the management of life‐threatening fungal infections. However, only few classes of FDA‐approved antifungal agents are available for therapy, which have limited efficacy, particularly in the treatment of disseminated and emerging fungal infections. These drugs include polyenes, azoles, echinocandins, and the nucleoside analogs. Depending on the strategy chosen, monotherapy and/or combination antifungal drugs can be used based on the clinical picture and the species identification of the etiologic agent. The use of antifungal drugs in the therapy of fungal diseases can lead to the development of resistance. Of note, some organisms are inherently resistant to these antifungal agents.

This chapter focuses on the currently available classes of systemic antifungal drugs in clinical use, innovative strategies in reformulation and delivery of available drugs, development of new agents of known antifungal drug classes, and new drugs of synthetic antifungal drugs under preclinical and clinical investigations. We further discuss the currently available evidence for the emergence of fungal resistance against these agents.
Allosterism and Drug Discovery
Authors: Bell John E. , Bell Jessica K.
Published: April 2021

Interest in allostery and drug development has significantly expanded with increasingly broad ranges of targets and diseases. Experimental and computational approaches have led to advances in understanding of the mechanisms and roles of protein dynamics and conformational states, and come together in the concept of conformational selection. The models of Monod, Wyman, and Changeux and Koshland, Nemethy, and Filmer provide conceptual explanations of homotropic cooperativity and heterotropic allostery, while conformational selection provides realistic detail that can be exploited in drug design. Distinction between allostery and cooperativity and development of approaches to identify cryptic sites on proteins significantly expands the range of targets for allosteric drug design. High‐throughput screening and SAR optimization remain a staple of drug design, however, increased understanding of the thermodynamics of protein–ligand interactions and conformational changes, and the mechanisms of information flow between existing allosteric sites and across subunit interfaces or between allosteric and active sites, rational design of ligands to interact with a cryptic “allosteric” site on any protein becomes possible. Recent “omics” approaches to identify druggable targets both genome wide andin vivofurther enhance the range of targets for drug design, both covalent and noncovalent, exploiting allosteric and cooperative properties of proteins.
Confronting theCOVID‐19 Pandemic: December 2019–May 2020
Authors: Dolle Roland E. , J. Abraham Donald , Norman Bryan , Kinch Michael
Published: April 2021

The SARS‐CoV‐2 (COVID‐19) pandemic was officially declared by the World Health Organization on 11 March, 2020. From the initial public reports from China in December 2019, the contagion blazed its way from ground zero in Wuhan, China into 165 countries. The health disaster caught the planet by surprise. At the time of this writing, 6.6 million COVID‐19 cases were confirmed worldwide. Central and South America are the latest hotspots. Utilizing state‐of‐the‐art science and technology, industry, government, and academic enterprises internationally are engaged in a monumental campaign to combat and eliminate the viral threat. Small‐molecule therapeutics discovery largely by way of drug repurposing and accelerated vaccine development are at the forefront of this campaign. Within five months time, 500 unique therapeutic agents have advanced into development, >150 clinical trials initiated, and seven agents authorized for emergency use. This article presents a snapshot of these activities as of 29 May 2020.
Evolution of
V1R
Repertoires in Subterranean Rodents
Authors: Zhao Huabin
Published: April 2021

Pheromones are chemicals released and perceived by members of the same species, triggering sexual and social behaviours or physiological changes in diverse animals. Although rodents are the first mammals in which vomeronasal receptors and their major roles in pheromonal olfaction were identified, little is known about the evolution of vomeronasal receptor gene repertoires in subterranean rodents. Recent genome‐wide surveys in rodents have shown that the number of functional vomeronasal type 1 receptor (
V1R
) genes was markedly reduced in phylogenetically distinct subterranean rodents compared with their superterranean relatives, possibly due to confined pheromonal signals in underground burrows. Interestingly, population genetic analysis proved that many
V1R
genes may have undergone positive selection rather than relaxed selection in one species of subterranean rodent. Exploration of functional roles of the reduced number of
V1R
genes would help to uncover the importance of pheromonal olfaction in subterranean rodents.

Key Concepts

Pheromones are odour molecules that elicit sexual and social behaviours or physiological changes in conspecific individuals.

Subterranean rodents live in underground burrows with confined pheromonal signals, which represent a contrasting lifestyle compared with their superterranean relatives.

Genome‐wide surveys have shown that convergent reduction in vomeronasal type 1 receptor (V1R) repertoires in multiple lineages of subterranean rodents was significantly associated with their lifestyle.

Population genetic analysis revealed that many
V1R
genes may have undergone positive selection rather than relaxed selection in one species of subterranean rodent.

Our understanding of the importance of pheromonal olfaction and its receptor genes appears to be incomplete in animals.
Microviridae
Authors: Breitbart Mya , Fane Bentley A
Published: April 2021

Members of the
Microviridae
comprise at least two subfamilies (
Bullavirinae
and
Gokushovirinae
), with divergent sequences from many uncultured representatives yet to be formally classified. Bullaviruses (canonical species φX174), which infect free‐living bacteria, are among the fastest known replicating viruses. Gokushoviruses were originally thought to occupy a unique niche, infecting obligate intracellular bacteria; however, genomic analyses suggest that this group infects free‐living hosts as well. Some gokushoviruses, unlike other members of the family, can undergo both lytic and lysogenic replication cycles.
Microviridae
contain small (4000–6000 bases), circular and single‐stranded deoxyribonucleic acid (ssDNA) genomes of positive polarity, which are packaged inside small (∼25 nm diameter)
T
 = 1 icosahedral capsids. The most well‐known member of the
Microviridae
, φX174, has been fundamental in uncovering the mechanisms of DNA replication and capsid assembly and become a model system for experimental evolution. In contrast, little is known about the replication, structure and host range of gokushoviruses despite viromics indicating their ubiquity throughout the biosphere.

Whilst overlapping reading frames increase the amount of genetic information encoded in small genomes, they do not appear to significantly impact the ability of the virus to genetically adapt to selective pressures.

Due to the genome's positive polarity, DNA replication must commence before viral genes can be transcribed.

Microvirus DNA replication occurs in three distinct stages: (1) ssDNA is first converted to a double‐stranded molecule, (2) amplification of the double‐stranded molecule and (3) single‐stranded genomic DNA synthesis and packaging.

Genomic DNA synthesis and packaging are concurrent processes; thus, a genome is not synthesised unless there exists a capsid in which to package it.

Gene expression is controlled by the finely tuned interplay of
cis
‐acting genetic elements: promoters, ribosome‐binding sites, mRNA stability sequences and transcription terminators.

Bullaviruses (φX174, G4 and α3) are distinguished by their two‐scaffolding protein system, whereas gokushoviruses utilise a single scaffolding protein. Scaffolding proteins induce conformational switches in the viral coat protein to control the timing and fidelity of morphogenesis.

Cell lysis is achieved by inhibiting host cell‐wall biosynthesis, a mechanism reminiscent of some antibiotics.

Viromics has revealed the ubiquity of
Microviridae
genomes throughout the biosphere, with gokushoviruses and uncharacterised divergent lineages being the most common.

Hosts are unknown for the vast majority of environmental
Microviridae
, leading to a dearth of knowledge on their gene functions, replication strategies, virion structures or even absolute abundance in the environment.

Although the
Microviridae
were traditionally thought to be purely lytic, genomic studies have demonstrated that some gokushoviruses are capable of lysogeny.
Catalytic RNA
Authors: Kent Alexandra D , Burke Cassandra R , Lupták Andrej
Published: April 2021

RNA molecules have diverse roles in biological systems. While some code for proteins or act to translate codons to amino acids, others fold into specific shapes that endow them with the ability to catalyse specific chemical transformations. These catalytic RNAs, ribozymes, are responsible for protein synthesis, tRNA processing, self‐splicing of certain introns, self‐scission during rolling circle replication of some single‐stranded RNA viruses and cofactor‐dependent gene regulation in bacteria. Other ribozymes have been evolved
in vitro
to perform a wide variety of transformations. Two of these, tRNA aminoacylase and RNA polymerase ribozymes, are featured here because molecules with such capabilities are thought to have existed on early Earth, before proteins took over as the dominant biological catalysts. Most of the ribozymes have been shown to perform multiturnover catalysis and thus act as true enzymes, either in their natural, biological form or as engineered constructs.

Key Concepts

RNA molecules can fold into specific conformations and accelerate chemical transformations, thus acting as catalytic biomacromolecules, ribozymes.

Ribozymes can accelerate chemical reactions by many orders of magnitude.

Many ribozymes are capable of multiturnover catalysis, acting as enzymes.

Protein synthesis templated by mRNA is catalysed by ribosomal RNA.

Most ribozymes are phosphoryl transferases.

In vitro
selected ribozymes have been shown to catalyse a wide variety of reactions.

The existence of ribozymes supports the RNA World hypothesis.
A minimal sensing and communication control strategy for adaptive platooning
Authors: Yang Kang , Liu Di , Yu Wenwu
Published: April 2021

Several cooperative driving strategies proposed in literature, sometimes known as cooperative adaptive cruise control strategies, assume that both relative spacing and relative velocity with preceding vehicle are available from on‐board sensors (laser or radar). Alternatively, these strategies assume communication of both velocity states and acceleration inputs from preceding vehicle. However, in practice, on‐board sensors can only measure relative spacing with preceding vehicle (since getting relative velocity requires additional filtering algorithms); also, reducing the number of variables communicated from preceding vehicle is crucial to save bandwidth. In this work we show that, after framing the cooperative driving task as a distributed model reference adaptive control problem, the platooning task can be achieved in a minimal sensing and communication scenario, that is, by removing relative velocity measurements with preceding vehicle and by removing communication from preceding vehicle of velocity states. In the framework we propose, vehicle parametric uncertainty is taken into account by appropriately designed adaptive laws. The proposed framework is illustrated and shown to be flexible to several standard architectures used in cooperative driving (one‐vehicle look‐ahead topology, leader‐to‐all topology, multivehicle look‐ahead topology).
Interfacial Engineering of Bifunctional Niobium (V)‐Based Heterostructure Nanosheet Toward High Efficiency Lean‐Electrolyte Lithium–Sulfur Full Batteries
Authors: Shi Haodong , Qin Jieqiong , Lu Pengfei , Dong Cong , He Jian , Chou Xiujian , Das Pratteek , Wang Jiemin , Zhang Liangzhu , Wu Zhong‐Shuai
Published: April 2021

High‐efficiency lithium–sulfur (Li–S) batteries depend on an advanced electrode structure that can attain high sulfur utilization at lean‐electrolyte conditions and minimum amount of lithium. Herein, a twinborn holey Nb4N5–Nb2O5 heterostructure is designed as a dual‐functional host for both redox–kinetics–accelerated sulfur cathode and dendrite‐inhibited lithium anode simultaneously for long‐cycling and lean‐electrolyte Li–S full batteries. Benefiting from the accelerative polysulfides anchoring–diffusion–converting efficiency of Nb4N5–Nb2O5, polysulfide‐shutting is significantly alleviated. Meanwhile, the lithiophilic nature of holey Nb4N5–Nb2O5 is applied as an ion‐redistributor for homogeneous Li‐ion deposition. Taking advantage of these merits, the Li–S full batteries present excellent electrochemical properties, including a minimum capacity decay rate of 0.025% per cycle, and a high areal capacity of 5.0 mAh cm−2 at sulfur loading of 6.9 mg cm−2, corresponding to negative to positive capacity ratio of 2.4:1 and electrolyte to sulfur ratio of 5.1 µL mg−1. Therefore, this work paves a new avenue for boosting high‐performances Li–S batteries toward practical applications.
Nanotoxoids: Biomimetic Nanoparticle Vaccines against Infections
Authors: Guo Zhongyuan , Kubiatowicz Luke J. , Fang Ronnie H. , Zhang Liangfang
Published: April 2021

Nanoparticles have been widely explored for vaccine applications based on their ability to elicit potent immune responses. Their advantages include protection of antigen payloads, improved in vivo distribution, enhanced cellular uptake, and codelivery with immunostimulatory adjuvants, among others. Of the various nanoparticulate platform technologies, cell membrane‐coated nanoparticles are an emerging class of nanocarrier that have been utilized for a wide range of biomedical applications. Here, the development and application of nanotoxoids as vaccines against infection are reviewed. Prepared by the complexation of toxins with cell membrane‐coated nanoparticles, nanotoxoids are able to safely deliver virulent proteins in their native conformation, thus generating strong and high avidity immune responses. The synthesis of nanotoxoids leverages the natural affinities of virulence factors with cell membranes, enabling for the rapid development of multiantigenic formulations from unknown mixtures of toxins. Considering their many advantages over conventional toxoids, it is envisioned that continued research on nanotoxoids will lead to new and more effective vaccine formulations against high priority infectious diseases.
Optimal Design and Performance Analysis of Thermoelectric Power Generation Device Based on Multi‐Objective Genetic Algorithm
Authors: Wu Jinmeng , Chen Yan , Dou Yinke , Ma Chunyan , Du Qian , Liu Qiang
Published: April 2021

The combined use of flue gas waste heat resources and thermoelectric generators (TEGs) is considered to be a relatively reliable method to generate electricity. The focus of this study is on the optimization and improvement of the hot‐end heat collection pipe. This paper aims to increase the temperature difference between hot and cold ends of TEG and enhance uniformity of temperature distribution, thereby improving the output power of the TEG system. To balance the temperature difference between the cold and hot ends of the TEG, the pressure drop from the inlet to the outlet and the mass of TEG hot end pipes, a finite element simulation model is constructed. Meanwhile, a multi‐objective genetic algorithm is applied to optimize the structure of four dimensions: fin bottom length, fin height, fin thickness, and outlet diameter. Three optimization objectives, namely, average temperature difference, total pressure drop from inlet to outlet, and pipeline mass are globally optimized to determine the best size, based on which the accuracy of the simulation model is verified by conducting experiments.
Evaluation of biosolids‐enriched ammonium sulfate vs. ammonium sulfate in soils and for plant growth
Authors: Chien Sen H. , Singh Upendra , Ruiz Diaz Dorivar A.
Published: April 2021

Nitrogen (N) and sulfur (S) are essential nutrients for optimum plant growth. A commercial‐grade biosolid‐enriched ammonium sulfate (Bio/AMS) was evaluated and compared with a conventional, commercial‐grade ammonium sulfate (AMS) to investigate the release patterns of N and S in soils. The laboratory‐based studies included (a) characterization of fertilizer sources, (b) soil leaching columns with 0.01% citric acid in an acid soil, (c) soil incubation followed by 1 M KCl extraction in a neutral soil, and (d) NH3 volatilization measurements in an alkaline soil. With one exception, the results showed no significant difference in the amount or the rate of N or S released from each between the two products in all the studies. In that one exception, the Bio/AMS leached significantly less N after 56 d, but not before 14 d, than the conventional AMS application. In greenhouse‐based evaluations, the Bio/AMS and AMS performed comparably at providing S nutrient to the biomass yield and S uptake by canola (Brassica napus L.) at maturity in neutral and alkaline soils. The studies also showed no significant N uptake differences between Bio/AMS and AMS by wheat (Triticum aestivum L.) biomass at maturity in acid and neutral soils. The results from these laboratory and greenhouse studies demonstrated that the Bio/AMS product is a simple physical mixture of biosolids with AMS.
Data‐driven modeling of mesoscale solids stress closures for filtered two‐fluid model in gas–particle flows
Authors: Ouyang Bo , Zhu Li‐Tao , Luo Zheng‐Hong
Published: April 2021

This study performs data‐driven modeling of mesoscale solids stress closures for filtered two‐fluid model (fTFM) in gas–particle flows via an artificial neural network (ANN) based machine learning method. The data used for developing the ANN‐based predictive data‐driven modeling framework is systematically filtered from fine‐grid simulations. The loss function optimization result reveals that coupling two loss functions promotes more accurate predictions of the mesoscale solids stresses than using a single loss function. Further comprehensive assessments of closure markers demonstrate a systematic dependence of the mesoscale solids stresses on the filtered particle velocity and its gradient as additional anisotropic markers, instead of using the conventional isotropic filtered rate of solid phase deformation as a closure marker. An optimal three‐marker mesoscale closure is thus proposed. Comparative analysis of the conventional filtered model and present three‐marker model shows that the data‐driven model can substantially enhance the prediction accuracy.
Using conjugated system from natural sources for the synthesis of sulfur copolymers by bi‐function catalysts at mild temperatures
Authors: Lyu Ya , Hu Qing , Chen Long , Luo Tianxiang , Liu Jianghui , Yin Xiaoxiao
Published: April 2021

Sulfur‐rich polymers are promising materials to cover several applications including mercury capture adsorbents. Tung oil, a natural conjugated triene triglyceride oil, were selected to prepare sulfur‐rich copolymers. The unique second monomer made reaching the gel point possible at a mild temperature of 130°C in 2.5 h. The reaction accomplishment was confirmed by the depletion of double bonds in tung‐oil‐sulfur copolymers measured by1H NMR, FTIR, XRD, and DSC. A bi‐function catalyst calcium hydroxide accelerates the reactions between triglyceride and sulfur before it is removed to increase the surface area and achieve the aims of preparing adsorbents, which has zero free sulfur, high crosslinking degree, and efficient mercury capture. Newly developed tung‐oil‐sulfur copolymers catalyzed by calcium hydroxide offer the possibility to synthesize sulfur‐rich copolymers that combine the advantages of the high performance and the utility of greener and more environmental friendly raw materials.
Enhanced mechanical and thermal properties of nanodiamond reinforced low density polyethylene nanocomposites
Authors: Morimune‐Moriya Seira , Hashimoto Taiki , Haga Ryohei , Tanahashi Hiroaki
Published: April 2021

In this study, the reinforcement effects of low‐content hydrophilic nanodiamond (ND) on linear low‐density polyethylene (PE) nanocomposites were investigated. ND was incorporated in PE via simple solution blending. The obtained PE/ND nanocomposites were characterized using scanning electron microscopy, ultraviolet–visible spectra, X‐ray diffraction, tensile test, thermogravimetry, and differential scanning calorimetry. Generally, PE/ND nanocomposites with poor interfacial interaction cause large agglomerates, resulting in brittle and poor mechanical properties. Owing to the different natures of non‐polar PE and polar ND, the higher the ND content, the larger the agglomerates formed in the nanocomposites. However, PE/ND nanocomposites show unique mechanical properties, that is, the Young's modulus, tensile strength, elongation at break, and toughness increased upon the incorporation of ND. The Young's modulus of the PE/ND nanocomposites exceeded the theoretical value calculated using the Halpin–Tsai model. In addition, the toughness increased by 18% at only 0.5 wt% ND loading. Furthermore, there was an increase in the thermal degradation temperature, melting temperature, and crystallization temperature.
Applied anatomy and surgical technique of the lateral single‐position L5–S1 fusion
Authors: Bodon Gergely , Kiraly Kristof , Baksa Gabor , Barany Laszlo , Kiss Mate , Hirt Bernhard , Pussert Arndt , Timothy Jake , Stubbs Lenny , Khajavi Kaveh , Braly Brett
Published: April 2021

The latest development in the anterior lumbar interbody fusion (ALIF) procedure is its application in the lateral position to allow for simultaneous posterior percutaneous screw placement. The technical details of the lateral ALIF technique have not yet been described. To describe the surgical anatomy relevant to the lateral ALIF approach we performed a comprehensive anatomical study. In addition, the preoperative imaging, patient positioning, planning of the skin incision, positioning of the C‐arm, surgical approach, and surgical technique are discussed in detail. The technique described led to the successful use of the lateral ALIF technique in our clinical cases. No lateral ALIF procedure needed to be aborted during these cases. Our present work gives detailed anatomical background and technical details for the lateral ALIF approach. This teaching article can provide readers with sufficient technical and anatomical knowledge to assist them in performing their first lateral ALIF procedure.
General histological woes: Definition and classification of tissues
Authors: Neumann Paul E. , Neumann Eve E.
Published: April 2021

The modern view that the human body is composed of tissues and body fluids, and that there are four basic tissue types, may be a more significant departure from Artistotle's homoeomeres, and from Bichat's membranes and tissues, than commonly appreciated. The older concepts described these body parts as structural and functional parts of organs, whereas it is now commonplace to consider a tissue to be a grouping of similar cells with a variable amount of extracellular matrix. The development of the microscope as a useful tool in human anatomy shifted focus from tissues to cells and led to changes in the definition of tissue and the classification of tissues. Not all of these changes have been consistent with observable facts: many tissues contain diverse cell types, not all “connective tissues” are proper connective tissues, and some specialized tissues are not easily classified as subtypes of one of the four basic types. Here we propose corrective measures, including re‐recognition of compound tissues, cataloging all adult human tissue types, and increasing the emphasis on function during the construction of a complete taxonomy of human adult tissues. Specific problems in the current scheme and a preliminary reclassification of human adult tissues are discussed.
In Vivo and in Silico Trypanocidal Activity Evaluation of (−)‐Cubebin Encapsulated in PLGA Microspheres as Potential Treatment in Acute Phase
Authors: Neres Nayara B. R. , Montagnini Daniel , Ferreira Daniele S. , Parreira Renato L. T. , Orenha Renato P. , Lima Thais C. , Molina Eduardo F. , Cunha Wilson R. , Silva Márcio L. A. , Esperandim Viviane R.
Published: April 2021

In this study, the trypomastigotes of a Y strain of Trypanosoma cruzi were inoculated intraperitoneally into male BALB/c mice weighing approximately 25 g each, which were divided into groups for evaluation of the trypanocidal activity. For the treatment of experimental groups, encapsulated and unencapsulated (−)‐cubebin, Benznidazole, and two groups as negative controls were used. The encapsulated (−)‐cubebin showed a 68.1 % encapsulation efficiency. The parasitemia peak of substances remained around the 9th day after the observed reduction in the number of circulating trypomastigotes. The encapsulated (−)‐cubebin and (−)‐cubebin unloaded showed a decrease of 61.3 % and 58.5 % in the number of parasites as compared to the negative control, respectively. Moreover, animals treated with encapsulated (−)‐cubebin had a higher survival time as compared to the other groups. In conclusion, the results obtained were more promising for encapsulated (−)‐cubebin as compared to unloaded particles.
SCAI expert consensus update on best practices in the cardiac catheterization laboratory
Authors: Naidu Srihari S. , Abbott J. Dawn , Bagai Jayant , Blankenship James , Garcia Santiago , Iqbal Sohah N. , Kaul Prashant , Khuddus Matheen A. , Kirkwood Lorrena , Manoukian Steven V. , Patel Manesh R. , Skelding Kimberly , Slotwiner David , Swaminathan Rajesh V. , Welt Frederick G. , Kolansky Daniel M.
Published: April 2021

The current document commissioned by the Society for Cardiovascular Angiography and Interventions (SCAI) and endorsed by the American College of Cardiology, the American Heart Association, and Heart Rhythm Society represents a comprehensive update to the 2012 and 2016 consensus documents on patient‐centered best practices in the cardiac catheterization laboratory. Comprising updates to staffing and credentialing, as well as evidence‐based updates to the pre‐, intra‐, and post‐procedural logistics, clinical standards and patient flow, the document also includes an expanded section on CCL governance, administration, and approach to quality metrics. This update also acknowledges the collaboration with various specialties, including discussion of the heart team approach to management, and working with electrophysiology colleagues in particular. It is hoped that this document will be utilized by hospitals, health systems, as well as regulatory bodies involved in assuring and maintaining quality, safety, efficiency, and cost‐effectiveness of patient throughput in this high volume area.
Impact of anemia on short‐term outcomes after TAVR: A subgroup analysis from the BRAVO‐3 randomized trial
Authors: Razuk Victor , Camaj Anton , Cao Davide , Nicolas Johny , Hengstenberg Christian , Sartori Samantha , Zhang Zhongjie , Power David , Beerkens Frans , Chiarito Mauro , Meneveau Nicolas , Tron Christophe , Dumonteil Nicolas , Widder Julian D. , Ferrari Markus , Violini Roberto , Stella Pieter R. , Jeger Raban , Anthopoulos Prodromos , Mehran Roxana , Dangas George D.
Published: April 2021

Objectives

To determine the prognostic impact of anemia in patients randomized to bivalirudin or unfractionated heparin (UFH) during transcatheter aortic valve replacement (TAVR).

Background

Whether the periprocedural use of bivalirudin as compared with UFH in anemic patients undergoing TAVR has an impact on outcomes remains unknown.

Methods

The BRAVO‐3 trial compared the use of bivalirudin versus UFH in 802 high risk patients undergoing transfemoral TAVR for severe symptomatic aortic stenosis. Patients were stratified according to the presence (defined as hemoglobin levels <13 g/dl in men and <12 g/dl in women) or absence of anemia. The primary outcomes were net adverse cardiac events (NACE; a composite of all‐cause mortality, myocardial infarction, stroke, or bleeding) and major bleeding (Bleeding Academic Research Consortium ≥3b) at 30 days.

Results

Among 798 patients with available baseline hemoglobin levels, 427 (54%) were anemic of whom 221 (52%) received bivalirudin. There were no significant differences in NACE and major bleeding at 30 days between patients with and without anemia, irrespective of the type of anticoagulant used (pinteraction = 0.71 for NACE, pinteraction = 1.0 for major bleeding). However, anemic patients had a higher risk of major vascular complications (adjusted OR 2.43, 95% CI 1.42–4.16, p = 0.001), and acute kidney injury (adjusted OR 1.74, 95% CI 1.16–2.59, p = 0.007) compared to non‐anemic patients at 30 days.

Conclusions

Anemia was not associated with a higher risk of NACE or major bleeding at 30 days after TAVR without modification of the treatment effects of periprocedural anticoagulation with bivalirudin versus UFH.
Diversified Polyketides and Nitrogenous Compounds from the Mangrove Endophytic Fungus Penicillium steckiiSCSIO 41025
Authors: Chen Chun‐Mei , Chen Wei‐Hao , Tao Hua‐Ming , Yang Bin , Zhou Xue‐Feng , Luo Xiao‐Wei , Liu Yong‐Hong
Published: April 2021

Main observation and conclusion

Four new polyketide decalin derivatives, penicisteck acids A—D (1—4), and three new nitrogenous compounds (7—9), together with eight previously reported compounds, were isolated from the mangrove endophytic fungus Penicillium steckii SCSIO 41025. Their structures and absolute configurations were characterized by analysis of comprehensive spectroscopic data combined with ECD calculations and modified Marfey's method. Structurally, compounds 1—3 were highly oxygenated decalin derivatives harboring an unusual propanoic acid unit at C‐1. Compound 8 was identified as a rare natural alkaloid‐N‐oxide confirmed by single crystal X‐ray diffraction analysis. A plausible biogenetic pathway of compounds 1—6 is proposed. Compounds 13 and 15 showed significant anti‐bacterial activity against Staphylococcus aureus with the MIC values of 3.9 and 7.8 μg/mL, respectively. Compounds 10 and 12 exhibited potent α‐glucosidase inhibitory activity with the IC50 values of 64.1 and 191.4 μmol/L, respectively.
Commiphoroids G1—G3, H and I, Five Terpenoid Dimers as Extracellular Matrix Inhibitors from Resina Commiphora
Authors: Dong Lu , Jiang Jian‐Bing , Yan Yong‐Ming , Wang Shu‐Mei , Cheng Yong‐Xian
Published: April 2021

Main observation and conclusion

Commiphoroids G1—G3, H and I (1—5), five new terpenoid dimers were isolated from Resina Commiphora. Their structures and absolute configurations were determined by using spectroscopic, computational and crystallographic methods. Biological evaluation of these terpenoid dimers against renal fibrosis reveals that 5 inhibits extracellular matrix components including fibronectin and collagen I in a concentration‐dependent manner.
Impact of environmental factors in predicting daily severity scores of atopic dermatitis
Authors: Hurault Guillem , Delorieux Valentin , Kim Young‐Min , Ahn Kangmo , Williams Hywel C. , Tanaka Reiko J.
Published: April 2021

Background

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 20% of children worldwide. Environmental factors including weather and air pollutants have been shown to be associated with AD symptoms. However, the time‐dependent nature of such a relationship has not been adequately investigated. This paper aims to assess whether real‐time data on weather and air pollutants can make short‐term prediction of AD severity scores.

Methods

Using longitudinal data from a published panel study of 177 paediatric patients followed up daily for 17 months, we developed a statistical machine learning model to predict daily AD severity scores for individual study participants. Exposures consisted of daily meteorological variables and concentrations of air pollutants, and outcomes were daily recordings of scores for six AD signs. We developed a mixed‐effect autoregressive ordinal logistic regression model, validated it in a forward‐chaining setting and evaluated the effects of the environmental factors on the predictive performance.

Results

Our model successfully made daily prediction of the AD severity scores, and the predictive performance was not improved by the addition of measured environmental factors. Potential short‐term influence of environmental exposures on daily AD severity scores was outweighed by the underlying persistence of preceding scores.

Conclusions

Our data does not offer enough evidence to support a claim that weather or air pollutants can make short‐term prediction of AD signs. Inferences about the magnitude of the effect of environmental factors on AD severity scores require consideration of their time‐dependent dynamic nature.
A novel histopathological scoring system to distinguish urticarial vasculitis from chronic spontaneous urticaria
Authors: Puhl Viktoria , Bonnekoh Hanna , Scheffel Jörg , Hawro Tomasz , Weller Karsten , von den Driesch Peter , Röwert‐Huber Hans‐Joachim , Cardoso José , Gonçalo Margarida , Maurer Marcus , Krause Karoline
Published: April 2021

Background

Urticarial vasculitis (UV) is defined by long‐lasting urticarial lesions combined with the histopathologic findings of leukocytoclastic vasculitis. As one of the major unmet needs in UV, diagnostic criteria are rather vague and not standardized. Moreover, there seems to be considerable overlap with chronic spontaneous urticaria (CSU), particularly for the normocomplementemic variant of UV. Therefore, this study aimed to develop a diagnostic scoring system that improves the histopathologic discrimination between UV and CSU.

Methods

Lesional skin sections of patients with clinical and histopathologic diagnosis of UV (n = 46) and CSU (n = 51) were analyzed (blinded to the diagnosis) for the following pre‐defined criteria: presence of leukocytoclasia, erythrocyte extravasation, fibrin deposits, endothelial cell swelling, ectatic vessels, blurred vessel borders, dermal edema, intravascular neutrophil, and eosinophil numbers and numbers of dermal neutrophils, macrophages and mast cells.

Results

The greatest differences between UV and CSU samples were observed for leukocytoclasia (present in 76% of UV vs. 3.9% of CSU samples;p < 0.0001), erythrocyte extravasation (present in 41.3% of UV vs. 2.0% of CSU samples;p < 0.0001), and fibrin deposits (present in 27.9% of UV vessels vs. 9.7% of CSU vessels;p < 0.0001). Based on these findings, we developed a diagnostic score, the urticarial vasculitis score (UVS), which correctly assigned 37 of 46 cases of UV and 49 of 51 cases of CSU to the previously established diagnosis.

Conclusion

Our results suggest that the UVS, a combined quantitative assessment of the three criteria leukocytoclasia, fibrin deposits and extravasated erythrocytes, distinguishes UV from CSU in skin histopathology. The UVS, if validated in larger patient samples, may help to improve the diagnostic approach to UV.
The synaptic inputs and thalamic projections of two classes of layer 6 corticothalamic neurons in primary somatosensory cortex of the mouse
Authors: Whilden Courtney Michelle , Chevée Maxime , An Seong Yeol , Brown Solange Pezon
Published: April 2021

Although corticothalamic neurons (CThNs) represent the largest source of synaptic input to thalamic neurons, their role in regulating thalamocortical interactions remains incompletely understood. CThNs in sensory cortex have historically been divided into two types, those with cell bodies in Layer 6 (L6) that project back to primary sensory thalamic nuclei and those with cell bodies in Layer 5 (L5) that project to higher‐order thalamic nuclei and subcortical structures. Recently, diversity among L6 CThNs has increasingly been appreciated. In the rodent somatosensory cortex, two major classes of L6 CThNs have been identified: one projecting to the ventral posterior medial nucleus (VPM‐only L6 CThNs) and one projecting to both VPM and the posterior medial nucleus (VPM/POm L6 CThNs). Using rabies‐based tracing methods in mice, we asked whether these L6 CThN populations integrate similar synaptic inputs. We found that both types of L6 CThNs received local input from somatosensory cortex and thalamic input from VPM and POm. However, VPM/POm L6 CThNs received significantly more input from a number of additional cortical areas, higher order thalamic nuclei, and subcortical structures. We also found that the two types of L6 CThNs target different functional regions within the thalamic reticular nucleus (TRN). Together, our results indicate that these two types of L6 CThNs represent distinct information streams in the somatosensory cortex and suggest that VPM‐only L6 CThNs regulate, via their more restricted circuits, sensory responses related to a cortical column while VPM/POm L6 CThNs, which are integrated into more widespread POm‐related circuits, relay contextual information.
A performance study of meta‐heuristic approaches for quadratic assignment problem
Authors: Achary Thimershen , Pillay Shivani , Pillai Sarah M. , Mqadi Malusi , Genders Emma , Ezugwu Absalom E.
Published: April 2021

The quadratic assignment problem (QAP) is a well‐known challenging combinatorial optimization problem that has received many researchers' attention with varied real‐world and industrial applications areas. It is noteworthy to mention that a plethora of nature‐inspired optimization algorithms have successfully been used to solve various optimization problems, including several variants of the QAPs. In this article, a comprehensive literature review is presented to show the most relevant nature‐inspired algorithms that have been used in solving the QAP. More so, extensive experiments are conducted and analyzed to show the performance of the well‐known state‐of‐the‐art nature‐inspired meta‐heuristic optimization algorithms in solving the QAP, including the ant colony optimization (ACO), bat algorithm, genetic algorithm (GA), particle swarm optimization (PSO), and tabu search algorithm. Besides, a modified variant of the discrete PSO algorithm is implemented and compared with existing approaches. The six selected algorithms' performances, including the modified PSO, are validated on eight commonly used QAP instances of varying complexity and size, considering the quality of solutions achieved and computational time consumed by the representative algorithms. The numerical results revealed that the most competitive algorithm was ACO, while the GA appeared to be the worst performed algorithm among the six compared meta‐heuristic algorithms. However, based on the extensive analysis conducted on the tested algorithms, further improvements are suggested, including implementing new modified versions of the tested algorithms to tackle the QAP and its variant instances.
The PhenX Toolkit: Establishing Standard Measures for COVID‐19 Research
Authors: Krzyzanowski Michelle C. , Terry Ian , Williams David , West Pat , Gridley Lauren N. , Hamilton Carol M.
Published: April 2021

The PhenX (consensus measures for Phenotypes and eXposures) Toolkit (https://www.phenxtoolkit.org/) is a publicly available, web‐based catalog of recommended, well‐established measurement protocols of phenotypes and exposures. The goal of PhenX is to facilitate the use of standard measures, enhance data interoperability, and promote collaborative and translational research. PhenX is driven by the scientific community and historically has depended on working groups of experts to recommend measures for release in the PhenX Toolkit. The urgent need for recommended, standard measures for COVID‐19 research triggered the development of a “rapid release” process for releasing new content in the PhenX Toolkit. Initially, PhenX collaborated with the National Institutes of Health (NIH) Office of Behavioral and Social Sciences Research, the National Human Genome Research Institute, and the NIH Disaster Research Response (DR2) program to create a library of COVID‐19 measurement protocols. With additional support from NIH, PhenX adapted crowdsourcing techniques to accelerate prioritization and recommendation of protocols for release in the PhenX Toolkit. Prioritized COVID‐19‐specific protocols were used to anchor and define specialty collections of protocols that were subject to review and approval by the PhenX Steering Committee. In addition to the COVID‐19‐specific protocols, the specialty collections include existing, well‐established PhenX protocols, use of which will further enhance data interoperability and cross‐study analysis. The COVID‐19 specialty collections are Behaviors and Risks; Ethnicity, Race and Demographics; History, Treatment and Outcomes; Information Resources; Psychosocial and Mental Health; and Socioeconomic. The development and usage of PhenX COVID‐19 specialty collections are described in this article. © 2021 The Authors.

Basic Protocol: Selecting COVID‐19 protocols
Simple, Inexpensive RNA Isolation and One‐Step RT‐qPCR Methods for SARS‐CoV‐2 Detection and General Use
Authors: Graham Thomas G.W. , Dugast‐Darzacq Claire , Dailey Gina M. , Darzacq Xavier , Tjian Robert
Published: April 2021

The most common method for RNA detection involves reverse transcription followed by quantitative polymerase chain reaction (RT‐qPCR) analysis. Commercial one‐step master mixes—which include both a reverse transcriptase and a thermostable polymerase and thus allow performing both the RT and qPCR steps consecutively in a sealed well—are key reagents for SARS‐CoV‐2 diagnostic testing; yet, these are typically expensive and have been affected by supply shortages in periods of high demand. As an alternative, we describe here how to express and purify Taq polymerase and M‐MLV reverse transcriptase and assemble a homemade one‐step RT‐qPCR master mix. This mix can be easily assembled from scratch in any laboratory equipped for protein purification. We also describe two simple alternative methods to prepare clinical swab samples for SARS‐CoV‐2 RNA detection by RT‐qPCR: heat‐inactivation for direct addition, and concentration of RNA by isopropanol precipitation. Finally, we describe how to perform RT‐qPCR using the homemade master mix, how to prepare in vitro−transcribed RNA standards, and how to use a fluorescence imager for endpoint detection of RT‐PCR amplification in the absence of a qPCR machine In addition to being useful for diagnostics, these versatile protocols may be adapted for nucleic acid quantification in basic research. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.

Basic Protocol 1: Preparation of a one‐step RT‐qPCR master mix using homemade enzymes

Basic Protocol 2: Preparation of swab samples for direct RT‐PCR

Alternate Protocol 1: Concentration of RNA from swab samples by isopropanol precipitation

Basic Protocol 3: One‐step RT‐qPCR of RNA samples using a real‐time thermocycler

Support Protocol: Preparation of RNA concentration standards by in vitro transcription

Alternate Protocol 2: One‐step RT‐PCR using endpoint fluorescence detection
Screening of spherical moulds manufactured isotropically in plasma etching conditions
Authors: Herth Etienne , Belharet Djaffar , Edmond Samson , Bouville David , Robert Laurent , Lardet‐Vieudrun Franck
Published: April 2021

Micro‐moulding is a critical rapid prototyping process chain used for a wide range of applications. This study demonstrates that it is possible to manufacture mould at low excitation frequency plasma (380 kHz), on a silicon substrate using fluorinated chemistry. According to the mask aperture designed and process time, the cavities profile characteristics, depending on the plasma chemistry, were analysed to predict the degree of anisotropy and the curvature. We show the possibility of creating curvature shapes with a desirable conic constant k of 1.25. In particular, we highlighted the smallest aperture sizes are more attractive for replicating optical micro‐lens arrays using silicon moulds. Otherwise, the largest aperture sizes gain more attention for optoelectronics, microsystems, and microfluidics applications.