bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolically Activated Proteostasis Regulators Protect Against Glutamate Toxicity by Activating NRF2
Authors: Rosarda Jessica D. , Baron Kelsey R. , Nutsch Kayla , Bollong Michael J. , Wiseman R. Luke
Published: June 2021

The extracellular accumulation of glutamate is a pathologic hallmark of numerous neurodegenerative diseases including ischemic stroke and Alzheimer’s disease. At high extracellular concentrations, glutamate causes neuronal damage by promoting oxidative stress which can lead to cellular death. This has led to significant interest in developing pharmacologic approaches to mitigate the oxidative toxicity caused by high levels of glutamate. Here, we show that the small molecule proteostasis regulator AA147 protects against glutamate-induced cell death in a neuronal-derived cell culture model by reducing intracellular levels of reactive oxygen species. While originally developed as an activator of the ATF6 arm of the unfolded protein response, we show AA147-dependent protection against glutamate toxicity is primarily mediated through activation of the NRF2-regulated oxidative stress response. We demonstrate that AA147 activates NRF2 through a mechanism involving metabolic activation to a reactive electrophile and covalent modification of KEAP1 – a mechanism analogous to that involved in AA147-dependent activation of ATF6. These results define the potential for AA147 to protect against glutamate induced oxidative toxicity and highlight the potential for metabolically-activated proteostasis regulators like AA147 to activate both protective ATF6 and NRF2 stress-responsive signaling pathways to mitigate oxidative damage associated with diverse neurologic diseases.
Direct detection of the myosin super-relaxed state and interacting heads motif in solution
Authors: Chu Sami , Muretta Joseph M. , Thomas David D.
Published: June 2021

We have used time-resolved fluorescence resonance energy transfer (TR-FRET) to detect the interacting-heads motif (IHM) of β-cardiac myosin in solution. Evidence for the IHM has been observed by several structural techniques, and it has been proposed to be the structural basis for the super-relaxed state (SRX), a low-ATPase state of myosin that has been observed biochemically in skinned muscle fibers using fluorescent ATP. It has been proposed that the disruption of this state, by mutation or chemical modification, is a major cause of heart disease, so drugs are being developed to stabilize it. The goal of the present study is to determine directly and quantitatively the correlation between the measured fractions of myosin in the IHM state and the SRX state under the same conditions in solution. We used TR-FRET to measure the distance between the two heads of bovine cardiac myosin, and found that there are two distinct populations, one of which is observable by FRET at a center distance of 2.0 nm, and the other is not detected, implying a distance greater than 4 nm. Under the same conditions, we also measured the fraction of heads in the SRX state using fluorescent nucleotide and stopped-flow kinetics. We found that, in the absence of crosslinking, the population of SRX exceeded that of IHM. In particular, the stabilizing effect of mavacamten was much greater on SRX (55% increase) than on IHM (4% increase). We conclude that the SRX and IHM states are related, but they are not identical.
Deep learning model for the prediction and classification of protein toxins across all domains of life
Authors: Caceres-Delpiano Javier , Ibañez Roberto , Correa Simon , Dunne Michael P. , Retamal Pedro , Álvarez Leonardo
Published: June 2021

Toxins are widely produced by different organisms to disrupt the physiology of other organisms, and support their own existence. Their study is useful to understand protein evolution, environmental adaptation and survival competition. In-silico predictions of toxic proteins can support empirical frameworks, and help in the safety measurements needed for various industrial related processes. Some in-silico methods are slow, hard to implement or lack taxa representation in their training datasets. Here we present a deep learning model to classify protein toxins, through the use of Convolutional Neural Networks (ConvTOX). ConvTOX is able to accurately identify toxic proteins across the domains of life, with accuracies over 80% for animal and plant toxins, and over 50% for bacterial toxins. Moreover, ConvTOX is able to generalize the identification of differences among toxin types, such as neurotoxins and myotoxins, and to accurately identify structural similarities between different protein toxins. ConvTOX overcomes limitations from previous models by being able to predict toxin proteins from across all domains of life, and by not being limited to only short toxin peptides. Limitations are still clear in terms of lower accuracies for specific phylogenetic groups (such as bacterial toxins), but still this works presents itself as a one step forward for the universal use, classification and study of toxic proteins.
Modeling Adsorption, Conformation, and Orientation of the Fis1 Tail Anchor at the Mitochondrial Outer Membrane
Authors: Ozgur Beytullah , Dunn Cory D. , Sayar Mehmet
Published: June 2021

Proteins can be targeted to organellar membranes using a tail anchor (TA), a stretch of hydrophobic amino acids found at the polypeptide carboxyl-terminus. The Fis1 protein (Fis1p), which promotes mitochondrial and peroxisomal division in the yeast Saccharomyces cerevisiae, is targeted to those organelles by its TA. Substantial evidence suggests that Fis1p insertion into the mitochondrial outer membrane can occur without the need for a translocation machinery. However, recent findings raise the possibility that Fis1p insertion into mitochondria might be promoted by a proteinaceous complex. Here, we have performed atomistic and coarse-grained simulations to analyze the adsorption, conformation and orientation of the Fis1(TA). Our results support stable insertion at the mitochondrial outer membrane in a monotopic, rather than a bitopic (transmembrane), configuration. Once inserted in the monotopic orientation, unassisted transition to the bitopic orientation is expected to be blocked by the highly charged nature of the TA carboxyl-terminus and by the Fis1p cytosolic domain. Our results are consistent with a model in which Fis1p does not require a translocation machinery for insertion at mitochondria.
Cystinosin deficient rats recapitulate the phenotype of nephropathic cystinosis
Authors: Hollywood Jennifer A , Kallingappa Prasanna K , Cheung Pang Yuk , Martis Renita M , Sreebhavan Sree , Chatterjee Aparajita , Buckels Emma J , Mathews Brya G , Lewis Paula M , Davidson Alan J
Published: June 2021

Background

The lysosomal storage disease cystinosis is caused by mutations in CTNS, encoding a cystine transporter, and in its severest form leads to proximal tubule dysfunction followed by kidney failure. Patients receive the drug-based therapy cysteamine from diagnosis. However, despite long-term treatment, cysteamine only slows the progression of end-stage renal disease and a kidney transplant is inevitable. Pre-clinical testing in cystinotic rodents is required to evaluate new therapies; however, the current models are sub-optimal. To solve this problem we generated a new cystinotic rat model.

Methods

We utilized CRISPR/Cas9-mediated gene editing to disrupt exon 3 of Ctns and measured various parameters over a 12-month time-course including blood and tissue cystine levels, urine and serum electrolytes, and analysed the histopathology and immunohistochemistry of the kidney.

Results

Ctns-/- rats display hallmarks of cystinosis by 3-6 months of age as seen by a failure to thrive, excessive thirst and urination, cystine accumulation in tissues, corneal cystine crystals, a loss of Lrp2 in proximal tubules and immune cell infiltration. High levels of glucose, calcium, albumin and protein are excreted at 6-months of age, consistent with the onset of Fanconi syndrome, with a progressive diminution of urine urea and creatinine from 9-months of age, indicative of chronic kidney disease. The kidney histology and immunohistochemistry showed proximal tubule atrophy and glomerular damage as well as classic ‘swan neck’ lesions. Overall, Ctns-/- rats show a disease progression that more faithfully recapitulates nephropathic cystinosis than existing rodent models.

Conclusions

The Ctns-/- rat provides an excellent new rodent model of nephropathic cystinosis that is ideally suited for conducting pre-clinical drug testing and a powerful tool to advance cystinosis research.

Translational Statement

Good animal models of disease are essential to perform pre-clinical testing of potential new drugs and therapies before they can progress to human clinical trials. Unfortunately, the cystinosis field has been hampered by a lack of suitable animal models that fully recapitulate the disease. We have overcome this by generating a new rat model of cystinosis by CRISPR-Cas9 gene editing. These rodents closely model the human condition in a time-frame that makes them an excellent model ideally suited for pre-clinical drug testing as well as being a powerful tool to advance cystinosis research.
Characterization of high-H2O2-tolerant bacterial cytochrome P450 CYP105D18: insights into papaverine N-oxidation
Authors: Pardhe Bashu Dev , Do Hackwon , Jeong Chang-Sook , Kim Ki-Hwa , Lee Jun Hyuck , Oh Tae-Jin
Published: June 2021

The bacterial CYP105 family is involved in secondary metabolite biosynthetic pathways and plays essential roles in the biotransformation of xenobiotics. This study investigates the newly identified H2O2-mediated CYP105D18 fromStreptomyces laurentiias the first bacterial CYP for N-oxidation. The catalytic efficiency of CYP105D18 for papaverine N-oxidation was 1.43 s−1 µM−1. The heme oxidation rate (k) was low (<0.3 min−1) in the presence of 200 mMH2O2. This high H2O2tolerance capacity of CYP105D18 led to higher turnover prior to heme oxidation. Additionally, the high-resolution papaverine complexed structure and substrate-free structure of CYP105D18 were determined. Structural analysis and activity assay results revealed that CYP105D18 had a strong substrate preference for papaverine because of its bendable structure. These findings establish a basis for biotechnological applications of CYP105D18 in the pharmaceutical and medicinal industries.
Crystal structures of Val58Ile tryptophan repressor in a domain-swapped array in the presence and absence ofL-tryptophan
Authors: Sprenger Janina , Lawson Catherine L. , von Wachenfeldt Claes , Lo Leggio Leila , Carey Jannette
Published: June 2021

The crystal structures of domain-swapped tryptophan repressor (TrpR) variant Val58Ile before and after soaking with the physiological ligand L-tryptophan (L-Trp) indicate that L-Trp occupies the same location in the domain-swapped form as in native dimeric TrpR and makes equivalent residue contacts. This result is unexpected because the ligand binding-site residues arise from three separate polypeptide chains in the domain-swapped form. This work represents the first published structure of a domain-swapped form of TrpR with L-Trp bound. The presented structures also show that the protein amino-terminus, whether or not it bears a disordered extension of about 20 residues, is accessible in the large solvent channels of the domain-swapped crystal form, as in the structures reported previously in this form for TrpR without N-terminal extensions. These findings inspire the exploration of L-Trp analogs and N-terminal modifications as labels to orient guest proteins that cannot otherwise be crystallized in the solvent channels of crystalline domain-swapped TrpR hosts for potential diffraction analysis.
Crystal structure and magnetic study of the complex salt [RuCp(PTA)2–μ-CN-1κC:2κN–RuCp(PTA)2][Re(NO)Br4(EtOH)0.5(MeOH)0.5]
Authors: Pacheco Mario , Alvarez Natalia , Cuevas Alicia , Romerosa Antonio , Lloret Francesc , Kremer Carlos
Published: June 2021

A new RuII–ReII complex salt, μ-cyanido-κ2
C:N-bis[(η5-cyclopentadienyl)bis(3,5,7-triazaphosphaadamantane-κP)ruthenium(II)] tetrabromido(ethanol/methanol-κO)nitrosylrhenate(II), [Ru(CN)(C5H5)2(C6H12N3P)4][ReBr4(NO)(CH4O)0.5(C2H6O)0.5] or [RuCp(PTA)2–μ-CN–1κC:2κ2
N-RuCp(PTA)2][Re(NO)Br4(EtOH)0.5(MeOH)0.5] (PTA = 3,5,7-triazaphosphaadamantane) was obtained and characterized by single-crystal X-ray diffraction, elemental analysis and infrared spectroscopy. The title salt was obtained by liquid–liquid diffusion of methanol/DMSO solutions of (NBu4)[Re(NO)Br4(EtOH)] and [(PTA)2CpRu–μ-CN–1κC:2κ2
N-RuCp(PTA)2](CF3SO3). The RuII and ReII independent moieties correspond to a binuclear and mononuclear complex ion, respectively. A deep geometrical parameter analysis was performed, and no significant differences were found with earlier reports containing similar molecules. The magnetic properties were investigated in the temperature range 2.0–300 K, and the complex behaves as a quasi-magnetically isolated spin doublet with weak antiferromagnetic interactions.
Crystal structure and Hirshfeld surface analysis of dimethyl 5-[2-(2,4,6-trioxo-1,3-diazinan-5-ylidene)hydrazin-1-yl]benzene-1,3-dicarboxylate 0.224-hydrate
Authors: Atioğlu Zeliha , Akkurt Mehmet , Mammadova Gunay Z. , Huseynov Fatali E. , Hajiyeva Sevinj R. , Shamilov Nazim T. , Bhattarai Ajaya
Published: June 2021

In the crystal, the whole molecule of the title compound, C14H12N4O7·0.224H2O, is nearly planar with a maximum deviation from the least-squares plane of 0.352 (1) Å. The molecular conformation is stabilized by an intramolecular N—H...O hydrogen bond, generating an S(6) ring motif. In the crystal, molecules are linked by centrosymmetric pairs of N—H...O hydrogen bonds, forming ribbons along the c-axis direction. These ribbons connected by van der Waals contacts, forming sheets parallel to the ac plane. There are also intermolecular van der Waals contacts and and C—H...π interactions between the sheets. A Hirshfeld surface analysis indicates that the most prevalent interactions are O...H/H...O (41.2%), H...H (19.2%), C...H/H...C (12.2%) and C...O/ O...C (8.4%).
Diethyl [(2,5-diiodo-4-methylphenyl)methyl]phosphonate
Authors: Schollmeyer Dieter , Sadovski Oleg , Detert Heiner
Published: June 2021

The title compound, C12H17I2O3P, was prepared in three steps from p-xylene. Heterodimers between nearly identical molecules are connected via three hydrogen bonds from benzylic and ester methylene groups to phosphonate. The dimers form chains along the a-axis direction, stabilized by C—H...O bridges.
Fighting the big bad wolf of global trends: technology transfer between HPC centres and SMEs
Authors: Besednjak Valič Tamara , Kolar Janez , Lamut Urša
Published: June 2021

Purpose

This paper aims to explore the dynamic relationships between high-performance computing centres (HPC centres) and small-to-medium-sized enterprises (SMEs) working in the automotive sector.

Design/methodology/approach

An empirical study was conducted in 14 European countries with a total of 92 participants, representatives of HPC centres and SMEs. Data were collected through focus groups.

Findings

Findings show there is a distinct manner of shaping collaboration and cooperation networks between both spheres. In shaping the relationships, cognitive frames play a role through specific values involved share. Institutions also play an important role.

Research limitations/implications

Research into relationships between HPC centres and SMEs conducted was qualitative; therefore, limitations arise on data not being able to be generalized. The cultural aspect is to be taken into account when conducting further studies.

Practical implications

Findings of this study can be used by policymakers, especially those interested in regional innovation. The results can be of use when tailoring innovation policies, especially when it comes to enhancing the regional and extra-regional cooperation between HPC centres and SMEs.

Originality/value

To the best of authors’ knowledge, this paper is one of the first research contributions to analyse the relationships between HPC centres and SMEs from the automotive sector in selected European countries.
A code-compliance assessment tool for fire prevention measures in educational facilities
Authors: Salaheldin Mohammad H. , Hassanain Mohammad A. , Hamida Mohammad B. , Ibrahim Ahmed M.
Published: June 2021

Purpose

This research presents the applicable international fire code requirements for educational facilities, in a comprehensive manner, and the findings of a case study to assess the level of compliance with these requirements.

Design/methodology/approach

A review of literature, fire codes and standards was conducted to identify the various sources of fire hazards in educational facilities and the required prevention measures. Accordingly, a code-compliance worksheet for assessing the fire prevention measures was developed. The worksheet included 34 prevention measures. It was implemented in a pharmacy college building, as a case study, to assess the compliance level with the code requirements. Recommendations were developed to improve the level of fire prevention in the case study facility.

Findings

The implemented worksheet facilitated identifying all the shortcomings in the prevention measures, in a methodological manner. These shortcomings included exceeded travel distance, absence of assembly point, inactive record keeping of fire inspection and maintenance works, deterioration of some extension cords and switches, alteration of some emergency doors, storage of combustibles in some electrical rooms and obstructions of the fire apparatus access road.

Practical implications

The research provides an assessment tool for fire prevention in educational facilities, which can be used by professionals for a code-compliant inspection. The findings of the case study as an example serve to expand the inspectors' observational significance while reducing subjectivity.

Originality/value

This research contributes to the educational facilities' context of health and safety domain in the literature. The research classifies the required fire prevention measures for an educational facility, according to the international applicable codes and standards. The case study demonstrates an applicable methodology for assessing the fire prevention measures and requirements.
Exploring risks in lean production implementation: systematic literature review and classification framework
Authors: Machado Fagundes da Silva Tâmara , Costa Santos Luciano , Fabiana Gohr Cláudia
Published: June 2021

Purpose

Studies addressing barriers to implement lean production (LP) from the perspective of risk management (RM) have not been so usual in the literature. Re-interpreting barriers to lean as potential risks that should be avoided or mitigated, this paper aims to identify and categorise risks in the implementation of LP to propose a framework, which provides an overview of risks that negatively influence this process.

Design/methodology/approach

Through a systematic literature review exploring papers in the Web of Knowledge database, 69 papers were selected. A descriptive analysis was first carried out to identify the evolution in the number of papers, usual terminologies, research methods, analytic tools and the RM phases approached by each paper. After that, an in-depth study of the paper sample was conducted to find risk factors and categories.

Findings

The authors found a list of 61 risk factors. Then, considering the sources of the identified risk factors, six broad categories of risks were defined, namely, top management risks, human resources risks, lean knowledge risks, technical risks, supply chain risks and cultural risks. The authors also defined 34 subcategories, resulting in a risk classification framework.

Research limitations/implications

Based on the review, the authors identified literature gaps and provided a research agenda. A noteworthy research limitation is that the authors only selected papers about LP, so the authors might have missed some potential risks in lean implementation that may arise from other-related areas. Thus, the exploration of lean risks adopting other perspectives may constitute a promising pathway for further research.

Practical implications

The classification framework may help practitioners and researchers in risk identification, evaluation and mitigation. It can also enable the creation of response plans to risks in lean production implementation, as it indicates the potential risks that may be faced along with this process.

Originality/value

This study contributed to add the perspective of RM to the literature on lean implementation. The introduction of RM concepts and tools may generate more robust models of lean implementation. Therefore, the classification framework may represent a starting point to produce new knowledge about this research topic.
An evaluator’s reflections and lessons learned about gang intervention strategies: an agenda for research
Authors: Roman Caterina G.
Published: June 2021

Purpose

This paper is designed to critically review and analyze the body of research on a popular gang reduction strategy, implemented widely in the United States and a number of other countries, to: (1) assess whether researchers designed their evaluations to align with the theorized causal mechanisms that bring about reductions in violence; and (2) discuss how evidence on gang programs is generated and consumed. That review and assessment is then used to frame a research agenda for studying gang interventions.

Design/methodology/approach

A case study design is used to generate a multi-faceted understanding of the possible avenues for evaluation research on the law enforcement-based strategy known as the Group Violence Intervention. The paper discusses questions that remain to be answered about the strategy, such as “what type of deterrence is operating?” and if the model actually works by the threat of deterrence, and not by removing high-risk offenders and shootings from the street, what activities are needed to maintain the effect?

Findings

Across roughly two dozen impact evaluations of GVI, none have examined the likely cause and effect components of this multi-partner strategy in reducing the violence. Furthermore, there are many issues related to the production and generation of criminal justice evaluation research that have adversely pushed the balance of evidence on what works in gang reduction toward law enforcement programming. However, there are many strategies that researchers can use to think broadly about appropriate and holistic research and evaluation on gangs and gang programming.

Practical implications

The recommendations for research, if implemented, can help build a body of knowledge to move toward community-based and restorative models of gang violence reduction.

Originality/value

This original piece is one of the first essays to contextualize and discuss how aspects of the production of social science research on gangs may directly impact what programs and strategies are implemented on the ground.
Corporate governance challenges and opportunities in mitigating corporate fraud in Malaysia
Authors: A. Girau Emelia , Bujang Imbarine , Paulus Jidwin Agnes , Said Jamaliah
Published: June 2021

Purpose

This study aims to examine the relationship between corporate governance and the likelihood of corporate fraud in Malaysia.

Design/methodology/approach

The sample of fraudulent companies in this study is the public listed companies that were charged with furnishing false statements to the Securities Commission of Malaysia and Bursa Malaysia Securities Berhad and was listed in the Malaysian Securities Commission Enforcement Release from the year 2000 to 2016. The non-fraudulent companies, which are the control companies in this study, were selected from public listed companies listed in Bursa Malaysia, based on their similarity to the fraudulent companies in terms of time, size and industry type. The panel probit regression analysis was used to examine the relationship between corporate governance characteristics and the occurrence of corporate fraud.

Findings

The findings of this study suggest that board size and executive directors’ compensation are the corporate governance characteristics that can effectively combat corporate fraud incidences in Malaysia. The corporate governance features, namely the board of directors’ independence, frequency of board meetings, CEO duality, CEO’s age, and share ownership owned by directors and CEO, do not significantly influence corporate fraud incidences in Malaysia.

Originality/value

Although previous studies provide inconsistent findings on the association between board size and corporate fraud incidences, this study contributes to the existing literature by providing empirical evidence that smaller board sizes provide more effective monitoring functions to minimize corporate fraud incidences in the Malaysian context. The empirical evidence also supports the agency theory proposition where managers with high compensation will act in the best interest of shareholders and less likely to focus on their interests, thus deterring them from committing fraudulent acts.
Beyond visual clutter: the interplay among products, advertisements, and the overall webpage
Authors: Im Hyunjoo , Ju Hae Won , Johnson Kim K.P.
Published: June 2021

Purpose

Little research has been done to understand how individual elements (e.g. advertisements) within a webpage are processed and evaluated when visual complexity is increased. Thus, this study aimed to investigate how consumers allocate attention and evaluate products and advertisements on complex webpages when they are casually browsing.

Design/methodology/approach

This study conducted two experiments to test the causal effects of different degrees of visual complexity on consumer responses to products and advertisements. An eye-tracking experiment (n = 90) and a follow-up online experiment (n = 121) were conducted using undergraduate students as participants.

Findings

Participants formed a global impression from the overall webpage complexity, which spilled over to evaluation of individual elements on the webpage (e.g. product, advertisement). The inverted U-shaped relationships (vs. linear negative relationships) between webpage visual complexity and attitude toward the webpage, products, and advertisements were observed. The focal product was given a consistent level of attention regardless of the complexity level.

Practical implications

This study provides implications for website organization and design to maximize positive consumer experiences and marketing effectiveness. The findings provide implications for retailers and advertisement buyers.

Originality/value

This study expanded the knowledge by examining the interplay between individual elements of webpages and the whole webpage complexity when consumers browse visually complex webpages. It is a novel finding that the overall webpage complexity effect spills over to locally attended products or advertisements.
Separation, kinetics of purification of syringin by macroporous resin from Syringa oblata Lindl. leaves and the evaluation of bioactivities
Authors: Zhao Meimei , Li Dalong , Xu Yaqin , Bu Xueying , Shen Chen , Wang Libo , Yang Yu , Bai Jingwen
Published: June 2021

Purpose

This paper aims to explore the adsorption kinetics of syringin from Syringa oblata Lindl. leaves on macroporous resin and develop an efficient, simple and recyclable technology for the separation and purification of syringin.

Design/methodology/approach

Static adsorption and desorption properties of six resins were tested to select a suitable resin for the purification of syringin. Langmuir and Freundlich isotherm models were used to estimate the adsorption behavior of syringin on AB-8 resin. Breakthrough point and eluent volume were determined by dynamic adsorption and desorption tests. High-performance liquid chromatography-electrospray ionization-mass spectrometry was applied to identify the syringin in the purified product [syringin product (SP)]. Antioxidant and antibacterial activities of SP in vitro were evaluated by free radical scavenging ability and biofilm formation inhibitory tests.

Findings

AB-8 exhibited the most suitable adsorption and desorption capacity. Adsorption isotherm parameters indicated favorable adsorption between AB-8 and syringin. The optimal results were as follows: for adsorption, the sample concentration was 1.85 mg/mL, the sample volume was 3.5 bed volume (BV), the flow rate was 0.5 mL/min; for desorption, the ethanol concentration was 70%, the elution volume was 2.5 BV, the elution velocity was 1.0 mL/min. SP with 80.28% syringin displayed the potent antioxidant activities and inhibitory effects on biofilm formation of Streptococcus suis.

Originality/value

To the best of authors’ knowledge, there are no reports on purifying syringin from Syringa oblata Lindl. leaves using macroporous resins. This paper may also provide a theoretical reference for the purification of other phenylpropanoid glucosides.
Comments on Rossow: The alcohol advertising ban in Norway: Effects on recorded alcohol sales
Authors: Nelson Jon P.
Published: June 2021

Rossow conducts an interrupted‐auto‐regressive integrated moving average (ARIMA) analysis of alcohol advertising bans in Norway for the 47‐year period from 1960 through 2006. Norway's comprehensive restrictions on alcohol advertising occurred in 1975 and 1977. Rossow uses annual data on recorded alcohol sales (litres of pure alcohol per capita) to determine an ‘immediate and lasting effect’ from the July 1975 ban of about −7%. A lasting effect is not apparent from a plot of the sales data. The sales data are adjusted for changes in real wages and real prices, although the exact method of adjustment and empirical results are not reported, for example, do the wage and price variables have the expected signs? As part of the analysis, Rossow offers two critical comments on my own work in this area. Her comments are incorrect. The purpose of this commentary is to provide a correct reporting of my methods and results. Also, as I have conducted an interrupted‐ARIMA analysis and engaged in a dynamic time‐series analysis of alcohol advertising, I assess the appropriateness of Rossow's ARIMA analysis for Norway's advertising bans.
A large remaining potential in lipid‐lowering drug treatment in the type 2 diabetes population: A Danish nationwide cohort study
Authors: Amadid Hanan , Rønn Pernille F. , Bekker‐Nielsen Dunbar Maria , Knudsen Jakob S. , Carstensen Bendix , Persson Frederik , Jørgensen Marit E.
Published: June 2021

Aim

To assess lipid‐lowering drug (LLD) use patterns during 1996‐2017 and examine lipid levels in relation to the use of LLDs and prevalent atherosclerotic cardiovascular disease (ASCVD).

Methods

Using a nationwide diabetes register, 404 389 individuals with type 2 diabetes living in Denmark during 1996‐2017 were identified. Individuals were followed from 1 January 1996 or date of type 2 diabetes diagnosis until date of emigration, death or 1 January 2017. Redemptions of prescribed LLDs were ascertained from the nationwide Register of Medicinal Products Statistics. Data on lipid levels were sourced from the National Laboratory Database since 2010. LLD coverage was calculated at any given time based on the redeemed amount and dose. Trends in lipid levels were estimated using an additive mixed‐effect model. Low‐density lipoprotein cholesterol (LDL‐C) goal attainment was assessed based on recommended targets by the 2011, 2016 and 2019 guidelines for management of dyslipidaemias.

Results

LLD use has decreased since 2012 and only 55% of those with type 2 diabetes were LLD users in 2017. A decline in levels of total cholesterol and LDL‐C, and an increase in triglycerides, was observed during 2010‐2017. Annual mean levels of LDL‐C were lower among LLD users compared with non‐users (in 2017: 1.84 vs. 2.57 mmol/L). A greater fraction of LLD users achieved the LDL‐C goal of less than 1.8 mmol/L compared with non‐users (in 2017: 51.7% and 19%, respectively). Among LLD users with prevalent ASCVD, 26.9% and 55% had, as recommended by current 2019 European guidelines, an LDL‐C level of less than 1.4 mmol/L and less than 1.8 mmol/L, respectively, in 2017.

Conclusions

LLD use and LDL‐C levels are far from optimal in the Danish type 2 diabetes population and improvement in LLD use could reduce ASCVD events.
Maxima of linear processes with heavy‐tailed innovations and random coefficients
Authors: Krizmanić Danijel
Published: June 2021

We investigate maxima of linear processes with i.i.d. heavy‐tailed innovations and random coefficients. Using the point process approach we derive functional convergence of the partial maxima stochastic process in the space of non‐decreasing càdlàg functions on [0, 1] with the Skorokhod M1 topology.
Jujube witches' broom phytoplasma effectors SJP1 and SJP2 induce lateral bud outgrowth by repressing the ZjBRC1‐controlled auxin efflux channel
Authors: Zhou Junyong , Ma Fuli , Yao Yu , Deng Mingsheng , Chen Mengting , Zhang Shanqi , Li Yamei , Yang Jian , Zhang Ning , Huang Jingqiu , Sun Qibao , Sun Jun
Published: June 2021

Comprehensively controlling phytoplasma‐associated jujube witches' broom (JWB) disease is extremely challenging for the jujube industry. Although the pathogenesis of phytoplasma disease has been highlighted in many plant species, the release of lateral buds from dormancy under JWB phytoplasma infection has not been characterized in woody perennial jujube. Here, two 16SrV‐B group phytoplasma effectors, SJP1 and SJP2, were experimentally determined to induce witches' broom with increased lateral branches. In vivo interaction and subcellular localization analyses showed that both SJP1 and SJP2 were translocated from the cytoplasm to the nucleus to target the CYC/TB1‐TCP transcription factor ZjBRC1. The N‐ and C‐terminal coiled‐coil domains of SJP1 and SJP2 were required for the TCP‐binding ability. ZjBRC1 bound directly to the auxin efflux carrier ZjPIN1c/3 promoters and down‐regulated their expression to promote the accumulation of endogenous auxin indole‐3‐acetic acid in jujube calli. Furthermore, JWB phytoplasma infection suppressed ZjBRC1 accumulation and induced ZjPIN1c/3 expression to stimulate lateral bud outgrowth. Therefore, SJP1 and SJP2 stimulate lateral bud outgrowth, at least partly, by repressing the ZjBRC1‐controlled auxin efflux channel in jujube, representing a potential strategy for comprehensive phytoplasma‐associated disease control and a resource for gene editing breeding to create new cultivars with varying degrees of shoot branching.
Network Structure and Its Impact on Commodity Markets
Authors: Birge John R.
Published: June 2021

Connections across commodity markets create the potential for risk to propagate and for failures to cascade as successive market agents fail. The structure of these networks is, however, often hidden and not directly observable. This article describes methods to uncover this hidden structure and the implications that these hidden connections may have for predicting risk propagation and cascading failures. The results are described in the context of electricity, gasoline, and financial markets. They illustrate the potential of this methodology to help address energy and commodity policy issues and their environmental implications.
Pain control and functional improvement in patients treated by autologous conditioned serum after failure of platelet rich plasma treatments in knee osteoarthritis
Authors: Leone Rosa , de Rosa Alessandro , Iudicone Paola , Fioravanti Daniela , Capua Giuseppe , Rossetti Francesca , Isgro’ Maria Antonietta , Pierelli Luca
Published: June 2021

Objective

To assess the efficacy of autologous conditioned serum (ACS) for the treatment of patients with knee osteoarthritis after failure of medical treatments and platelet rich plasma (PRP) injections.

Background

Knee osteoarthritis is the most common form of arthritis. Prior to prosthetic surgery these patients might benefit from medical treatments, physiotherapy, and in case of their ineffectiveness, from autologous blood component injections.

Methodology

We have treated 30 patients with Kellgren‐Lawrence I‐III knee osteoarthritis with ACS after failure of standard medical treatments/physiotherapy and platelet rich plasma (PRP) injections for a full cycle, within the previous year from enrollment. Results: ACS administration was performed in all patients with mild side effects and produced prompt (1 month) improvements of VAS and Lequesne scales in 67% of patients and this result persisted at 6 and 12 months. No relationship between the rate of response and Kellgren‐Lawrence scale at enrollment was observed whilst responders had a significantly higher amount of interleukin‐1 receptor antagonist (IL1‐RA) in ACS as compared to nonresponders.

Conclusion

The present study confirms the efficacy of ACS in pain control and functional recovery of patients with knee osteoarthritis resistant to medical and PRP treatment. These results were obtained in a well‐defined cohort of resistant patients and seem to be related with IL1‐RA content in injected ACS.
Editors’ Introduction: Best Papers from the 18th International Conference on Cognitive Modeling
Authors: Stewart Terrence C. , Myers Christopher W.
Published: June 2021

The International Conference on Cognitive Modeling brings together researchers from around the world whose main goal is to build computational systems that reflect the internal processes of the mind. In this issue, we present the four best representative papers on this work from our 18th meeting, ICCM 2020, which was also the first meeting to be held virtually. Two of these papers develop novel techniques for building larger and more complex models using Reinforcement Learning and Learning By Instruction, respectively. The other two show how cognitive models connect to neuroscience, drawing on details of the hippocampus and cerebellum to constrain and explain the cognitive processes involved in memory and conditioning.
A Study on Low Cycle Fatigue Life Assessment of Notched Specimens Made of 316 LN Austenitic Stainless Steel
Authors: Abarkan Ikram , Khamlichi Abdellatif , Shamass Rabee
Published: June 2021

The local strains obtained from the best-known analytical approximations, namely, Neuber's rule, equivalent strain energy density method, and linear rule, were compared with those resulting from finite element analysis. It was found that apart from Neuber's rule with the elastic stress concentration factor Kt, all the aforementioned analytical methods underestimate the local strains for all notch root radius, strain amplitude levels, at room temperature and 550 °C. Neuber's rule with Kt slightly overestimates the maximum strains for lower notch root radius, namely, 1.25 mm, at high temperature. Based on the analytically and numerically obtained notch root strains, the fatigue lives were estimated using the Coffin–Manson–Basquin equation. Besides, a numerical assessment of fatigue lives was made based on Brown–Miller and maximum shear strain multi-axial fatigue life criteria. It was found that all these methods provide inaccurate fatigue life results for all notch root radius, strain amplitude level, and under both temperatures conditions. Therefore, a new method was suggested, for which only the applied strain amplitude is needed to calculate the fatigue life of notched components. It was revealed that the suggested method provides a good fatigue life prediction at a higher temperature loading state.
Why I Get Up Off My Butt: Older Adults’ Motives to Limit Their Sedentary Behavior
Authors: Collins Liam , Pope J. Paige
Published: June 2021

Older adults spend more time, on average, engaged in sedentary behaviors (SBs) compared with younger cohorts. This is concerning, because prolonged SB is associated with detrimental outcomes. The purpose of this study was to explore the degree to which older adults’ motives to limit their SB were internalized, consistent with self-determination theory. Following the qualitative description approach, seven focus groups (n = 27) of community-dwelling older adults were conducted. Focus groups were transcribed verbatim and coded using a thematic approach. Results revealed some motivation subthemes, which appeared to endorse similar content, varied in the degree to which participants internalized them, differentiating these motives along the self-determination theory motivational continuum. These findings demonstrated that not all motives are equal, highlighting the importance of theory-driven future SB interventions.
Exercise Physiology From 1980 to 2020: Application of the Natural Sciences
Authors: Kent Jane A. , Hayes Kate L.
Published: June 2021

The field of exercise physiology has enjoyed tremendous growth in the past 40 years. With its foundations in the natural sciences, it is an interdisciplinary field that is highly relevant to human performance and health. The focus of this review is on highlighting new approaches, knowledge, and opportunities that have emerged in exercise physiology over the last four decades. Key among these is the adoption of advanced technologies by exercise physiologists to address fundamental research questions, and the expansion of research topics to range from molecular to organismal, and population scales in order to clarify the underlying mechanisms and impact of physiological responses to exercise in health and disease. Collectively, these advances have ensured the position of the field as a partner in generating new knowledge across many scientific and health disciplines.
Single-step label-free nanowell immunoassay accurately quantifies serum stress hormones within minutes
Authors: Mahmoodi S. Reza , Xie Pengfei , Zachs Daniel P. , Peterson Erik J. , Graham Rachel S. , Kaiser Claire R. W. , Lim Hubert H. , Allen Mark G. , Javanmard Mehdi
Published: June 2021

Single-step label-free nanowell array immunoassay accurately detects serum stress hormones within minutes at small volumes.
Electrostatic footpads enable agile insect-scale soft robots with trajectory control
Authors: Liang Jiaming , Wu Yichuan , Yim Justin K. , Chen Huimin , Miao Zicong , Liu Hanxiao , Liu Ying , Liu Yixin , Wang Dongkai , Qiu Wenying , Shao Zhichun , Zhang Min , Wang Xiaohao , Zhong Junwen , Lin Liwei
Published: June 2021

Soft insect-scale robots achieve swift translational and rotational motion through electrostatic engineering.
Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis
Authors: So Wing Yan , Liu Wai Nam , Teo Adrian Kee Keong , Rutter Guy A. , Han Weiping
Published: June 2021

PAX6 replenishment improves glucose-stimulated insulin secretion and glucose homeostasis in diabetic mice and primary human islets.
Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice
Authors: Fang Xiaoguang , Huang Zhi , Zhai Kui , Huang Qian , Tao Weiwei , Kim Leo , Wu Qiulian , Almasan Alexandru , Yu Jennifer S. , Li Xiaoxia , Stark George R. , Rich Jeremy N. , Bao Shideng
Published: June 2021

Targeting DNA-PK induces glioma stem cell differentiation by destabilizing SOX2 to inhibit tumor growth in mouse glioblastoma models.
Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes
Authors: Md Dom Zaipul I. , Satake Eiichiro , Skupien Jan , Krolewski Bozena , O’Neil Kristina , Willency Jill A. , Dillon Simon T. , Wilson Jonathan M. , Kobayashi Hiroki , Ihara Katsuhito , Libermann Towia A. , Pragnell Marlon , Duffin Kevin L. , Krolewski Andrzej S.
Published: June 2021

Global proteomics profiling identified FGF20, TNFSF12, and ANGPT1 as protective against progression of renal function decline in those with diabetes.
Student Association of Lecture Content with the Five Core Concepts of Biology: Novel Results from an Introductory Biology Course
Authors: Chatzikyriakidou Kyriaki , Tacloban Marie-Janelle , Concepcion Kassandra , Geiger John , McCartney Melissa
Published: June 2021

Challenges in integration of concepts persist among undergraduate biology students. The 5 core concepts (5CCs) of biology presented in
Vision and Change
provide a comprehensive, concept-based description of the knowledge of biology, summarized in five main biological scales and five overarching principles that dictate natural biological phenomena and processes.
Microbial Model Construction Activity for Introducing Students to Microbiome and Metagenomic Fields
Authors: Rabelo-Fernandez Robert J. , Rios-Velazquez Carlos
Published: June 2021

Educational activities in biology teaching focused on model construction allow students to make the invisible evident. The development and integration of these pedagogical strategies in emerging sciences is essential and necessary in the classroom of noncollege academia.
Aromatic Side Chain at Position 412 of SERINC5 Exerts Restriction Activity toward HIV-1 and Other Retroviruses
Authors: Tan Toong Seng , Toyoda Mako , Tokunaga Kenzo , Ueno Takamasa
Published: June 2021

The host protein SERINC5 is incorporated into progeny virions of certain retroviruses and restricts the infectivity of these viruses or sensitizes the envelope glycoprotein to a class of neutralizing antibodies. However, how and which part of SERINC5 engages with the diverse array of retroviral envelopes and exerts its antiretroviral functions remain elusive.
Molecular Epidemiology of SARS-CoV-2 in Greece Reveals Low Rates of Onward Virus Transmission after Lifting of Travel Restrictions Based on Risk Assessment during Summer 2020
Authors: Kostaki Evangelia Georgia , Pavlopoulos Georgios A. , Verrou Kleio-Maria , Ampatziadis-Michailidis Giannis , Harokopos Vaggelis , Hatzis Pantelis , Moulos Panagiotis , Siafakas Nikolaos , Pournaras Spyridon , Hadjichristodoulou Christos , Chatzopoulou Fani , Chatzidimitriou Dimitrios , Panagopoulos Periklis , Lourida Panagiota , Argyraki Aikaterini , Lytras Theodoros , Sapounas Spyros , Gerolymatos Gerasimos , Panagiotakopoulos Georgios , Prezerakos Panagiotis , Tsiodras Sotirios , Sypsa Vana , Hatzakis Angelos , Anastassopoulou Cleo , Spanakis Nikolaos , Tsakris Athanasios , Dimopoulos Meletios Athanasios , Kotanidou Anastasia , Sfikakis Petros , Kollias Georgios , Magiorkinis Gkikas , Paraskevis Dimitrios
Published: June 2021

Our study based on current state-of-the-art molecular epidemiology methods suggests that virus screening and public health measures after the lifting of travel restrictions prevented SARS-CoV-2 onward transmission from imported cases during summer 2020 in Greece. These findings provide important data on the efficacy of targeted public health measures and have important implications regarding the safety of international travel during a pandemic.
Fossil illustrations from the work of William Smith
Authors: Wigley Peter
Published: June 2021

William Smith’s Strata Identified by Organized Fossils, published between 1816 and 1819, was one of the most important books in the development of stratigraphy; it was also significant in the evolution of paleontological art and illustration. For the first time, Smith organized fossil illustrations in plates according to the order of the strata. Each stratigraphic plate showed characteristic assemblages of fossils. The publication was a joint venture between Smith and James Sowerby and it was Sowerby who elevated the work into the realm of art. Smith had been influenced by the work of previous authors, in particular Robert Plot and John Morton, who, some 150 years earlier, had published texts illustrated by fossil engravings. The difference between these engravings and those of Sowerby shows the extent to which fossil illustration had evolved. Unlike previous work where the engravings were very mechanical, Sowerby’s were extraordinarily naturalistic. By means of subtle lines, stipple, and water coloring, Sowerby was able to achieve extremely realistic and aesthetically pleasing artwork. Unusually, many of Smith’s originals fossils are still intact and when photographs of these specimens are compared to the illustrations, the quality of Sowerby’s work is striking. Smith also selected earth-colors for the paper on which the illustrations were produced, with colors reflecting the strata in which the fossils were embedded. Although this technique had some disadvantages, it aimed to bridge the gap between science and art.