bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterodimers of functionally divergent ARF-GEF paralogues prevented by self-interacting dimerisation domain
Authors: Brumm Sabine , Singh Manoj K. , Beckmann Hauke , Richter Sandra , Huhn Kerstin , Kucera Tim , Baumann Sarah , Kriechbaum Choy , Wolters Hanno , Takada Shinobu , Jürgens Gerd
Published: September 2021

Functionally divergent paralogs of homomeric proteins do not form potentially deleterious heteromers, which requires distinction between self and non-self (Hochberg et al., 2018; Marchant et al, 2019; Marsh and Teichmann, 2015). In Arabidopsis, two ARF guanine-nucleotide exchange factors (ARF-GEFs) related to mammalian GBF1, named GNOM and GNL1, can mediate coatomer complex (COPI)-coated vesicle formation in retrograde Golgi-endoplasmic reticulum (ER) traffic (Geldner et al., 2003; Richter et al., 2007; Teh and Moore, 2007). Unlike GNL1, however, GNOM is also required for polar recycling of endocytosed auxin efflux regulator PIN1 from endosomes to the plasma membrane. Here we show that these paralogues form homodimers constitutively but no heterodimers. We also address why and how GNOM and GNL1 might be kept separate. These paralogues share a common domain organisation and each N-terminal dimerisation (DCB) domain can interact with the complementary fragment (ΔDCB) of its own and the other protein. However, unlike self-interacting DCBGNOM (Grebe et al., 2000; Anders et al., 2008), DCBGNL1 did not interact with itself nor DCBGNOM. DCBGNOM removal or replacement with DCBGNL1, but not disruption of cysteine bridges that stabilise DCB-DCB interaction, resulted in GNOM-GNL1 heterodimers which impaired developmental processes such as lateral root formation. We propose precocious self-interaction of the DCBGNOM domain as a mechanism to preclude formation of fitness-reducing GNOM-GNL1 heterodimers.
Enhanced Specificity Mutations Perturb Allosteric Signaling in CRISPR-Cas9
Authors: Nierzwicki Łukasz , East Kyle W. , Morzan Uriel N. , Arantes Pablo R. , Batista Victor S. , Lisi George P. , Palermo Giulia
Published: September 2021

CRISPR-Cas9 is a molecular tool with transformative genome editing capabilities. At the molecular level, an intricate allosteric signaling is critical for DNA cleavage, but its role in the specificity enhancement of the Cas9 endonuclease is poorly understood. Here, solution NMR is combined with multi-microsecond molecular dynamics and graph theory-derived models to probe the allosteric role of key enhancement specificity mutations. We show that the mutations responsible for increasing the specificity of Cas9 alter the allosteric structure of the catalytic HNH domain, impacting the signal transmission from the DNA recognition region to the catalytic sites for cleavage. Specifically, the K855A mutation strongly disrupts the HNH domain allosteric structure, exerting the highest perturbation on the signaling transfer, while K810A and K848A result in more moderate effects on the allosteric intercommunication. This differential perturbation of the allosteric signaling reflects the different capabilities of the single mutants to increase Cas9 specificity, with the mutation achieving the highest specificity also strongly perturbing the signaling transfer. These outcomes reveal that the allosteric regulation is critical for the specificity enhancement of the Cas9 enzyme, and are valuable to harness the signaling network to improve the system’s specificity.
Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling
Authors: Pei Jimin , Zhang Jing , Cong Qian
Published: September 2021

Recent development of deep-learning methods has led to a breakthrough in the prediction accuracy of 3-dimensional protein structures. Extending these methods to protein pairs is expected to allow large-scale detection of protein-protein interactions and modeling protein complexes at the proteome level. We applied RoseTTAFold and AlphaFold2, two of the latest deep-learning methods for structure predictions, to analyze coevolution of human proteins residing in mitochondria, an organelle of vital importance in many cellular processes including energy production, metabolism, cell death, and antiviral response. Variations in mitochondrial proteins have been linked to a plethora of human diseases and genetic conditions. RoseTTAFold, with high computational speed, was used to predict the coevolution of about 95% of mitochondrial protein pairs. Top-ranked pairs were further subject to the modeling of the complex structures by AlphaFold2, which also produced contact probability with high precision and in many cases consistent with RoseTTAFold. Most of the top ranked pairs with high contact probability were supported by known protein-protein interactions and/or similarities to experimental structural complexes. For high-scoring pairs without experimental complex structures, our coevolution analyses and structural models shed light on the details of their interfaces, including CHCHD4-AIFM1, MTERF3-TRUB2, FMC1-ATPAF2, ECSIT-NDUFAF1 and COQ7-COQ9, among others. We also identified novel PPIs (PYURF-NDUFAF5, LYRM1-MTRF1L and COA8-COX10) for several proteins without experimentally characterized interaction partners, leading to predictions of their molecular functions and the biological processes they are involved in.
Insights into regulation of C2 and C4 photosynthesis in Amaranthaceae/Chenopodiaceae using RNA-Seq
Authors: Siadjeu Christian , Lauterbach Maximilian , Kadereit Gudrun
Published: September 2021

Amaranthaceae (incl. Chenopodiaceae) show an immense diversity of C4 syndromes. More than 15 independent origins of C4 photosynthesis, partly in halophytic and/or succulent lineages, and the largest number of C4 species in eudicots signify the importance of this angiosperm lineage in C4 evolution. Here, we conduct RNA-Seq followed by comparative transcriptome analysis of three species from Camphorosmeae representing related clades with different photosynthetic types: Threlkeldia diffusa (C3), Sedobassia sedoides (C2), and Bassia prostrata (C4). Results show that B. prostrata belongs to the NADP-ME type and core genes encoding for C4 cycle are significantly up-regulated when compared to Sed. sedoides and T. diffusa, Sedobassia sedoides and B. prostrata share a number of up-regulated C4-related genes, however, two C4 transporters (DIT and TPT) are found significantly up-regulated only in Sed. sedoides. Combined analysis of transcription factors (TFs) of the closely related lineages (Camphorosmeae and Salsoleae) revealed that no C3 specific TFs is higher in C2 species as compared to C4 species, instead the C2 species show their own set of up-regulated TFs. Taken together, our study indicates that the hypothesis of the C2 photosynthesis as a proxy towards C4 photosynthesis is questionable in Sed. sedoides and more in favour of an independent evolutionary stable-state.

Highlight

Transcript expression profiles of C2 species are distinct and best explained as representing an independent evolutionary stable state.
Dissecting the allosteric networks governing agonist efficacy and potency in G protein-coupled receptors
Authors: Heydenreich Franziska M. , Marti-Solano Maria , Sandhu Manbir , Kobilka Brian K. , Bouvier Michel , Babu M. Madan
Published: September 2021

G protein-coupled receptors (GPCRs) translate binding of extracellular ligands into intracellular responses through conformational changes. Ligand properties are described by the maximum response (efficacy) and the agonist concentration at half-maximal response (potency). Integrating structural changes with pharmacological properties remains challenging and has not yet been performed at the resolution of individual amino acids. We use epinephrine and β2-adrenergic receptor as a model to integrate residue-level pharmacology data with intramolecular residue contact data describing receptor activation. This unveils the allosteric networks driving ligand efficacy and potency. We provide detailed insights into how structural rearrangements are linked to fundamental pharmacological properties at single-residue level in a receptor-ligand system. Our approach can be used to determine such pharmacological networks for any receptor-ligand complex.
Characterizing flexibility and mobility in the natural mutations of the SARS-CoV-2 spikes
Authors: Panayis James , Römer Navodya S. , Bellini Dom , Wallis A. Katrine , Römer Rudolf A.
Published: September 2021

We use in silico modelling of the SARS-CoV-2 spike protein and its mutations, as deposited on the Protein Data Bank (PDB), to ascertain their dynamics, flexibility and rigidity. Identifying the precise nature of the dynamics for the spike proteins enables, in principle, the use of further in silico design methods to quickly screen for existing and novel drug molecules that might prohibit the natural protein dynamics. We employ a recent protein flexibility modeling approach, combining methods for deconstructing a protein structure into a network of rigid and flexible units with a method that explores the elastic modes of motion of this network, and a geometric modeling of flexible motion. Our results thus far indicate that the overall motion of wild-type and mutated spike protein structures remains largely the same.
Multiplexed profiling of kinase interactomes quantifies cellular network plasticity
Authors: Golkowski Martin , Lius Andrea , Sapre Tanmay , Lau Ho-Tak , Moreno Taylor , Maly Dustin J. , Ong Shao-En
Published: September 2021

Cells utilize protein-protein interaction (PPI) networks to receive, transduce, and respond to stimuli. Interaction network rewiring drives devastating diseases like cancers, making PPIs attractive targets for pharmacological intervention. Kinases are druggable nodes in PPI networks but high-throughput proteomics approaches to quantify disease-associated kinome PPI rewiring are lacking. We introduce kinobead competition and correlation analysis (Ki-CCA), a chemoproteomics approach to simultaneously map hundreds of endogenous kinase PPIs. We identified 2,305 PPIs of 300 kinases across 18 diverse cancer lines, quantifying the high plasticity of interaction networks between cancer types, signaling, and phenotypic states; this database of dynamic kinome PPIs provides deep insights into cancer cell signaling. We discovered an AAK1 complex promoting epithelial-mesenchymal transition and drug resistance, and depleting its components sensitized cells to targeted therapy. Ki-CCA enables rapid and highly multiplexed mapping of kinome PPIs in native cell and tissue lysates, without epitope tagged baits, protein labeling, or antibodies.
Identification of two pathways mediating protein targeting from ER to lipid droplets
Authors: Song Jiunn , Mizrak Arda , Lee Chia-Wei , Cicconet Marcelo , Lai Zon Weng , Lu Chieh-Han , Mohr Stephanie E. , Farese Robert V. , Walther Tobias C.
Published: September 2021

Pathways localizing proteins to their sites of action within a cell are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, little is known about how proteins, such as key metabolic enzymes, target from the ER to cellular lipid droplets (LDs). Here, we identify two distinct pathways for ER-to-LD (ERTOLD) protein targeting: early ERTOLD, occurring during LD formation, and late ERTOLD, targeting mature LDs after their formation. By using systematic, unbiased approaches, we identified specific membrane-fusion machinery, including regulators, a tether, and SNARE proteins, that are required for late ERTOLD targeting. Components of this fusion machinery localize to LD-ER interfaces and appear to be organized at ER exit sites (ERES) to generate ER-LD membrane bridges. We also identified multiple cargoes for early and late ERTOLD. Collectively, our data provide a new model for how proteins target LDs from the ER.

HIGHLIGHTS

Proteins localize to LDs either during formation or later through ER-LD bridges

Specific membrane fusion machinery localizes to LDs and mediates protein targeting

Specific ER exit site proteins associate with LDs and participate in ERTOLD targeting

Proteomic studies reveal cargoes for early and late ERTOLD targeting
Monomeric IgA antagonizes IgG-mediated enhancement of DENV infection
Authors: Wegman Adam D. , Fang HengSheng , Rothman Alan L. , Thomas Stephen J. , Endy Timothy P. , McCracken Michael K. , Currier Jeffrey R. , Friberg Heather , Gromowski Gregory D. , Waickman Adam T.
Published: September 2021

Dengue virus (DENV) is a prevalent human pathogen, infecting approximately 400 million individuals per year and causing symptomatic disease in approximately 100 million. A distinct feature of dengue is the increased risk for severe disease in some individuals with preexisting DENV-specific immunity. One proposed mechanism for this phenomenon is antibody-dependent enhancement (ADE), in which poorly-neutralizing IgG antibodies from a prior infection opsonize DENV to increase infection of Fcgamma receptor-bearing cells. While IgM and IgG are the most commonly studied DENV-reactive antibody isotypes, our group and others have described the induction of DENV-specific serum IgA responses during dengue. We hypothesized that monomeric IgA would be able to neutralize DENV without the possibility of ADE. To test this, we synthesized IgG and IgA versions of two different DENV-reactive monoclonal antibodies. We demonstrate that isotype-switching does not affect the antigen binding and neutralization properties of the two mAbs. We show that DENV-reactive IgG, but not IgA, mediates ADE in an Fcgamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of serum DENV-reactive IgA induced by DENV infection might regulate the overall ADE activity of DENV-immune plasmain vivoand warrants further study as a predictor of disease risk and/or therapeutic.
Predicting Individual Cell Division Events from Single-Cell ERK and Akt Dynamics
Authors: Stern Alan D , Smith Gregory R , Santos Luis C , Sarmah Deepraj , Zhang Xiang , Lu Xiaoming , Iuricich Federico , Pandey Gaurav , Iyengar Ravi , Birtwistle Marc R
Published: September 2021

Predictive determinants of stochastic single-cell fates have been elusive, even for the well-studied mammalian cell cycle. What drives proliferation decisions of single cells at any given time? We monitored single-cell dynamics of the ERK and Akt pathways, critical cell cycle progression hubs and anti-cancer drug targets, and paired them to division events in the same single cells using the non-transformed MCF10A epithelial line. Following growth factor treatment, in cells that divide both ERK and Akt activities are significantly higher within the S-G2 time window (∼8.5-40 hours). Such differences were much smaller in the pre-S-phase, restriction point window which is traditionally associated with ERK and Akt activity dependence, suggesting unappreciated roles for ERK and Akt in S through G2. Machine learning algorithms show that simple metrics of central tendency in this time window are most predictive for subsequent cell division; median ERK and Akt activities classify individual division events with an AUC=0.76. Surprisingly, ERK dynamics alone predict division in individual cells with an AUC=0.74, suggesting Akt activity dynamics contribute little to the decision driving cell division in this context. We also find that ERK and Akt activities are less correlated with each other in cells that divide. Network reconstruction experiments demonstrated that this correlation behavior was likely not due to crosstalk, as ERK and Akt do not interact in this context, in contrast to other transformed cell types. Overall, our findings support roles for ERK and Akt activity throughout the cell cycle as opposed to just before the restriction point, and suggest ERK activity dynamics are substantially more important than Akt activity dynamics for driving cell division in this non-transformed context. Single cell imaging along with machine learning algorithms provide a better basis to understand cell cycle progression on the single cell level.
Evaluating the utility of identity-by-descent segment numbers for relatedness inference via information theory and classification
Authors: Smith Jesse , Qiao Ying , Williams Amy L.
Published: September 2021

Despite decades of methods development for classifying relatives in genetic studies, pairwise relatedness methods’ recalls are above 90% only for first through third degree relatives. The top-performing approaches, which leverage identity-by-descent (IBD) segments, often use only kinship coefficients, while others, including ERSA, use the number of segments relatives share. To quantify the potential for using segment numbers in relatedness inference, we leveraged information theory measures to analyze exact (i.e., produced by a simulator) IBD segments from simulated relatives. Over a range of settings, we found that the mutual information between the relatives’ degree of relatedness and a tuple of their kinship coefficient and segment number is on average 4.6% larger than between the degree and the kinship coefficient alone. We further evaluated IBD segment number utility by building a Bayes classifier to predict first through sixth degree relationships using different feature sets. When trained and tested with exact segments, the inclusion of segment numbers improves the recall by between 0.0028 and 0.030 for second through sixth degree relatives. However, the recalls improve by less than 0.018 per degree when using inferred segments, suggesting limitations due to IBD detection accuracy. Lastly, we compared our Bayes classifier that includes segment numbers with ERSA and IBIS and found comparable results, with the Bayes classifier and ERSA slightly outperforming each other across different degrees. Overall, this study shows that IBD segment numbers can improve relatedness inference but that errors from current SNP array-based detection methods yield dampened signals in practice.
Disruption of the autism-associated gene SCN2A alters synaptic development and neuronal signaling in patient iPSC-glutamatergic neurons
Authors: Brown Chad O. , Uy Jarryll , Murtaza Nadeem , Rosa Elyse , Alfonso Alexandria , Xing Sansi , Dave Biren M. , Kilpatrick Savannah , Cheng Annie A. , White Sean H. , Howe Jennifer , Scherer Stephen W. , Lu Yu , Singh Karun K.
Published: September 2021

SCN2A is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of autism-associated SCN2A de novo variants on human neuron development is unknown. We studied SCN2A using isogenic SCN2A-/- induced pluripotent stem cells (iPSCs), and patient-derived iPSCs harboring a p.R607* or a C-terminal p.G1744* de novo truncating variant. We used Neurogenin2 to generate excitatory glutamatergic neurons and found that SCN2A+/p.R607* and SCN2A-/- neurons displayed a reduction in synapse formation and excitatory synaptic activity using multielectrode arrays and electrophysiology. However, the p.G1744* variant, which leads to early-onset seizures in addition to ASD, altered action-potential dynamics but not synaptic activity. Proteomic and functional analysis of SCN2A+/p.R607* neurons revealed defects in neuronal morphology and bioenergetic pathways, which were not present in SCN2A+/p.G1744* neurons. Our study reveals that SCN2A de novo variants can have differential impact on human neuron function and signaling.

HIGHTLIGHTS

- Isogenic SCN2A-/- neurons display intrinsic hyperexcitability and impaired excitatory synapse function

- SCN2A+/p.R607* variant reduces excitatory synapse function in patient neurons

- C-terminal SCN2A+/p.G1744* variant enhances action potential properties but not synaptic transmission in patient neurons

- SCN2A+/p.R607* variant display impacts on morphological and bioenergetic signaling networks through proteomic and functional analysis

eTOC

- Brown et al. examined Autism-associated SCN2A variants using patient-derived iPSC NGN2-neurons. They discover that genetic variants differentially impact neuronal development and synaptic function, and highlight neuronal and bioenergetic signaling networks underlying SCN2A loss-of-function.
Nucleolin loss-of-function leads to aberrant FGF signaling and craniofacial anomalies
Authors: Dash Soma , Trainor Paul A.
Published: September 2021

rRNA transcription and ribosome biogenesis are global processes required for growth and proliferation of all cells, yet perturbation of these processes in vertebrates leads to tissue-specific defects termed ribosomopathies. Mutations in rRNA transcription and processing proteins often lead to craniofacial anomalies, however the cellular and molecular reasons for this are poorly understood. Therefore, we examined the function of the most abundant nucleolar phosphoprotein, Nucleolin (Ncl), in vertebrate development. We discovered that Nucleolin is dynamically expressed during embryonic development with high enrichment in the craniofacial tissues. Consistent with this pattern of expression,nclhomozygous mutant (ncl-/-) zebrafish present with craniofacial anomalies such as mandibulofacial hypoplasia. We observe thatncl-/-mutants exhibit decreased rRNA synthesis and p53-dependent neuroepithelial cell death. In addition, the half-life offgf8amRNA is reduced inncl-/-mutants, which perturbs Fgf signaling, resulting in misregulation of Sox9a mediated chondrogenesis and Runx2 mediated osteogenesis. Exogenous addition of human recombinant FGF8 to the mutant zebrafish significantly rescues the cranioskeletal phenotype, suggesting that Nucleolin regulates osteochondroprogenitor differentiation during craniofacial development by post-transcriptionally regulating Fgf signaling. Our work has therefore uncovered a novel tissue-specific function for Nucleolin in rRNA transcription and growth factor signaling during embryonic craniofacial development.
Sequential accumulation of dynein and its regulatory proteins at the spindle region in the Caenorhabditis elegans embryo
Authors: Torisawa Takayuki , Kimura Akatsuki
Published: September 2021

Cytoplasmic dynein is responsible for various cellular processes during the cell cycle. The mechanism by which its activity is regulated spatially and temporarily inside the cell remains elusive. There are various regulatory proteins of dynein, including dynactin, NDEL1/NUD-2, and LIS1. Characterizing the spatiotemporal localization of regulatory proteins in vivo will aid understanding of the cellular regulation of dynein. Here, we focused on spindle formation in the Caenorhabditis elegans early embryo, wherein dynein and its regulatory proteins translocated from the cytoplasm to the spindle region upon nuclear envelope breakdown (NEBD). We found that (i) a limited set of dynein regulatory proteins accumulated in the spindle region, (ii) the spatial localization patterns were distinct among the regulators, and (iii) the regulatory proteins did not accumulate in the spindle region simultaneously but sequentially. Furthermore, the accumulation of NUD-2 was unique among the regulators. NUD-2 started to accumulate before NEBD (pre-NEBD accumulation), and exhibited the highest enrichment compared to the cytoplasmic concentration. Using a protein injection approach, we revealed that the C-terminal helix of NUD-2 was responsible for pre-NEBD accumulation. These findings suggest a fine temporal control of the subcellular localization of regulatory proteins.
The tomato yellow leaf curl virus C4 protein alters the expression of plant developmental genes correlating to leaf upward cupping phenotype in tomato
Authors: Padmanabhan Chellappan , Zheng Yi , Shamimuzzaman Md , Wilson Jennifer R. , Fei Zhangjun , Ling Kai-Shu
Published: September 2021

Tomato yellow leaf curl virus (TYLCV), a monopartite begomovirus in the family Geminiviridae, is efficiently transmitted by the whitefly, Bemisia tabaci, and causes serious economic losses to tomato crops around the world. TYLCV-infected tomato plants develop distinctive symptoms of yellowing and leaf upper cupping. In recent years, excellent progress has been made in the characterization of TYLCV C4 protein function as a pathogenetic determinant in experimental plants, including Nicotiana benthamiana and Arabidopsis thaliana. However, molecular mechanism leading to disease symptom development in natural host plant tomato has yet to be characterized. The aim of the current study was to generate transgenic tomato plants expressing the TYLCV C4 gene and evaluate differential gene expression through comparative transcriptome analysis between the transgenic C4 plants and the transgenic green fluorescent protein (Gfp) gene control plants. Transgenic tomato plants expressing the TYLCV C4 developed phenotypes, including leaf upward cupping and yellowing that are similar the disease symptom expressed on tomato plants infected with TYLCV. In a total of 241 differentially expressed genes identified in the transcriptome analysis, a series of plant development-related genes, including transcription factors, glutaredoxins, protein kinases, R-genes and microRNA target genes, were significantly altered. These results provide further evidence to support the important function of the C4 protein in begomovirus pathogenicity. These transgenic tomato plants could serve as basic genetic materials for further characterization of plant receptors that are interacting with the TYLCV C4.
Pacemaking function of two simplified cell models
Authors: Ryzhii Maxim , Ryzhii Elena
Published: September 2021

Simplified nonlinear models of biological cells are widely used in computational electrophysiology. The models reproduce qualitatively many of the characteristics of various organs, such as the heart, brain, and intestine. In contrast to complex cellular ion-channel models, the simplified models usually contain a small number of variables and parameters, which facilitates nonlinear analysis and reduces computational load. In this paper, we consider pacemaking variants of the Aliev-Panfilov and Corrado two-variable excitable cell models. We conducted a numerical simulation study of these models and investigated the main nonlinear dynamic features of both isolated cells and 1D coupled pacemaker-excitable systems. Simulations of the 2D sinoatrial node and 3D intestine tissue as application examples of combined pacemaker-excitable systems demonstrated results similar to obtained previously. The uniform formulation for the conventional excitable cell models and proposed pacemaker models allows a convenient and easy implementation for the construction of personalized physiological models, inverse tissue modeling, and development of real-time simulation systems for various organs that contain both pacemaker and excitable cells.
CRISPR Activation/Inhibition Experiments Reveal that Expression of Intronic MicroRNA miR-335 Depends on the Promoter Activity of its Host Gene Mest
Authors: Courtes Mathilde , Lemmers Céline , Digarcher Anne Le , Coku Ilda , Monteil Arnaud , Hong Charles , Varrault Annie , Bouschet Tristan
Published: September 2021

MicroRNAs are small non-coding RNAs that act as rheostats to modulate gene expression during development, physiology, and disease. Approximately half of mammalian microRNAs are intronic. It is unknown whether intronic miRNA transcription depends on their host gene or a microRNA-specific promoter. Here, we show that CRISPR inhibition of host gene Mest downregulated hosted miR-335 in mouse embryonic stem cells and brain organoids. Reciprocally, CRISPR transactivation of Mest upregulated miR-335. By contrast, activation of miR-335 predicted promoter had no effect. Thus, intronic miR-335 expression depends on the promoter activity of its host gene. This approach could serve to map microRNA promoters.
Trajectory tracking control of quadrotor under variable payloads with model-free controller and sliding mode control technology
Authors: Zou Xu , Liu Zhenbao , Gao HongGang , Zhao Wen
Published: September 2021

Purpose

This study aims to deal with the problem of trajectory tracking control for the quadrotor under external environmental disturbance and variable payloads.

Design/methodology/approach

In the field of unmanned aerial vehicle (UAV) control, external environmental disturbance and internal variable payloads as two major interference factors lead to control performance degradation or even instability, thus a trajectory tracking controller which innovatively combines sliding mode control technology and model-free control technique is proposed. The proposed controller is constructed with a learning rate-based sliding mode controller and an ultra-local model. Based on the proposed controller, the nonlinear system model of variable load quadrotor is locally estimated and the system’s uncertainties and disturbances can be compensated.

Findings

The simulation and actual test results demonstrate the satisfactory control performance and the robustness of the proposed controller compared with the PID and Backstepping controller under external environmental disturbance and variable payloads. Moreover, the proposed controller solves the trajectory tracking control problem not only when payloads change at the center of gravity but also when the position of load variation deviates from the center of gravity.

Practical implications

In both military and civilian domains, the quadrotor may encounter such situations that the payloads change, such as transporting goods, aerial refueling and so on. As a large internal interference factor, variable load tends to lead to unstable control. The research results provide theoretical guidance and technical support for trajectory tracking control of quadrotor under variable payloads.

Originality/value

The proposed controller combines learning rate-based sliding mode controller and model-free control technique to achieve a more efficient and accurate trajectory control of the quadrotor when considering system uncertainties and the load variation that happens in the unknown location.
Extending information poverty theory to better understand the digital access and inequalities among young people who are not in education, employment or training in South Africa
Authors: Matli Walter , Ngoepe Mpho
Published: September 2021

Purpose

The objective of this study is to present evidence regarding how young people, who are not in education, employment or training (NEET) in South Africa, lack literacy skills and access to enabling resources to actively search and navigate information services systems that are primarily web-based. Information Poverty Theory is adopted to better understand the technological and social strata challenges experienced by young NEET people.

Design/methodology/approach

The study used semi-structured interviews for collecting data over two months in 2018, employing snowball sampling with 24 key participants, representing a diversity of educational backgrounds and previous experience of economic participation.

Findings

The findings of this study suggest that most interviewed young people, who are NEET, lack advanced information literacy and digital skills to access information services. The results also indicate that access to information services that are primed for online information is a challenge for most of these NEET young people residing in underserviced communities. The high cost of an Internet connection means that the Internet is out of reach for most low-income households. In communities that are underserviced with no adequate information and communication technology (ICT) infrastructure, people residing in such areas are subjected to living in circumstances where there is poverty and thus a lack of access to online information.

Research limitations/implications

This paper reports on data collected in 2018 using intense interviews, while acknowledging limitations in terms of the sample size. Hence, it is not fully representative of the whole population of young people, who are NEET, residing in the Gauteng Province of South Africa.

Practical implications

The findings illustrate the need for further collaboration among relevant stakeholders to strengthen existing programmes and for stronger partnerships. The arguments presented herein enhance knowledge and understanding concerning the digital literacy skills divide that exists among young people who are NEET. It includes a discussion to contribute to policy development.

Originality/value

This study focuses on challenges young people who are NEET experience when looking for work and developmental opportunities. This qualitative study adopts Information Poverty Theory and uses prior studies to link the undertaken survey and research. It is expected that this study may serve as a pilot for future studies and may also contribute to the ongoing discussions around the use of ICTs on their use and access, especially the effect on young people when searching for information related to jobs and other developmental opportunities using online services.
Exploring the jazz festival experience amongst local and non-local residents: The case of the Jazzaldia Festival in Spain
Authors: Bakić Sonja , Cuenca-Amigo Macarena , Cuenca Jaime
Published: September 2021

Purpose

The purpose of this paper is to explore the jazz festival experience at the Heineken Jazzaldia Festival in San Sebastian, Spain. It focuses especially on the relationship between participants’ area of residence and their experience of the festival, concert expectations, preference for different festival settings and perception of the best aspects of the festival.

Design/methodology/approach

This study modifies and applies the Audience Experience Survey (Radbourne et al., 2009) to the Heineken Jazzaldia Festival in San Sebastian, Spain. A total of 406 valid questionnaires were obtained. A quantitative analysis technique was used for the area of residence, on the one hand, and for concert expectations, audience experience and venue setting, on the other. A qualitative approach was applied for identifying the best aspects of the festival.

Findings

The results suggest that the audiences’ festival preferences differed according to their area of residence. Audience members who lived in Spain outside of the Basque Country were more motivated to attend the festival, had higher concert expectations and greater indoor venue concert attendance, and considered music diversity to be one of the most important aspects of the festival. Local participants were more likely not to have expectations prior to concerts, had higher outdoor venue concert attendance rates and preferred ambience compared with residents from outside of the Basque Country.

Practical implications

Findings could be relevant to festivals’ organisers for management and marketing purposes in terms of their audiences’ needs and preferences. One of the main results obtained is that local residents were more likely not to have expectations prior to concerts. They also equalised music diversity, artists, stages and atmosphere as the best Festival’s aspects while participants from outside of the Basque Country prioritised music diversity aspect.

Originality/value

This paper contributes to the literature regarding residents’ behaviour in the Spanish music festival context. Our findings add to the body of knowledge around local audiences’ and non-local audience’s experience in jazz festivals.
If the Cure for the Ills of Democracy Is More Democracy, Might the Cure Be Worse than the Disease?☆
Authors: Katz Richard S.
Published: September 2021

Declining turnout, declining party membership, declining aggregate vote for mainstream parties and increasing vote for anti‐party‐system parties all suggest a crisis of liberal party democracy. One suggested cure for the crisis of party democracy is more democracy within parties. But increased intraparty democracy, and increased use of instruments of direct democracy, such as recall, have their own potential costs. Following the example of de Tocqueville in looking to the United States, where intraparty democracy has a longer and deeper history, for lessons and warnings that might be applicable to Europe, this article points to polarization, alienation, intransigence, and decreased responsibility of political leaders – all feeding the anti‐party‐system narrative – as suggesting that the cure of more democracy may indeed be worse than the disease.
Medicalising the Jewish Ritual Bath: Women, Health and Purity in the Late Ottoman Empire
Authors: Esperanza Anabella
Published: September 2021

Menstrual impurity is among the most important religious practices in Jewish lore. Examining two case studies of Judeo–Spanish Ottoman Jewry: discussions of the temperature of the ritual bath water; and purity, hygiene and the collective of the Jewish body, this article demonstrates that menstrual impurity in Ottoman Judaism underwent an intensive medicalisation process. This process reframed menstruation from a religious concern to one involving medicine, health and hygiene. This article offers a glimpse of how non‐Western Jews dealt with European conceptions of medicalisation, actively debating them according to their Ottoman cultural surroundings. Moreover, it illuminates the mechanisms women used to negotiate their immersion and command their own bodies, emphasising their anxieties, demands and resistance.
Impact of COVID‐19 on Prescriptions for Controlled Substances for Veterans with Opioid Use Disorder
Authors: Myers Ursula , Bishu Kinfe , Gauthier‐Wetzel Holly , Grubaugh Anouk , Axon R. Neal , Ana Elizabeth Santa , Gebregziabher Mulugeta
Published: September 2021

Research Objective

Veterans with opioid use disorder (OUD) are at significant risk of overdose, unintentional death, and a wide range of negative health‐related consequences. While evidenced‐based treatments for OUD exist, including medications for opioid use disorder (MOUD) like buprenorphine (suboxone), there are a number of barriers preventing veterans from accessing this care. A potential avenue to increase the numbers of veterans who can access high quality mental healthcare such as MOUD is through telemental healthcare using VA Video Connect (VVC). While telehealth can mitigate this access to care issue, the opioid crisis led to the Ryan Haight Act of 2008, which mandates that the first visit with a prescriber of schedule II‐IV controlled substances be conducted in person. However, due to the public health emergency caused by COVID‐19, the in person requirement for controlled substances is temporarily waived.

Study Design

The aims of this project were to examine temporal changes in controlled substances from September 2019 – August 2020 (6 months before and after the requirement was waived), to understand the impacts of this waiver for veterans with OUD.

Population Studied

We examined prescription information from the VA Corporate Data Warehouse for 42,579 Veterans diagnosed with OUD (91.6% male, 71% white, 16.8% black, 27% rural dwelling).

Principal Findings

During this 12‐month window, 56.6% of the sample were prescribed suboxone, 53.6% were prescribed sedatives, and 13.8% were prescribed anxiolytics. Monthly an average of 33,323 (SD = 3190) prescriptions were filled, with an average of 1.45 (SD = 0.08) medications prescribed per visit. As expected, the largest dip was seen in April 2020, with only 28,376 prescriptions filled, with an 1.33 prescriptions written per visit. As of August 2020, the rates for prescriptions for controlled substances had not returned to pre‐COVID levels.

Conclusions

These data suggest that while telehealth is a legal option to appropriately prescribe controlled substances, it was not utilized in a way that replicated in person care. Future projects that focus on understanding and addressing barriers providers face when attempting to provide care via telehealth are an important next step. Additionally, there was no dramatic increase in prescriptions for controlled substances as a result of the Ryan Haight waiver.

Implications for Policy or Practice

These data support keeping the wavier of in person appointments in the Ryan Haight Act is one useful avenue to help providers to provide access to life saving MOUDs.

Primary Funding Source

Department of Veterans Affairs.
Effect of a Value‐Based Health Insurance Design on Acute Diabetes Complications
Authors: Wharam J. Frank , Zhang Fang , Garabedian Laura , Lakoma Matthew , Ross‐Degnan Dennis
Published: September 2021

Research Objective

Employers are increasingly purchasing “value‐based health insurance” designs that reduce out‐of‐pocket costs for select beneficial health services. For example, “preventive drug list” (PDL) plans make cardioprotective medications $0 to encourage adherence. Research has demonstrated that PDL designs substantially improved cardioprotective medication adherence among low‐income diabetes patients enrolled in health savings account‐eligible high‐deductible health plans (HSA‐HDHP). However, effects on health outcomes are unknown.

Study Design

Interrupted time series with matched control group.

Population Studied

Using data from 2004–2017, we analyzed a large commercial health insurance claims dataset with enrollees in all US states. The intervention group included 1498 low‐income commercially‐insured HSA‐HDHP patients with diabetes age 12–64 years who experienced employer‐mandated switches to PDL coverage; the control group included 11,984 matched HSA‐HDHP counterparts whose employers offered no PDL. We defined the index date as the day that the intervention group received the PDL benefit that reduced cardioprotective drugs to $0 out‐of‐pocket, and matched controls had a corresponding contemporaneous index date. We measured monthly rates of aggregated acute preventable diabetes complications (such as hyperglycemic coma, hypoglycemia, angina, cellulitis, and pneumonia) presenting to the outpatient setting or the emergency department. We constructed cumulative interrupted time series plots of these two measures and conducted segmented regression analysis and marginal effects estimation.

Principal Findings

In both the intervention and control groups, 46% of subjects were female, 49% lived in low‐income neighborhoods, and 2.2% lived in predominantly black neighborhoods. The study groups had similar baseline trends in outcomes. From before to after the index date, the PDL intervention group experienced a 16.2% decrease (absolute change, −8.3/1000) in emergency department visits for acute, preventable diabetes complications relative to controls. Corresponding relative and absolute changes for outpatient complication visits were 0.6% and 1.0 visit/1000.

Conclusions

Low‐income HSA‐HDHP members with diabetes who were switched to a generous value‐based medication benefit experienced a 16% reduction in emergency department visits for acute, preventable diabetes complications.

Implications for Policy or Practice

Value‐based health insurance designs might improve health outcomes of vulnerable populations. Policymakers, health insurers, and employers should consider encouraging uptake among low‐income, chronically ill patients.

Primary Funding Source

Centers for Disease Control and Prevention.
COVID‐19‐Related Knowledge, Protective Behaviors and the Moderating Role of Primary Sources of Information: Findings from a Cross‐Sectional Online Survey in the United States
Authors: Kim Sooyoung , Ali Shahmir H. , Jones Abbey , Capasso Ariadna , Foreman Joshua , DiClemente Ralph Joseph , Tozan Yesim
Published: September 2021

Research Objective

To assess the moderating effects of primary sources of COVID‐19 information on the association between knowledge and protective behaviors against COVID‐19.

Study Design

This is a secondary analysis of data from a cross‐sectional online COVID‐19 survey conducted among US adults in April 2020 using advertisement‐based recruitment on social media. A total of 6518 people completed the survey. Linear regression analysis was performed on COVID‐19 knowledge and protective behavior scores. An interaction term between knowledge and primary source of information was included in order to examine any moderating effects of the information source on the relationship between knowledge and protective behaviors. The analysis was adjusted for demographic and socio‐economic factors and was conducted using R software (version 3.6.3).

Population Studied

Adult population (age > 18) living in the United States.

Principal Findings

Overall, higher level of COVID‐19‐related knowledge was associated with higher level of self‐reported engagement in protective behaviors. More specifically, our results indicate that the primary source of information modified the association between knowledge and protective behaviors. The most effective sources of information to translate incremental knowledge into higher engagement in protective behaviors were interpersonal communication and social media. Official sources such US government, CDC, and WHO websites had significantly weaker effects. Our results also showed that respondents with lower knowledge scores preferred social media or interpersonal communication as their primary source for seeking COVID‐19‐related information.

Conclusions

This study shows the important role that the different COVID‐19 information sources can play on influencing people's engagement in protective behaviors while delivering the COVID‐19‐related knowledge.

Implications for Policy or Practice

Overflowing information and misinformation are influencing people's degree of engagement in protective behaviors against COVID‐19. Policy makers should carefully monitor the use of different information sources by the public so that they can effectively target, influence decision‐making, and promote behavior change to fight the current pandemic and the infodemic concurrently.