bluuebunny/crossref_metadata_2025 huggingface dataset:
Similar pharmacokinetics of three dosing regimens comprising two oral delayed‐release mesalamine formulations in healthy adult volunteers: Randomised, open‐label, parallel‐group study
Authors: Vande Casteele Niels , Jakate Abhijeet , McNamee Brian , Sandborn William J.
Published: July 2020

Aims

Mesalamine is the first‐line therapy for treating mild‐to‐moderate ulcerative colitis. Multiple mesalamine formulations are available, with similar safety and efficacy profiles. Mesalamine is commonly administered as divided dosing, although once‐daily dosing may provide benefits for patients. We evaluated the pharmacokinetics of three dosing regimens of two oral delayed‐release mesalamine formulations in healthy adult volunteers.

Methods

A randomised, open‐label, parallel‐group study of mesalamine pharmacokinetics following Lialda 2 × 1.2 g once daily (QD) (dose A), Asacol 6 × 400 mg QD (dose B), or Asacol 2 × 400 mg three times daily (TID) (dose C) over 7 days. Assessments included 5‐aminosalicylic acid (5‐ASA) and N‐acetyl 5‐aminosalicylic acid (N‐Ac‐5‐ASA, primary metabolite) pharmacokinetics (Ae(%), AUC0‐24 and Cmax), safety and tolerability.

Results

All enrolled volunteers (n = 37) completed the study. Steady state was achieved for all treatments by day 4. Ratios (95% CI) of means for steady‐state AUC0‐24 (dose A vs B 90.3% [39.8, 204.8], dose A vs C 123.5% [55.3, 275.7], dose B vs C 136.8% [61.3, 305.5]) and Cmax (dose A vs B 106.0% [46.4, 242.2], dose A vs C 133.0% [59.1, 299.0], dose B vs C 125.5% [55.8, 282.1]) were similar for all 5‐ASA treatments. Mean urinary excretion of 5‐ASA plus N‐Ac‐5‐ASA was comparable between treatments (dose A 21.3%, dose B 20.2%, dose C 17.9%). All treatment regimens were well tolerated; no safety issues were observed.

Conclusions

Plasma and urine pharmacokinetics for Asacol TID, Asacol QD, and Lialda QD are similar, suggesting similar daily systemic exposures can be obtained with either TID or QD dosing. NCT00751699.
School systems as breeding grounds for shadow education: Factors contributing to private supplementary tutoring in West Bengal, India
Authors: Ghosh Pubali , Bray Mark
Published: July 2020

In the academic literature, private supplementary tutoring is widely known as shadow education, in part because it is commonly indistinct and because much of its content mimics that in mainstream schooling. Around the world, shadow education has become an important part of students' lives and in some places it diminishes the body that it mimics. This paper builds on studies that have focused on relationships between schooling and shadow education. The paper uses the conceptual lens of privatisation‐by‐default, and employs qualitative methods to understand the roles of both government and private schools in promoting tutoring in West Bengal, India. It finds that substantial proportions of shadow education emanate from and are fostered by school systems. On the one hand private tutoring as a form of privatisation‐by‐default gives freedom of choice, but on the other hand it limits choice. Further, school‐bred tutoring can have a negative backwash on school systems. As such, private supplementary tutoring is not just a neutral shadow but affects the body that it imitates. The study recommends researchers to look back at schools to gain a deeper understanding of private supplementary tutoring.
Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1
Authors: Unni Sruthi , Deshmukh Prashant , Krishnappa Gopinatha , Kommu Padmini , Padmanabhan Balasundaram
Published: July 2020

The activation of the nuclear factor erythroid 2‐related factor 2 (Nrf2) transcription function has been implicated in the protection of neurodegenerative diseases. The cytoplasmic protein, Kelch‐like ECH‐associated protein 1 (Keap1), negatively regulates Nrf2. The Keap1‐Nrf2 pathway is a potential therapeutic target for tackling free‐radical damage. Dimethyl fumarate (DMF) is currently an approved drug for the treatment of relapsing multiple sclerosis. Recent studies showed that DMF modifies the reactive cysteines in the BTB domain of Keap1 and thus activates Nrf2 transcription function. Intriguingly, our crystal structure studies revealed that DMF also binds to the β‐propeller domain (Keap1‐DC) of Keap1. The crystal structure of the complex, refined to 1.54 Å resolution, revealed unexpected features: DMF binds (a) to the Nrf2‐binding site (bottom region of Keap1‐DC, site 1) with moderate interaction, and (b) to the top region of Keap1‐DC, near to the blade II (site 2). The specificity of the binding ‘site 2’ was found to be unique to blade II of the β‐propeller domain. The newly identified ‘site 2’ region in Keap1‐DC may have a different functional role to regulate Nrf2. Moreover, the crystal structures of Keap1‐DC in complex with the DMF analogs, including monoethyl fumarate, fumarate, and itaconate, also exhibited similar binding modes with Keap1‐DC. Binding studies confirmed that DMF binds, in a nanomolar range, to the Keap1‐DC region as well as the BTB domain of Keap1. Furthermore, the competitive binding assay in the presence of the Nrf2 peptide affirmed the direct binding of DMF at the Nrf2‐binding region of Keap1‐DC. Overall, our studies suggest that the drug molecule, DMF, binds at multiple sites of Keap1 and thus potentially activates Nrf2 function through covalent as well as the noncovalent mode of action, to combat oxidative stress.

Database

Structural data are available in RCSB‐protein data bank database(s) under the accession numbers 6LRZ, 7C60, and 7C5E.
‘It’s common sense that an individual must eat’: Advocating for food justice with people with psychiatric disabilities through photovoice
Authors: Weinstein Lara Carson , Chilton Mariana , Turchi Renee , Klassen Ann C , LaNoue Marianna , Silvero Alexis , Cabassa Leopoldo J
Published: July 2020

Background

People with SMI have often been excluded in advocacy efforts focused on physical health, health care and health and social policy.

Objective

Following a Photovoice project focused on barriers to healthy eating and physical activity in urban neighbourhoods, participant‐researchers were invited to present their insights in community advocacy settings. The purpose of this study was to explore the feasibility and participant–researchers’ experience of these community advocacy activities.

Design

We held four focus groups with the eight participant‐researchers after each community advocacy activity to explore their experience with public speaking, presenting their experiences and advocating.

Setting and Participants

People with serious mental illness who were overweight/obese living in supportive housing.

Analysis approach

Qualitative analysis of the focus group transcripts, using a modified grounded theory approach followed by structured coding focused on empowerment, participation and non‐discrimination.

Results

Participant‐researchers gave three oral presentations of their photographs at a variety of community‐based programmes and settings and participated in a rally to advocate for SNAP benefits. Two themes emerged from analysis: (a) Empowerment (the level of choice, influence and control that users of mental health services can exercise over events in their lives) and (b) Barriers to Empowerment (obstacles to participation and well‐being).

Conclusions

This evaluation strengthens the evidence that it is feasible for participant‐researchers in Photovoice projects to engage in robust advocacy activities, such as presentations and discussions with local policymakers. During focus groups, participant‐researchers demonstrated realistic optimism towards their roles as change agents and influencers in spite of acknowledged systemic barriers.
Polypharmacy and potential drug–drug interactions for people with HIV in the UK from the Climate‐HIV database
Authors: Okoli C , Schwenk A , Radford M , Myland M , Taylor S , Darley A , Barnes J , Fox A , Grimson F , Reeves I , Munshi S , Croucher A , Boxall N , Benn P , Paice A , van Wyk J , Khoo S
Published: July 2020

Objectives

People with HIV (PWHIV) are likely to need therapies for comorbidities as they age. We assessed risk of drug–drug interactions (DDIs) in PWHIV.

Methods

The Climate‐HIV electronic recording system was used to cross‐sectionally analyse records from PWHIV aged ≥ 18 years attending four UK HIV units with a current antiretroviral (ARV) prescription in February 2018. Antiretroviral and non‐ARV medications were categorized by clinical significance of DDIs (University of Liverpool DDI tool). Potential DDIs were predicted using treatment guidelines for commonly recorded comorbidities.

Results

Among 4630 PWHIV (44% female), 41% were ≥ 50 years old. The average number of non‐ARV comedications increased from < 1 for patients aged ≤ 24 years to > 5 for patients aged ≥ 75 years; 65% were taking one or more non‐ARV comedications. The median (interquartile range) number of non‐ARVs was 1 (0–2) and 2 (1–5) for those aged < 50 and ≥ 50 years, respectively. Common comorbidities/concurrent health conditions occurred more frequently in patients aged ≥ 50 years vs. < 50 (53% vs. 34%). Boosted protease inhibitors were associated with the highest proportion of contraindicated comedications; dolutegravir and raltegravir had the fewest. For non‐ARVs, sildenafil and quetiapine were most likely to result in DDIs. Guideline‐recommended treatments for hepatitis C, hepatitis B, and tuberculosis had the highest proportions of contraindications when combined with ARV regimens, while treatments for hepatitis C, malignancy, and mental health conditions had the highest proportion of combinations potentially causing DDIs requiring dose monitoring or adjustment.

Conclusions

Non‐ARV use by PWHIV is high and increases with age. Treatment decisions for ageing PWHIV should consider guideline recommendations for comorbidities.
Discussion
Authors: Narisetty Naveen Naidu
Published: July 2020

I thoroughly enjoyed reading the article by Bhadra et. al. (2020) and convey my congratulations to the authors for providing a comprehensive and coherent review of horseshoe‐based regularization approaches for machine learning models. I am thankful to the editors for providing this opportunity to write a discussion on this useful article, which I expect will turn out to be a good guide in the future for statisticians and practitioners alike.

It is quite amazing to see the rapid progress and the magnitude of work advancing the horseshoe regularization approach since the seminal paper by Carvalho et al. (2010). The current review article is a testimony for this. While I have been primarily working with continuous spike and slab priors for high‐dimensional Bayesian modeling, I have been following the literature on horseshoe regularization with a keen interest. For my comments on this article, I will focus on some comparisons between these two approaches particularly in terms of model building and methodology and some computational considerations. I would like to first provide some comments on performing valid inference based on the horsheshoe prior framework.
Evaluation of information quality on the internet for periodontal disease patients
Authors: Kanmaz Burcu , Buduneli Nurcan
Published: July 2020

Objective

To evaluate the quality of accessible information on periodontal diseases on the Internet using different scales.

Materials and Methods

A search was performed using the Google search engine with questions about periodontal disease symptoms. The first 30 web sites obtained after searching for each question were evaluated. Duplicate web sites, advertisements, discussion groups, links to research articles, videos, and images were excluded. A total of 90 web sites were included and evaluated with Health on the Net Code of Conduct Certification (HONCode) presence, Journal of American Medical Association (JAMA) benchmarks, and the quality criteria for consumer health information (DISCERN) toolkit.

Results

Only 27.8% of the analyzed web sites contain HONCode certificates. No webpages fulfilled all JAMA criteria, whereas 32.2% of the web sites did not provide any of them. Majority of the web sites’ (44.4%) overall rating score was 2 with the DISCERN instrument. In the DISCERN Section Scores comparison between various types of web sites, information web site scores were higher than Dental Health Center Web sites in Section 1 and Section 3 scores (p = .000 and p = .001, respectively).

Conclusion

Overall quality of periodontal information based on patients’ questions on the Internet has serious shortcomings especially in terms of attribution and the quality of information on treatment choices.
Engineering creativity: Prior experience modulates electrophysiological responses to novel metaphors
Authors: Jończyk Rafal , Kremer Gül E. , Siddique Zahed , van Hell Janet G.
Published: July 2020

Novel metaphorical language use exemplifies human creativity through production and comprehension of meaningful linguistic expressions that may have never been heard before. Available electrophysiological research demonstrates, however, that novel metaphor comprehension is cognitively costly, as it requires integrating information from distantly related concepts. Herein, we investigate if such cognitive cost may be reduced as a factor of prior domain knowledge. To this end, we asked engineering and nonengineering students to read for comprehension literal, novel metaphorical, and anomalous sentences related to engineering or general knowledge, while undergoing EEG recording. Upon reading each sentence, participants were asked to judge whether or not the sentence was original in meaning (novelty judgment) and whether or not it made sense (sensicality judgment). When collapsed across groups, our findings demonstrate a gradual N400 modulation with N400 being maximal in response to anomalous, followed by metaphorical, and literal sentences. Between‐group comparisons revealed a mirror effect on the N400 to novel metaphorical sentences, with attenuated N400 in engineers and enhanced N400 in non‐engineers. Critically, planned comparisons demonstrated reduced N400 amplitudes to engineering novel metaphors in engineers relative to non‐engineers, pointing to an effect of prior knowledge on metaphor processing. This reduction, however, was observed in the absence of a sentence type × knowledge × group interaction. Altogether, our study provides novel evidence suggesting that prior domain knowledge may have a direct impact on creative language comprehension.
Present and Perspectives of the Adult Education Theory in the System of Andragogical Sciences
Authors: Pavlov Ivan
Published: July 2020

The adult education theory belongs to the fundamental theoretical disciplines of andragogy and the development of its fundamental assumptions is an important prerequisite for the development of andragogy. The current level of its terminology and system apparatus in comparison to other disciplines of andragogy currently does not fully enable to develop primarily practical-application functions, and thus leaves its potential unfulfilled. Building of an education theory on interdisciplinary, multidisciplinary and trans-disciplinary principles is now legitimate and allows the use of research results of other sciences (philosophy, anthropology, pedagogy, sociology, psychology, ethics, cultural studies, etc.). The adult education theory cannot be built only as a theory for theory (normative aspect), but it should develop its own exploratory, explanatory and analytical potential for the needs of support of self-development of an adult. It envisages the creation of a scientifically justified system of adult education and self-education as a theory providing sufficiently developed and socially applicable model of andragogical action. Prospects of the adult education theory are combined with the need to define and understand the basic terms (education and self-education of adults), their relations in the system of science, explanation of subject and functions (normative and practical, through the development of basic and applied research and creation of the curriculum components (objectives, principles, contents, education process and others).
Wave speeds in single-crystal and polycrystalline copper
Authors: Thomas Sarah A. , Hixson Robert S. , Hawkins M. Cameron , Strand Oliver T.
Published: July 2020

While the equation of state for copper has been fairly well studied, wave speeds at low stress are not as well known. Systematic errors may be present in the lowest stress data presented in the Marsh [1] compendium due to the use of the flash gap method to collect the data. Additionally, little data has been gathered on the wave speeds in single-crystal copper, which may vary from polycrystalline due to the different longitudinal and shear sound speeds. Hugoniot information at low pressures is useful in constraining and improving predictive hydrodynamic codes. Knowledge of single-crystal behavior provides input for mesoscale computer models that use tens-of-micron-sized grains of single crystals to build a model of polycrystalline systems. We undertook experiments to measure wave speeds in polycrystalline and single-crystal copper at low pressures using a novel technique to limit error, and to determine if single-crystal shock velocities are systematically different than polycrystalline shock velocities at the same stress. The best previous research on this topic is from Chau et al. [2] at relatively high shock stress; they reported no observed difference between orientations. It is of interest to do careful measurements at low stress, and that is the principal goal of this work.
Development of Arl’s Multi-Energy Flash Computed Tomography Diagnostic: Capability to Track Mass-Flux Through a Reconstruction Volume
Authors: Zellner Michael B. , Love Melissa S. , Champley Kyle
Published: July 2020

The U.S. Combat Capabilities Development Command Army Research Laboratory and Lawrence Livermore National Laboratory are currently developing a Multi-Energy Flash Computed Tomography (MEFCT) diagnostic for multi-frame, in situ, three-dimensional radiographic assessment of ballistic impact phenomena. To accomplish this, we combine the capabilities of medical X-ray computed tomography and high-speed computed tomography, to produce a system that captures three independent, time-sequenced volume reconstructions throughout the timespan of a typical dynamic ballistic event. Because this system has the capability to image an event across three spatial dimensions and time, it is the first of its kind to track mass/material-flux of an un-bounded system through a volume at ballistic timescales.

To demonstrate the diagnostic’s capabilities, an assessment of a bullet penetrating an aluminum plate is performed. A compilation of the three volume reconstructions were computed to describe the event. The results were compared to a state-of-the-art simulation of the event using EPIC, a Lagrangian hydrocode with penetration applications. This comparison shows how using a four-dimensional computed tomography system can benefit the validation of physical failure and mass/material-flow models.
Statistics of energy dissipation in the hypervelocity impact shock failure transition
Authors: Grady Dennis
Published: July 2020

In the hypervelocity impact event, shock waves subject material to failure transitions with the attendant dissipation of the imparted energy. Under shock compression, failure and dissipation entail intense compression, inelastic shear and compaction. Through shock interactions, states of dynamic tension are achieved and further failure dissipation involves fracture and fragmentation. The nature of failure of solids in the shock environment has encouraged considerable experimental effort through the past several decades. Such efforts have yielded results that suggest universality in the shock failure response over significant spans of shock intensity. Examples include the fourth-power relation between pressure and strain rate in solid-material compressive shock waves, and power-law relations capturing spall fracture strength and fragmentation size scale in dynamic tensile failure. Comparable power-laws also describe the shock compaction of distended solids. The present paper explores a statistical perspective of the underlying micro failure dynamics for the purpose of achieving better understanding of the macro failure trends noted above. A statistical correlation function description of the random micro velocity field is introduced. Through the attendant kinetic dissipation, the statistical fluctuation-dissipation principle is applied to the shock failure transition. From this statistical approach, power-law relations for compressive and tensile shock failure emerge that replicate the reported experimental behaviors.
Simulating Lateral Drift of a Shaped Charge Jet in ALEGRA
Authors: Coppinger Matthew J. , Uhlig W. Casey , Niederhaus John H. J.
Published: July 2020

Shaped charge jet (SCJ) research has long been an active area for industrial, academic, and defense organizations. Traditionally, the depth of penetration (DOP) has been one of the most important metrics for the evaluation of shaped charge jet performance, and early 1D analytical penetration models based on hydrodynamic penetration were created with this metric in mind [1]. As the standoff of a shaped charge jet increases, the DOP reaches a maximum and then begins to decrease. A simple 1D hydrodynamic penetration model must account for the totality of the jet material on axis penetrating, and as a result experimental DOP at longer standoffs is lower than the analytical models predicted. Some analytical models reasoned that since a velocity gradient evolves as a SCJ forms, contributions to penetration from jet material below a minimum jet or penetration velocity should be eliminated. These were better able to account for the difference between analytical hydrodynamic and experimental DOPs [2]. The actual difference between analytical hydrodynamic penetration theory and experimentally recorded values is now regarded to be a result of 3D phenomena including particle tumbling and motion transverse to the jet axis known as lateral drift [2]. The origins of these 3D phenomena have been attributed to sources including variability in the uniformity of the explosive charge or the microstructure of the liner [2,3].
Experiments using a light gas gun to investigate the impact melting of gunshot residue analogues
Authors: Spathis V. , Price M. C.
Published: July 2020

In this set of experiments, the versatility of the University of Kent's light gas gun was utilised to obtain a selection of corroborative data regarding the formation and impact of metallic gunshot residues onto high purity silicon wafers. The results from the two experiments are presented. The first experiment investigated how the formation of metallic residues varied as gunshot residue analogues traversed through air under a range of pressures from 0.056 millibar (5.6 Pa) to 1 bar (100 kPa), using solely the energy released during primer ignition; the second involved firing a metallic powder mix of pre-determined composition (via a split-sabot) under vacuum at two velocities- 500 ms-1 and 2000 ms-1. This ensured that there was no ignition or heating of the powders, unlike the first experiment, and so the morphology of the particles collected would be solely due to impact. The residues on the substrates were then analysed using a cold Field Emission Gun Scanning Electron Microscope (FEG) and Energy Dispersive X-ray (EDX) detector. By separating the ignition process of the primers from the residue impacts, it allows for a closer look into the formation of these particles and helps determine whether their varied morphologies are due to the heating caused during the activation and combustion of the primer or whether its due to impact melting. This information can aid in the understanding of metallic particle formation in different pressure environments and give insight into the physical state of firearm residues when they impact a surface. Hydrocode modelling was also incorporated to corroborate the results observed during these experiments and gave results which mimicked the experimental data.
Depth of penetration criteria on metallic surfaces for use in MMOD risk assessment
Authors: Nahra Henry , Ghosn Louis , Christiansen Eric , Miller Joshua , Davis Bruce A.
Published: July 2020

System level assessment of hypervelocity impacts by micrometeoroids and orbital debris (MMOD) relies on the definition of the spacecraft geometry and trajectory, the natural environment of the micrometeoroids and induced environment of the orbital space debris, ballistic limit equations and the failure criteria. The definition of the MMOD environments provides the particles flux and when is combined with the ballistic limit equations will determine the number of the critical penetrating particles that could result in the failure of the underlying component is calculated and is used to calculate the risk based on some failure criterion. Spacecraft geometry provides the shielding configuration over the spacecraft critical body which defines the selection of the ballistic limit equations to be used in the risk assessment. The definition of the failure criterion for metallic pressure systems involves the definition of the allowable depth of penetration that could result in leakage or burst of the component. This paper addresses the definition of the allowable depth of penetration of generic metallic tanks from MMOD impacts. The allowable penetration depth of metal tanks is based on a fracture mechanics approach calibrated using biaxially stressed coupons tests subjected to Hypervelocity Impacts (HVI). The planar crack-crack spacing was based on the craters spacing distribution of the HVI coupon tests. The Stress Intensity Factor (SIF) as a function of crater depths and crater spacing and applied remote stress is calculated using NASGRO®, a linear fracture mechanics software. The calculated SIF is compared with the material fracture toughness to determine if the craters result in a failure of the coupons under biaxial stress. This work resulted in a recommended allowable depth of penetration of 20% on the surfaces of metallic pressure vessels on spacecraft.
A penetration model for semi-infinite ultra-high molecular weight polyethylene composite
Authors: Nguyen Long H. , Ryan Shannon , Orifici Adrian C. , Cimpoeru Stephen J.
Published: July 2020

Ultra-high molecular weight polyethylene (UHMW-PE) composite has been shown to be an effective material for ballistic protection against blunt penetrators [1]. The material exhibits multiple stages of penetration, typically characterised by an initial local penetration phase followed by large bulge deformation of the back face [2]. The location at which transition occurs between the localised penetration stage and non-localised bulging stage is an important property of UHMW-PE composite armour. However, the conditions required to induce transition are poorly understood with a range of different mechanisms proposed to explain the behaviour [2,3], none of which can be used to predict the transition location within the target.
Study on jet formation and penetration of double-layer sub-caliber shaped charge
Authors: Wang Yu-ting , Xiao Qiang-qiang , Huang Zheng-xiang , Zu Xu-dong , Ma Bin
Published: July 2020

The ordinary shaped charge has a low kill-radius because of its structure. In order to adapt to the different battlefields, this paper proposed the double-layer sub-caliber shaped charge, which is modified from an ordinary shaped charge with insensitive explosive appended to its outer layer. In this paper, a study of the Ø56 mm shaped charge was conducted as a benchmark case. The simulations were carried out using AUTODYN for jet formation and penetration of different axial thicknesses of additional insensitive explosive and the additional height of the charge, with the aim to obtain the optimal size of double-layer sub-caliber shaped charge. The results show that the optimum axial thickness of additional insensitive explosive is ΔR/R0 = 0.8, and the optimum size of the additional height of charge is ΔL/L0 = 0.4.
Experiment guided simulation of multi-fragment impact into PBXs
Authors: Schmalzer Andrew M. , Yeager John D. , Bowden Patrick R. , Guildenbecher Daniel R. , Olles Joseph D.
Published: July 2020

Multi-fragment impact of energetic materials can provide the impetus initiation and growth to detonation when shockwaves from these discrete fragments collide. The Sandia hydrocode CTH is used with reactive burn modeling to identify relationships between spherical fragment separation distances, variable fragment arrival timing, and initiability in energetic materials. This work demonstrates that detonation is most likely to occur is when multiple fragments collide with a surface simultaneously, because of the cumulative pressure rise of two equal colliding waves compared to the colliding waves generated by fragment impacts offset in time.
Characterization and rheology of platelet-rich plasma
Authors: Mitra H. , Jayaram P. , Bratsman A. , Gabel T. , Alba K.
Published: July 2020

Blood-derived products, particularly platelet-rich plasma (PRP), have received increased attention in the past several years due to their great potential as a therapy for osteoarthritis and tendon injuries. Therefore, characterizing the mechanical properties of PRP becomes important to better understand its therapeutic efficacy. This paper aims to investigate the rheological properties of PRP in order to provide further insight into its mechanism of action. The PRP samples in our study may have higher erythrocyte count than the average PRP reported in the literature. Flow-sweep, small amplitude oscillatory shear (SAOS), large amplitude oscillatory shear (LAOS), and thixotropy tests have been performed at room and physiological temperatures to characterize the non-Newtonian properties of PRP samples. Flow-sweep tests reveal shear-thinning behavior, with higher apparent viscosity observed at a lower temperature. Rheological models such as Carreau, Casson, power-law, and Herschel–Bulkley have been fitted to flow-sweep data with the latter showing the closest agreement. Over the acceptable narrow range of frequency in SAOS tests, the loss modulus appears to be slightly larger than the storage modulus with both moduli decreasing at higher temperature. The nonlinear viscoelastic properties are furthermore quantified through the static and dynamic LAOS analyses. For a given strain and angular frequency, the former identifies strain-softening and shear-thinning, while the latter discloses a range of other transient behavior within an oscillation cycle. Lastly, peak-hold tests have revealed consistent thixotropy in PRP solutions.
Herpes Simplex Virus 2 Counteracts Neurite Outgrowth Repulsion during Infection in a Nerve Growth Factor-Dependent Manner
Authors: Kropp Kai A. , López-Muñoz Alberto Domingo , Ritter Birgit , Martín Rocío , Rastrojo Alberto , Srivaratharajan Sangar , Döhner Katinka , Dhingra Akshay , Czechowicz Julia S. , Nagel Claus-Henning , Sodeik Beate , Alcami Antonio , Viejo-Borbolla Abel
Published: July 2020

Herpes simplex virus 2 (HSV-2) is a prevalent human pathogen that establishes lifelong latency in neurons of the peripheral nervous system. Colonization of neurons is required for HSV-2 persistence and pathogenesis. The viral and cellular factors required for efficient infection of neurons are not fully understood. We show here that nonneuronal cells repel neurite outgrowth of sensory neurons, while HSV-2 infection overcomes this inhibition and, rather, stimulates neurite outgrowth. HSV-2 glycoprotein G and nerve growth factor contribute to this phenotype, which may attract neurites to sites of infection and facilitate virus spread to neurons. Understanding the mechanisms that modulate neurite outgrowth and facilitate HSV-2 infection of neurons might foster the development of therapeutics to reduce HSV-2 colonization of the nervous system and provide insights on neurite outgrowth and regeneration.
USH2A variants in Chinese patients with Usher syndrome type II and
non-syndromic retinitis pigmentosa
Authors: Zhu Tian , Chen De-Fu , Wang Lei , Wu Shijing , Wei Xing , Li Hui , Jin Zi-Bing , Sui Ruifang
Published: July 2020

Aims

To reveal the Usher syndrome type IIA (USH2A)
gene variant profile in a large cohort of Chinese patients with non-syndromic
retinitis pigmentosa (RP) or Usher syndrome type II (USH2) and to explore the
genotype–phenotype correlation.

Methods

Targeted exome capture plus next-generation sequencing confirmed that 284
patients from 260 unrelated Chinese families carried
USH2A disease-associated variants. Both personal
medical history and family histories were reviewed. Ocular examinations were
performed and audiograms were recorded if hearing loss was suspected. The
genotype–phenotype correlation was evaluated by statistical analyses.

Results

A total of 230 variants in the USH2A gene were
identified, of which 90 (39.13%) were novel. The most common variants in the RP
and USH2 probands were p.Cys934Trp and p.Tyr2854_2894del, respectively, and
26.42% and 63.64% of the alleles in the RP and USH2 groups were truncating,
respectively. Patients harbouring biallelic truncating variants had a younger
age at the initial clinical visit and symptom onset than patients with missense
variants; furthermore, the patients with USH2 had a younger age at the initial
clinical visit and nyctalopia onset compared with the patients with RP
(p<0.001). For the patients with USH2, the age of nyctalopia onset was
positively correlated with that of hearing loss (p<0.05, r=0.219). In
addition, three pseudo-dominant pedigrees were identified carrying biallelic
USH2A variants.

Conclusions

This study enrolled the largest cohort of Chinese patients with
USH2A and identified the most prevalent
USH2A variants in USH2 and RP. We found that the
patients with USH2 had more truncating variants and experienced an earlier
decline in visual function. The findings enhance the current knowledge of
USH2A heterogeneity and provide valuable
information for future therapies.
Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy
Authors: Chuckran Christopher A , Liu Chang , Bruno Tullia C , Workman Creg J , Vignali Dario AA
Published: July 2020

Checkpoint blockade immunotherapy established a new paradigm in cancer treatment: for certain patients curative treatment requires immune reinvigoration. Despite this monumental advance, only 20%–30% of patients achieve an objective response to standard of care immunotherapy, necessitating the consideration of alternative targets. Optimal strategies will not only stimulate CD8+T cells, but concomitantly modulate immunosuppressive cells in the tumor microenvironment (TME), most notably regulatory T cells (Tregcells). In this context, the immunoregulatory receptor Neuropilin-1 (NRP1) is garnering renewed attention as it reinforces intratumoral Tregcell function amidst inflammation in the TME. Loss of NRP1 on Tregcells in mouse models restores antitumor immunity without sacrificing peripheral tolerance. Enrichment of NRP1+Tregcells is observed in patients across multiple malignancies with cancer, both intratumorally and in peripheral sites. Thus, targeting NRP1 may safely undermine intratumoral Tregcell fitness, permitting enhanced inflammatory responses with existing immunotherapies. Furthermore, NRP1 has been recently found to modulate tumor-specific CD8+T cell responses. Emerging data suggest that NRP1 restricts CD8+T cell reinvigoration in response to checkpoint inhibitors, and more importantly, acts as a barrier to the long-term durability of CD8+T cell-mediated tumor immunosurveillance. These novel and distinct regulatory mechanisms present an exciting therapeutic opportunity. This review will discuss the growing literature on NRP1-mediated immune modulation which provides a strong rationale for categorizing NRP1 as both a key checkpoint in the TME as well as an immunotherapeutic target with promise either alone or in combination with current standard of care therapeutic regimens.
Recycling of Gold Using Anodic Electrochemical Deposition from Molten Salt Electrolyte
Authors: Ouchi Takanari , Wu Shuang , Okabe Toru H.
Published: July 2020

Recycling of precious metals is becoming increasingly important as our living standards improve and electronic technologies advance. Conventional recycling processes involve multi-step hydrometallurgical treatments, in which precious metals are dissolved in aqueous solutions using a combination of strong complexing agents and oxidizing agents. However, these processes are time consuming and produce a large amount of hazardous liquid waste. Here, we present a new recycling process for Au, which is based on the direct anodic electrochemical deposition of anionic Au ions dissolved in a molten salt electrolyte. Moreover, this process is simple and does not generate harmful waste. In this process, Au is alloyed with Na to facilitate its dissolution in a molten mixture of NaCl–NaI. The existence of Au as an anionic species (Au
n−) in the molten salt was proven and its anodic deposition (oxidation reaction) by application of an anodic current was demonstrated. During the anodic deposition of Au, Na is deposited on the cathode and can be recovered and reused in the process. It is expected that this electrodeposition technique to recycle Au from scrap metal could result in the development of a new environmentally friendly Au recycling process that does not generate hazardous waste.
Crystallographic Orientation Dependence of Nanopattern Morphology and Size in Electropolished Polycrystalline and Monocrystalline Aluminum: An EBSD and SEM Study
Authors: Yuan Yuan , Zhang Dan , Zhang Feihu , Yang Chunhui , Gan Yang
Published: July 2020

Electropolishing of aluminum (Al) has been applied to form surface nanopatterns of various morphologies and sizes. However, the effect of crystallographic orientation on nanopattern morphology and size in electropolished Al is unclear. Here, annealed polycrystalline and monocrystalline Al samples were electropolished at 40 V in an electrolyte of perchloric acid, ethanol, butyl cellusolve and water, the correlation between crystallographic orientation and nanopattern morphology and size was firmly established through systematic EBSD and SEM examination. Heterogeneity in nanopattern morphology and nanopattern size is induced by crystallographic anisotropy of grains. Nanopattern morphology and size change gradually for grains and planes oriented with varying misorientation angles against each primary direction [101]//ND, [101]//ND and [111]//ND. The transitions between nanopattern morphologies also occur for grain surface planes with near identical misorientation angles. The surface structure sensitivity of nanopattern morphology and size was firmly established and then qualitatively explained by invoking step-terrace and step-ledge surface structure models and by developing a refined adsorption-diffusion perspective based on a reported theoretical model. The findings reported here contribute significantly to gaining new insights into the crystallographic orientation dependence of nanopattern morphology and nanopattern size in electropolished Al and other metals.
A Computationally Efficient Multidiode Model for Optimizing the Front Grid of Multijunction Solar Cells under Concentration
Authors: van de Stadt Chris H. , Espinet Gonzalez Pilar , Atwater Harry A. , Saive Rebecca
Published: July 2020

We have developed a computationally efficient simulation model for the optimization of redirecting electrical front contacts for multijunction solar cells under concentration, and we present its validation by comparison with experimental literature results. The model allows for fast determination of the maximum achievable efficiency under a wide range of operating conditions and design parameters such as the contact finger redirecting capability, period and width of the fingers, the light concentration, and the metal and emitter sheet resistivity. At the example of a state-of-the-art four-junction concentrator solar cell, we apply our model to determine ideal operating conditions for front contacts with different light redirection capabilities. We find a 7% relative efficiency increase when enhancing the redirecting capabilities from 0% to 100%.
Shear Behaviour of RC Beams Strengthened by Various Ultrahigh Performance Fibre‐Reinforced Concrete Systems
Authors: Mansour Walid , Tayeh Bassam A.
Published: July 2020

This study presents a numerical investigation on the shear behaviour of shear‐strengthened reinforced concrete (RC) beams by using various ultrahigh performance fibre‐reinforced concrete (UHPFRC) systems. The proposed 3D finite element model (FEM) was verified by comparing its results with those of experimental studies in the literature. The validated numerical model is used to analyse the crucial parameters, which are mainly related to the design of RC beams and shear‐strengthened UHPFRC layers, such as the effect of shear span‐to‐depth ratio on the shear behaviour of the strengthened or nonstrengthened RC beams and the effect of geometry and length of UHPFRC layers. Moreover, the effect of the UHPFRC layers’ reinforcement ratio and strengthening of one longitudinal vertical face on the mechanical performance of RC beams strengthened in shear with UHPFRC layers is investigated. Results of the analysed beams show that the shear span‐to‐depth ratio significantly affects the shear behaviour of not only the normal‐strength RC beams but also the RC beams strengthened with UHPFRC layers. However, the effect of shear span‐to‐depth ratio has not been considered in existing design code equations. Consequently, this study suggests two formulas to estimate the shear strength of normal‐strength RC beams and UHPFRC‐strengthened RC beams considering the effect of the shear span‐to‐depth ratio.
Pathologic Disparities Between Peripheral Artery Disease and Coronary Artery Disease
Authors: Narula Nupoor , Olin Jeffrey W. , Narula Navneet
Published: July 2020

Atherosclerosis is a systemic disease that involves multiple vascular beds. The pathological characteristics and clinical presentation, however, vary among the different vascular territories. Acute coronary syndrome is a relatively common manifestation of coronary atherosclerotic disease, wherein the thrombosis occurs secondary to disruption (65%–75%) and erosion (25%–35%) of the fibrous caps of atheromatous plaques. The plaques associated with plaque rupture have large necrotic cores and thin and inflamed fibrous caps. However, the pathological manifestations of peripheral artery disease result from thrombosis regardless of the extent of atherosclerosis. Approximately 75% of peripheral arteries with significant stenosis demonstrate presence of thrombi, of which two-thirds have thrombi associated with insignificant atherosclerosis. The presence of obliterative thrombi in peripheral arteries of patients with critical limb ischemia in the absence of coronary artery–like lesions suggests a locally thrombogenic or remotely embolic basis of disease. Extensive calcification of the medial vascular layer is commonly observed. In this review, we have described and compared the pathological basis of coronary and peripheral artery disease in patients with acute coronary syndrome and critical limb ischemia. It is expected that pathogenetic characterization would allow for definition of strategic targets for superior management of peripheral artery disease.
Sustained Focal Vascular Inflammation Accelerates Atherosclerosis in Remote Arteries
Authors: Lavin Plaza Begoña , Phinikaridou Alkystis , Andia Marcelo E. , Potter Myles , Lorrio Silvia , Rashid Imran , Botnar Rene M.
Published: July 2020

Objective:

Evidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown.

Approach and Results:

We used a novel
ApoE
−/−
knockout mouse model of sustained arterial inflammation, initiated by mechanical injury in the abdominal aorta. Using serial in vivo molecular MRI and ex vivo histology and flow cytometry, we demonstrate that focal arterial inflammation triggered by aortic injury, accelerates atherosclerosis in the remote brachiocephalic artery. The brachiocephalic artery atheroma had distinct histological features including increased plaque size, plaque permeability, necrotic core to collagen ratio, infiltration of more inflammatory monocyte subsets, and reduced collagen content. We also found that arterial inflammation following focal vascular injury evoked a prolonged systemic inflammatory response manifested as a persistent increase in serum IL-6 (interleukin 6). Finally, we demonstrate that 2 therapeutic interventions—pravastatin and minocycline—had distinct anti-inflammatory effects at the plaque and systemic level.

Conclusions:

We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.
Coupling of Integrin α5 to Annexin A2 by Flow Drives Endothelial Activation
Authors: Zhang Chenghu , Zhou Ting , Chen Zhipeng , Yan Meng , Li Bochuan , Lv Huizhen , Wang Chunjiong , Xiang Song , Shi Lei , Zhu Yi , Ai Ding
Published: July 2020

Rationale:

Atherosclerosis preferentially occurs at specific sites of the vasculature where endothelial cells (ECs) are exposed to disturbed blood flow. Translocation of integrin α5 to lipid rafts promotes integrin activation and ligation, which is critical for oscillatory shear stress (OSS)-induced EC activation. However, the underlying mechanism of OSS promoted integrin α5 lipid raft translocation has remained largely unknown.

Objective:

The objective of this study was to specify the mechanotransduction mechanism of OSS-induced integrin α5 translocation and subsequent EC activation.

Methods and Results:

Mass spectrometry studies identified endothelial ANXA2 (annexin A2) as a potential carrier allowing integrin α5β1 to traffic in response to OSS. Interference by siRNA of
AnxA2
in ECs greatly decreased OSS-induced integrin α5β1 translocation to lipid rafts, EC activation, and monocyte adhesion. Pharmacological and genetic inhibition of PTP1B (protein tyrosine phosphatase 1B) blunted OSS-induced integrin α5β1 activation, which is dependent on Piezo1-mediated calcium influx in ECs. Furthermore, ANXA2 was identified as a direct substrate of activated PTP1B by mass spectrometry. Using bioluminescence resonance energy transfer assay, PTP1B-dephosphorylated ANXA2 at Y24 was found to lead to conformational freedom of the C-terminal core domain from the N-terminal domain of ANXA2. Immunoprecipitation assays showed that this unmasked ANXA2-C-terminal core domain specifically binds to an integrin α5 nonconserved cytoplasmic domain but not β1. Importantly, ectopic lentiviral overexpression of an ANXA2
Y24F
mutant increased and shRNA against
Ptp1B
decreased integrin α5β1 ligation, inflammatory signaling, and progression of plaques at atheroprone sites in apolipoprotein E (
ApoE
)
−/−
mice. However, the antiatherosclerotic effect of
Ptp1B
shRNA was abolished in
AnxA2
−/−
ApoE
−/−
mice.

Conclusions:

Our data elucidate a novel endothelial mechanotransduction molecular mechanism linking atheroprone flow and activation of integrin α5β1, thereby identifying a class of potential therapeutic targets for atherosclerosis.

Graphic Abstract:

An
graphic abstract
is available for this article.