bluuebunny/crossref_metadata_2025 huggingface dataset:
High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme
Authors: Appadurai Rajeswari , Nagesh Jayashree , Srivastava Anand
Published: June 2020

Determining the conformational ensemble for proteins with multi-funneled complex free-energy landscapes is often not possible with classical structure-biology methods that produce time and ensemble averaged data. With vastly improved force fields and advances in rare-event sampling methods, molecular dynamics (MD) simulations offer a complementary approach towards determining the collection of 3-dimensional structures that proteins can adopt. However, in general, MD simulations need to either impose restraints or reweigh the generated data to match experiments. The limitations extend beyond systems with high free-energy barriers as is the case with metamorphic proteins such as RFA-H. The predicted structures in even weakly-funneled intrinsically disordered proteins (IDPs) such as Histatin-5 (His-5) are too compact relative to experiments. Here, we employ a new computationally-efficient parallel-tempering based advanced-sampling method applicable across proteins with extremely diverse free-energy landscapes. And we show that the calculated ensemble averages match reasonably well with the NMR, SAXS and other biophysical experiments without the need to reweigh. We benchmark our method against standard model systems such as alanine di-peptide, TRP-cage and β-hairpin and demonstrate significant enhancement in the sampling efficiency. The method successfully scales to large metamorphic proteins such as RFA-H and to highly disordered IDPs such as His-5 and produces experimentally-consistent ensemble. By allowing accurate sampling across diverse landscapes, the method enables for ensemble conformational sampling of deep multi-funneled metamorphic proteins as well as highly flexible IDPs with shallow multi-funneled free-energy landscape.

Significance/Authors’ Summary

Generating high-resolution ensemble of intrinsically disordered proteins, particularly the highly flexible ones with high-charge and low-hydrophobicity and with shallow multi-funneled free-energy landscape, is a daunting task and often not possible since information from biophysical experiments provide time and ensemble average data at low resolutions. At the other end of the spectrum are the metamorphic proteins with multiple deep funnels and elucidating the structures of the transition intermediates between the fold topologies is a non-trivial exercise. In this work, we propose a new parallel-tempering based advanced-sampling method where the Hamiltonian is designed to allow faster decay of water orientation dynamics, which in turn facilitates accurate and efficient sampling across a wide variety of free-energy landscapes.
Mitotic retention of H3K27 acetylation promotes rapid topological and transcriptional resetting of stem cell-related genes and enhancers upon G1 entry
Authors: Pelham-Webb Bobbie , Polyzos Alexander , Wojenski Luke , Kloetgen Andreas , Li Jiexi , Di Giammartino Dafne Campigli , Core Leighton , Tsirigos Aristotelis , Apostolou Effie
Published: June 2020

The identity of dividing cells is challenged during mitosis, as transcription is halted and chromatin architecture drastically altered. How cell type-specific gene expression and genomic organization are faithfully reset upon G1 entry in daughter cells remains elusive. To address this issue, we characterized at a genome-wide scale the dynamic transcriptional and architectural resetting of mouse pluripotent stem cells (PSCs) upon mitotic exit. This revealed distinct patterns of transcriptional reactivation with rapid induction of stem cell genes and their enhancers, a more gradual recovery of metabolic and cell cycle genes, and a weak and transient activation of lineage-specific genes only during G1. Topological reorganization also occurred in an asynchronous manner and associated with the levels and kinetics of transcriptional reactivation. Chromatin interactions around active promoters and enhancers, and particularly super enhancers, reformed at a faster rate than CTCF/Cohesin-bound structural loops. Interestingly, regions with mitotic retention of the active histone mark H3K27ac and/or specific DNA binding factors showed faster transcriptional and architectural resetting, and chemical inhibition of H3K27 acetylation specifically during mitosis abrogated rapid reactivation of H3K27ac-bookmarked genes. Finally, we observed a contact between the promoter of an endoderm master regulator,Gata6, and a novel enhancer which was preestablished in PSCs and preserved during mitosis. Our study provides an integrative map of the topological and transcriptional changes that lead to the resetting of pluripotent stem cell identity during mitotic exit, and reveals distinct patterns and features that balance the dual requirements for self-renewal and differentiation.
miR-203 imposes an intrinsic barrier during cellular reprogramming by targeting NFATC2
Authors: Salazar-Roa María , Martínez-Martínez Sara , Graña-Castro Osvaldo , Álvarez-Fernández Mónica , Trakala Marianna , Redondo Juan-Miguel , Malumbres Marcos
Published: June 2020

Cellular reprogramming from somatic to pluripotent cells is the basis for multiple applications aimed to replace damaged tissues in regenerative medicine. However, this process is limited by intrinsic barriers that are induced in response to reprogramming factors. In this manuscript we report that miR-203, a microRNA with multiple functions in differentiation and tumor suppression, acts as an endogenous barrier to reprogramming. Genetic ablation of miR-203 results in enhanced reprogramming whereas its expression prevents the formation of pluripotent cells both in vitro and in vivo. Mechanistically, this effect correlates with the direct repression of NFATC2, a transcription factor involved in the early phases of reprogramming. Inhibition of NFATC2 mimics miR-203 effects whereas NFATC2 overexpression rescues inducible cell pluripotency in miR-203-overexpressing cultures. These data suggest that miR-203 repression may favor the efficiency of reprogramming in a variety of cellular models.
Substitution of nucleotide-sugar by trehalose-dependent glycogen synthesis pathways in Chlamydiales underlines an unusual requirement for storage polysaccharides within obligate intracellular bacteria
Authors: Colpaert Matthieu , Kadouche Derifa , Ducatez Mathieu , Pillonel Trestan , Kebbi-Beghdadi Carole , Cenci Ugo , Huang Binquan , Chabi Malika , Maes Emmanuel , Coddeville Bernadette , Couderc Loïc , Touzet Hélène , Bray Fabrice , Tirtiaux Catherine , Ball Steven , Greub Gilbert , Christophe Colleoni
Published: June 2020

All obligate intracellular pathogens or symbionts of eukaryotes lack glycogen metabolism. Most members of theChlamydialesorder are exceptions to this rule as they contain the classical GlgA-GlgC-dependent pathway of glycogen metabolism that relies on the ADP-Glucose substrate. We surveyed the diversity of Chlamydiales and found glycogen metabolism to be universally present with the important exception ofCriblamydiaceaeandWaddliaceaefamilies that had been previously reported to lack an active pathway. However, we now find elements of the more recently described GlgE maltose-1-P-dependent pathway in several protist-infecting Chlamydiales. In the case ofWaddliaceaeandCriblamydiaceae, the substitution of the classical pathway by this recently proposed GlgE pathway was essentially complete as evidenced by the loss of both GlgA and GlgC. Biochemical analysis of recombinant proteins expressed fromWaddlia chondrophilaandEstrella lausannensisestablished that both enzymes do polymerize glycogen from trehalose through the production of maltose-1-P by TreS-Mak and its incorporation into glycogen’s outer chains by GlgE. UnlikeMycobacteriaceaewhere GlgE-dependent polymerization is produced from both bacterial ADP-Glc and trehalose, glycogen synthesis seems to be entirely dependent on host supplied UDP-Glc and Glucose-6-P or on host supplied trehalose and maltooligosaccharides. These results are discussed in the light of a possible effector nature of these enzymes, of the chlamydial host specificity and of a possible function of glycogen in extracellular survival and infectivity of the chlamydial elementary bodies. They underline that contrarily to all other obligate intracellular bacteria, glycogen metabolism is indeed central to chlamydial replication and maintenance.
Multi-parametric disease dynamics study and analysis of the COVID-19 epidemic and implementation of population-wide intrusions: The Indian perspective
Authors: Bharti Samuel , Narad Priyanka , Chugh Parul , Choudhury Alakto , Bhatnagar Seema , Sengupta Abhishek
Published: June 2020

The outbreak of COVID-19 had spread at a deadly rate since its onset at Wuhan, China and is now spread across 216 countries and has affected more than 6 million people all over the world. The global response throughout the world has been primarily the implementation of lockdown measures, testing and contact tracing to minimise the spread of the disease. The aim of the present study was to predict the COVID-19 prevalence and disease progression rate in Indian scenario in order to provide an analysis that can shed light on comprehending the trends of the outbreak and outline an impression of the epidemiological stage for each state of a diverse country like India. In addition, the forecast of COVID-19 incidence trends of these states can help take safety measures and policy design for this epidemic in the days to come. In order to achieve the same, we have utilized an approach where we test modelling choices of the spatially unambiguous kind, proposed by the wave of infections spreading from the initial slow progression to a higher curve. We have estimated the parameters of an individual state using factors like population density and mobility. The findings can also be used to strategize the testing and quarantine processes to manipulate the spread of the disease in the future. This is especially important for a country like India that has several limitations about healthcare infrastructure, diversity in socioeconomic status, high population density, housing conditions, health care coverage that can be important determinants for the overall impact of the pandemic. The results of our 5-phase model depict a projection of the state wise infections/disease over time. The model can generate live graphs as per the change in the data values as the values are automatically being fetched from the crowd-sourced database.
CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition
Authors: Musicant Adele M. , Parag-Sharma Kshitij , Gong Weida , Sengupta Monideepa , Chatterjee Arindam , Henry Erin C. , Tsai Yi-Hsuan , Hayward Michele C. , Sheth Siddharth , Betancourt Renee , Hackman Trevor G. , Padilla Ricardo J. , Parker Joel S. , Giudice Jimena , Flaveny Colin A. , Hayes David N. , Amelio Antonio L.
Published: June 2020

Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1α splice variant PGC-1α4, which regulates PPARγ-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγinhibition with inverse agonists. These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.
Evolutionarily related small viral fusogens hijack distinct but modular actin nucleation pathways to drive cell-cell fusion
Authors: Chan Ka Man Carmen , Arthur Ashley L. , Morstein Johannes , Jin Meiyan , Bhat Abrar , Schlesinger Dörte , Son Sungmin , Stevens Donté A. , Drubin David G. , Fletcher Daniel A.
Published: June 2020

Fusion-associated small transmembrane (FAST) proteins are a diverse family of non-structural viral proteins that, once expressed on the plasma membrane of infected cells, drive fusion with neighboring cells, increasing viral spread and pathogenicity. Unlike viral fusogens with tall ectodomains that pull two membranes together through conformational changes, FAST proteins have short fusogenic ectodomains that cannot bridge the inter-membrane gap between neighboring cells. One orthoreovirus FAST protein, p14, has been shown to hijack the actin cytoskeleton to drive cell-cell fusion, but the actin adaptor-binding motif identified in p14 is not found in any other FAST protein. Here, we report that an evolutionarily divergent FAST protein, p22 from aquareovirus, also hijacks the actin cytoskeleton but does so through different adaptor proteins, Intersectin-1 and Cdc42, that trigger N-WASP-mediated branched actin assembly. We show that despite using different pathways, the cytoplasmic tails of p22 and p14 can be exchanging to create a potent chimeric fusogen, suggesting they are modular and play similar functional roles. When we replace p22’s branched actin nucleator, N-WASP, with the parallel filament nucleator, formin, its ability to drive fusion is maintained, indicating that localized mechanical pressure on the plasma membrane coupled to a membrane-disruptive ectodomain is sufficient to drive cell-cell fusion. This work points to a common biophysical strategy used by FAST proteins to push rather than pull membranes together to drive fusion, one that may be harnessed by other short fusogens responsible for physiological cell-cell fusion.
Discovering compounds mimicking calorie restriction using mammalian gene expression profiles
Authors: Vazquez Alexei
Published: June 2020

Obesity is a risk factor for cardiovascular diseases, diabetes and cancer. In theory the obesity problem could be solve by the adherence to a calorie restricted diet, but that is not generally achieved in practice. An alternative is a pharmacological approach, using compounds that trigger the same metabolic changes associated with calorie restriction. Here I expand in the pharmacological direction by identifying compounds that induce liver gene signature profiles that mimic those induced by calorie restriction. Using gene expression profiles from mice and rat I identify corticosteroids, PPAR agonists and some antibacterial/antifungal as candidate compounds mimicking the response to calorie restriction in the liver gene signatures. Liver gene signature analysis can be used to identify compounds that mimic calorie restriction.
Novel Serine/Threonine-O-glycosylation with N-Acetylneuraminic acid and 3-Deoxy-D-manno-octulosonic acid by Maf glycosyltransferases
Authors: Khairnar Aasawari , Sunsunwal Sonali , Babu Ponnusamy , Ramya T.N.C.
Published: June 2020

Some bacterial flagellins are O-glycosylated on surface-exposed Serine/Threonine residues with nonulosonic acids such as pseudaminic acid, legionaminic acid, and their derivatives by flagellin nonulosonic acid glycosyltransferases, also called Motility associated factors (Maf). We report here two new glycosidic linkages previously unknown in any organism, Serine/Threonine-O-linked N-Acetylneuraminic acid (Ser/Thr-O-Neu5Ac) and Serine/Threonine-O-linked 3-Deoxy-D-manno-octulosonic acid (Ser/Thr-O-KDO), both catalysed byGeobacillus kaustophilusMaf (putative flagellin sialyltransferase) andClostridium botulinumMaf (putative flagellin legionaminic acid transferase). We identified these novel glycosidic linkages in recombinantG. kaustophilusandC. botulinumflagellins that were co-expressed with their cognate recombinant Maf protein inEscherichia colistrains producing the appropriate nucleotide sugar glycosyl donor. The glycosylation ofG. kaustophilusflagellin with KDO, and that ofC. botulinumflagellin with Neu5Ac and KDO indicates that Maf glycosyltransferases display donor substrate promiscuity. Maf glycosyltransferases have the potential to radically expand the scope of neoglycopeptide synthesis and posttranslational protein engineering.

Significance Statement

Glycosylation, the modification of proteins with sugars, is one of the most common post-translational modifications observed in proteins. While glycosylation is versatile, the most common forms of glycosylation are N-glycosylation, where the N atom of Asparagine is modified with a glycan, and O-glycosylation where the O atom of serine or threonine residues is modified with a glycan. Here, we report a novel type of O-glycosylation in the bacterial flagellin proteins of two Gram-positive bacteria,Geobacillus kaustophilusandClostridium botulinum. We demonstrate for the first time that the enzyme flagellin Maf glycosyltransferase is capable of transferring the monosaccharides, N-acetylneuraminic acid and 3-Deoxy-D-manno-octulosonic acid, on to serine and threonine residues of these proteins.
The Hitchhiker’s Guide to the Periplasm: Unexpected Molecular Interactions of Antibiotics Revealed by Considering Crowding Effects inE. coli
Authors: Pedebos Conrado , Smith Iain P. S. , Boags Alister , Khalid Syma
Published: June 2020

The periplasm of Gram-negative bacteria is a highly crowded environment comprised of many different molecular species. Antibacterial agents that causes lysis of Gram-negative bacteria by their action against the inner membrane must cross the periplasm to arrive at their target membrane. Very little is currently known about their route through the periplasm, and the interactions they experience. To this end, here atomistic molecular dynamics simulations are used to study the path taken by the antibiotic polymyxin B1 through a number of models of the periplasm which are crowded with proteins and osmolytes to different extents. The simulations reveal that PMB1 forms transient and long-lived interactions with proteins and osmolytes that are free in solution as well as lipoproteins anchored to the outer membrane and bound to the cell wall. We show that PMB1 may be able to ‘hitchhike’ within the periplasm by binding to lipoprotein carriers. Overall our results show that PMB1 is rarely uncomplexed within the periplasm; an important consideration for interpretations of its therapeutic mechanism of action. It is likely that this observation can be extended to other antibiotics that rely on diffusion to cross the periplasm.
The inhibitory effect of a Corona virus spike protein fragment with ACE2
Authors: Peter E. K. , Schug A.
Published: June 2020

In this paper, we investigate the molecular assembly processes of a Coronavirus Spike protein fragment, the hexapeptide YKYRYL on the ACE2 receptor and its inhibitory effect on the aggregation and activation of the CoV-2 spike receptor protein at the same receptor protein. In agreement with an experimental study, we find a high affinity of the hexapeptide to the binding interface between the spike receptor protein and ACE2, which we investigate using 20 independent equilibrium MD simulations over a total of 1μs and a 200 ns enhanced MD simulation. We then evaluate the effect of the hexapeptide on the aggregation process of the spike receptor protein to ACE2 in long-time enhanced MD simulations. In that set of simulations, we find that the spike receptor protein does not bind to ACE2 with the binding motif shown in experiments, but it rotates due to an electrostatic repulsion and forms a hydrophobic interface with ACE2. Surprisingly, we observe that the hexapeptide binds to the spike receptor domain, which has the effect that this protein only weakly attaches to ACE2, so that the activation of the spike protein receptor might be inhibited in this case. Our results indicate that the hexapeptide might be a possible treatment option which prevents the viral activation through the inhibition of the interaction between ACE2 and the spike receptor protein.

SIGNIFICANCE

A novel coronavirus, CoV-19 and a later phenotype CoV-2 were identified as primary cause for a severe acute respiratory syndrome (SARS CoV-2). The spike (S) protein of CoV-2 is one target for the development of a vaccine to prevent the viral entry into human cells. The inhibition of the direct interaction between ACE2 and the S-protein could provides a suitable strategy to prevent the membrane fusion of CoV-2 and the viral entry into human cells. Using MD simulations, we investigate the assembly process of a Coronavirus Spike protein fragment, the hexapeptide YKYRYL on the ACE2 receptor and its inhibitzory effect on the aggregation and activation of the CoV-2 spike receptor protein at the same receptor protein.
Transcranial ultrasonic propagation and enhanced brain imaging exploiting the focusing effect of the skull
Authors: Amanatiadis Stamatis A. , Apostolidis Georgios K. , Bekiari Chrysanthi S. , Kantartzis Nikolaos V.
Published: June 2020

Purpose

The reliable transcranial imaging of brain inner structures for diagnostic purposes is deemed crucial owing to the decisive importance and contribution of the brain in human life. The purpose of this paper is to investigate the potential application of medical ultrasounds to transcranial imaging using advanced techniques, such as the total focussing method.

Design/methodology/approach

Initially, the fundamental details of the total focussing method are presented, while the skull properties, such as the increased acoustic velocity and scattering, are thoroughly examined. Although, these skull characteristics constitute the main drawback of typical transcranial ultrasonic propagation algorithms, they are exploited to focus the acoustic waves towards the brain. To this goal, a virtual source is designed, considering the wave refraction, to efficiently correct the reconstructed brain image. Finally, the verification of the novel method is conducted through numerical simulations of various realistic setups.

Findings

The theoretically designed virtual source resembles a focussed sensor; therefore, the directivity increment, owing to the propagation through the skull, is confirmed. Moreover, numerical simulations of real-world scenarios indicate that the typical artifacts of the conventional total focussing method are fully overcome because of the increased directivity of the proposed technique, while the reconstructed image is efficiently corrected when the proposed virtual source is used.

Originality/value

A new systematic methodology along with the design of a flexible virtual source is developed in this paper for the reliable and precise transcranial ultrasonic image reconstruction of the brain. Despite the slight degradation owing to the skull scattering, the combined application of the total focussing method and the featured virtual source can successfully detect arbitrary anomalies in the brain that cannot be spotted by conventional techniques.
Social network analysis: organizational implications in tourism management
Authors: Valeri Marco , Baggio Rodolfo
Published: June 2020

Purpose

The purpose of this paper is to provide an overview of how quantitative analysis methods have been and can be used to improve the competitiveness of tourism destination. The focus of the study is social network analysis (SNA).

Design/methodology/approach

The research methodology is qualitative and consists of the review literature relevant to this thesis. This methodology is necessary to give an account of the methods and the techniques adopted for the data collection used in other economic sectors.

Findings

SNA is needed to analyze the creation and configuration of communities of practice within destination and to identify possible barriers to effective interaction. Essentially, it is a complex adaptive socio-economic system. It shares many (if not all) of the characteristics usually associated with such entities, namely, non-linear relationships among the components, self-organization and emergence of organizational structures, robustness to external shocks.

Research limitations/implications

The most important limit of this paper is that all the results presented here do not concern a single case study. Future research studies will provide a larger number of cases and examples to give the necessary validation to the findings presented here.

Practical implications

This paper provides a view into the network of relationships that may give tourism organization managers a strong leverage to improve the flow of information and to target opportunities where this flow may have the most impact on regulatory or business activities.

Originality/value

SNA can help to detect actual expertise and consequently project the potential losses deriving from an inefficient flow of knowledge. In addition, the authors will be able to define roles in the organizational networks and make an evaluation of informal organizational structures over the formal ones. Traditional organizational theories lack a concrete correspondence with mathematical studies and in this respect the authors sought to identify a correspondence.
Factors for performance measurement systems design in nonprofit organizations and public administration
Authors: Moura Louisi Francis , Pinheiro de Lima Edson , Deschamps Fernando , M. Van Aken Eileen , Gouvea Da Costa Sergio E. , Tavares Treintaa Fernanda , Almeida Prado Cestari José Marcelo , Assumpção Silva Ronan
Published: June 2020

Purpose

The purpose of this research is to examine the factors that influence the design of performance measurement systems (PMSs) in nonprofit organizations (NPOs) and public administration and explore inter-relationships among these factors.

Design/methodology/approach

Findings resulted through the identification of design factors from the paper portfolio of a previous systematic literature review on this topic and the construction of a factor co-occurrence network for the identified factors. 

Findings

The methodology helped to determine the relationships among factors and show how these factors influence PMSs in NPOs and public administration. It also helped to demonstrate how PMSs in these organizations are different from PMSs in traditional companies because of the impact of the factors on the complexity and dynamics of NPOs and public administration. The findings and discussion contribute to the performance measurement literature on NPOs and public administration by presenting a set of design factors related to purpose, stakeholders and management.

Practical implications

This paper presents practical implications for managers regarding the PMS design process and shows how some design factors can be particularly related to these organizations

Originality/value

The design factors are particular to the organizational dynamic and should be considered by managers involved with the design (or redesign) process of performance measurement systems.
Identification of binding domains and key amino acids involved in the interaction between BmLARK and G4 structure in the BmPOUM2 promoter in Bombyx mori
Authors: Peng Yuling , Niu Kangkang , Yu Guoxing , Zheng Mingxi , Wei Qiulan , Song Qisheng , Feng Qili
Published: June 2020

It has been found that the non‐B form DNA structures, like G‐quadruplex (G4) and i‐motif, are involved in many important biological processes. Our previous study showed that the silkworm transcription factor BmLARK binds to the G4 structure in the promoter of the transcription factor BmPOUM2 and regulates its promoter activity. However, the binding mechanism between BmLARK and BmPOUM2 G4 structure remains unclear. In this study, binding domains and key amino acid residues involved in the interaction between BmLARK and BmPOUM2 G4 were studied. The electrophoretic mobility shift assay results indicated that the two RNA‐recognition motifs (RRM) of BmLARK are simultaneously required for the binding with the G4 structure. Either RRM1 or RRM2 alone could not bind with the G4 structure. The zinc‐finger motif was not involved in the binding. A series of mutant proteins with specific amino acid mutations were expressed and used to identify the key amino acid residues involving the interaction. The results indicated that β sheets, especially the β1 and β3 sheets, in the RRM domains of BmLARK played critical roles in the binding with the G4 structure. Several amino acid mutations of RRM1/2 in ribonucleoprotein domain 1 (RNP1) (motif in β3 strand) and RNP2 (motif in β1 strand) caused loss of binding ability, indicating that these amino acids are the key sites for the binding. All the results suggest that RRM domains, particularly their the RNP1 and RNP2 motifs, play important roles not only in RNA recognition, but also in the G4 structure binding.
Estimating dynamic games of oligopolistic competition: an experimental investigation
Authors: Salz Tobias , Vespa Emanuel
Published: June 2020

We evaluate standard assumptions in the estimation of dynamic oligopoly models with laboratory data. Using an entry/exit game, we estimate structural parameters under the assumption that the data are generated by a Markov‐perfect equilibrium and subsequently predict counterfactual behavior. If behavior was collusive, however, the assumption would be violated and one would mispredict counterfactuals. The laboratory allows us to compare predicted behavior to true counterfactuals implemented as treatments. Our main finding is that prediction errors due to collusion are modest in size. We also document a different deviation from equilibrium behavior (inertia) that can lead to large prediction errors.
Exploration of multi‐target effects of 3‐benzoyl‐5‐hydroxychromen‐2‐one in Alzheimer’s disease cell and mouse models
Authors: Lin Te‐Hsien , Chiu Ya‐Jen , Lin Chih‐Hsin , Lin Chung‐Yin , Chao Chih‐Ying , Chen Yu‐Chieh , Yang Shu‐Mei , Lin Wenwei , Mei Hsieh‐Li Hsiu , Wu Yih‐Ru , Chang Kuo‐Hsuan , Lee‐Chen Guey‐Jen , Chen Chiung‐Mei
Published: June 2020

Microtubule‐associated protein Tau, abundant in the central nervous system (CNS), plays crucial roles in microtubule assembly and stabilization. Abnormal Tau phosphorylation and aggregation are a common pathogenic hallmark in Alzheimer's disease (AD). Hyperphosphorylation of Tau could change its conformation and result in self‐aggregation, increased oxidative stress, and neuronal death. In this study, we examined the potential of licochalcone A (a natural chalcone) and five synthetic derivatives (LM compounds) for inhibiting Tau misfolding, scavenging reactive oxygen species (ROS) and providing neuroprotection in human cells expressing proaggregant ΔK280 TauRD‐DsRed. All test compounds were soluble up to 100 μM in cell culture media and predicted to be orally bioavailable and CNS‐active. Among them, licochalcone A and LM‐031 markedly reduced Tau misfolding and associated ROS, promoted neurite outgrowth, and inhibited caspase 3 activity in ΔK280 TauRD‐DsRed 293 and SH‐SY5Y cells. Mechanistic studies showed that LM‐031 upregulates HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB‐dependent BDNF/AKT/ERK/BCL2 pathway in ΔK280 TauRD‐DsRed SH‐SY5Y cells. Decreased neurite outgrowth upon induction of ΔK280 TauRD‐DsRed was rescued by LM‐031, which was counteracted by knockdown of NRF2 or CREB. LM‐031 further rescued the downregulated NRF2 and pCREB, reduced Aβ and Tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin‐induced hyperglycemic 3 × Tg‐AD mice. Our findings strongly indicate the potential of LM‐031 for modifying AD progression by targeting HSPB1 to reduce Tau misfolding and activating NRF2 and CREB pathways to suppress apoptosis and promote neuron survival, thereby offering a new drug development avenue for AD treatment.
Response of preterm infants with transient hypothyroxinaemia of prematurity to the thyrotropin‐releasing hormone stimulation test is characterized by a delayed decrease in thyroid‐stimulating hormone after the peak
Authors: Yamamoto Akane , Iwanaga Kogoro , Matsukura Takashi , Niwa Fusako , Morimoto Takeshi , Takita Junko , Kawai Masahiko
Published: June 2020

Objectives

We evaluated the response to the thyrotropin‐releasing hormone (TRH) stimulation test in very low‐birth weight (VLBW) infants to elucidate the aetiology of transient hypothyroxinaemia of prematurity (THOP).

Design and Methods

We performed TRH stimulation tests on 43 VLBW infants. Subjects were divided into two groups; a THOP group (N = 11; basal TSH < 15 mU/L and basal FT4 ≤ 0.8 ng/dL) and a non‐THOP group (N = 32; basal TSH < 15 mU/L and basal FT4 > 0.8 ng/dL). Basal FT4 and FT3 were measured before, and TSH (0, 30, 60, 90, 120 and 180 minutes) was measured after, the administration of TRH (7 µg/kg). We calculated the ratio of TSH 180 minutes to THS 0 minute as the primary outcome. We also collected data on T3 and rT3 in this study.

Results

In both groups, TSH 30 minutes values were the highest. However, the ratios of TSH 180 minutes to THS 0 minutes in the non‐THOP group and the THOP group were (median [IQR]) 1.3 [1.0‐1.7] and 3.0 [1.5‐5.3] (P < .01). No significant differences were observed in T3 (1.0 [0.8‐1.3] and 0.7 [0.4‐0.7] ng/mL, P = .06). However, in the THOP group, rT3 was significantly lower than that of the non‐THOP group (168.0 [148.1‐197.0] and 92.9 [74.7‐101.6] pg/mL, P < .01).

Conclusions

The delayed decrease in the TSH concentration after the peak for the TRH tests and decreased levels of rT3 suggest that the main aetiology for THOP is suppression at the level of the hypothalamus, but not inactivation of peripheral thyroid hormone metabolism.
Maxillary implant overdenture retained by four unsplinted attachments and opposed by a natural or fixed dentition: One‐year clinical outcomes
Authors: Bouhy Alice , Rompen Eric , Lamy Marc , Legros Caroline , Lecloux Geoffrey , Lambert France
Published: June 2020

Objectives

The aim of this prospective study was to evaluate the implant, prosthesis, and patient‐reported outcomes of maxillary removable prostheses retained by 4 implant‐supported study abutments after a follow‐up period of 1 year in patients with natural teeth or a fixed rehabilitation in the mandible.

Materials and Methods

A total of 30 patients were included, and all received 4 implants in the upper maxilla. After 12 weeks, the prostheses were connected to the implant with unsplinted attachments. The implant and prosthodontics outcomes were assessed over a follow‐up period of 1 year. Patient‐reported outcome measures (PROMs) were evaluated with the Oral Health Impact Profile (OHIP‐20) questionnaire and an adaptation of the McGill Denture Satisfaction Instrument using a visual analogue scale (VAS).

Results

A single patient dropped out. At the post‐operative 12‐week follow‐up, 79.3% (95% CI: 64.6%–94.1%) of the patients displayed peri‐implant mucosa hyperplasia and 69.0% (95% CI: 52.1%–85.8%) showed pain. After 1 year, 16 implants failed in 10 patients, leading to an implant survival rate of 86.2% (95% CI: 79.0%–92.5%), and the mean peri‐implant bone loss was 1.01 ± 0.77 mm (95% CI: 0.85–1.16 mm). The prosthesis survival rate was 96.6% (95% CI: 82.2%–99.9%). The OHIP‐20 and VAS scores both improved significantly from baseline to 1 year (p < .001).

Conclusion

The implant survival rate was lower compared to the literature for the upper maxilla. Despite the encountered problems, PROMs showed significant improvement with the implant overdenture retained by 4 unsplinted implants compared to conventional dentures.
Sociodemographic factors, current asthma and lung function in an urban child population
Authors: Yang‐Huang Junwen , van Grieken Amy , van Meel Evelien R. , He Huan , de Jongste Johan C. , Duijts Liesbeth , Raat Hein
Published: June 2020

Background

We aimed to assess which sociodemographic factors are associated with current asthma and indicators of lung function in 10‐year‐old children.

Methods

We analysed data of 5237 children (Mean age: 9.7, SD: 0.3) from the Generation R Study (2012‐2016), a population‐based cohort study in the Netherlands. Indicators of sociodemographic factors included parental educational level, net household income, financial difficulties, parental employment status and child ethnic background. Current asthma (yes/no) was defined as ever doctor‐diagnosed‐asthma combined with wheezing symptoms or asthma‐medication use in the past 12 months. Lung function was measured by spirometry and included forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow after exhaling 75% of FVC (FEF75). Within‐study sex‐, height‐ and age‐adjusted lung function measurements’ z‐scores were converted.

Results

After adjustment for all sociodemographic factors, an independent association was observed between ethnic background with current asthma and lung function. Compared with children with a Dutch background, children with a nonwestern ethnic background had a higher odds of having current asthma (OR: 1.61, 95% CI: 1.02, 2.53), lower FVC z‐score (−0.25, 95% CI: −0.35, −0.14), higher FEV1/FVC z‐score (0.26, 95% CI: 0.14, 0.37) and higher FEF75% z‐score (0.15, 95% CI: 0.04, 0.25).

Conclusions

Among 10‐year‐old children, ethnic background was associated with current asthma and lung function after adjusting for a wide range of sociodemographic factors. No associations were found between socioeconomic status indicators and current asthma. Explanations for these associations such as language barriers, suboptimal care or pathophysiological differences require further investigation.
Sintering and final properties of kaolinite‐magnesite tapes for the manufacture of cordierite‐mullite ceramics
Authors: Hammas Aghiles , Lecomte‐Nana Gisèle , Daou Imane , Zibouche Fatima
Published: June 2020

The present work aims at studying the effect of the sintering temperature and magnesite addition on the structure and final properties of silicate ceramics tapes. A kaolinitic clay from Algeria was selected and mixed with different magnesite contents (≤12 mass%). Tape casting process was used to produce the green tapes in an aqueous system with optimized amount of surfactants. The green tapes were fired from 1000°C to 1200°C using a dwelling time of 30 minutes. The effect of the dwelling time was investigated for a firing temperature of 1200°C namely: 30 minutes, 1 hour 30 minutes and 3 hours for samples with 6 and 12 mass% of magnesite. Regarding firing conditions, crystalline phases, thermal conductivity, porosity, and flexural strength were analyzed. The results showed that increasing the sintering temperature to 1200°C tended to significantly decrease the total porosity of samples, which led to the improvement of the stress to rupture values. Specimens with 6 and 12 mass% sintered during 3 hours exhibited highest stress to rupture values (≈117 MPa) and lowest thermal conductivity (<0.2 W.m−1.K−1) and moderate open porosity (27%). The as‐obtained ceramics appeared promising for further utilization in refractory industry, thanks to the presence of both cordierite and mullite phases.
C/C‐SiC component for metallic phase change materials
Authors: Stahl Veronika , Shi Yuan , Kraft Werner , Lanz Tim , Vetter Peter , Jemmali Raouf , Kessel Fiona , Koch Dietmar
Published: June 2020

Thanks to their high energy density and thermal conductivity, metallic Phase Change Materials (mPCM) have shown great potential to improve the performance of thermal energy storage systems. However, the commercial application of mPCM is still limited due to their corrosion behavior with conventional container materials. This work first addresses on a fundamental level, whether carbon‐based composite‐ceramics are suitable for corrosion critical components in a thermal storage system. The compatibility between the mPCM AlSi12 and the Liquid Silicon Infiltration (LSI)‐based carbon fiber reinforced silicon carbide (C/C‐SiC) composite is then investigated via contact angle measurements, microstructure analysis, and mechanical testing after exposure. The results reveal that the C/C‐SiC composite maintains its mechanical properties and microstructure after exposure in the strongly corrosive mPCM. Based on these results, efforts were made to design and manufacture a container out of C/C‐SiC for the housing of mPCM in vehicle application. The stability of the component filled with mPCM was proven nondestructively via computer tomography (CT). Successful thermal input‐ and output as well as thermal storage ability were demonstrated using a system calorimeter under conditions similar to the application. The investigated C/C‐SiC composite has significant application potential as a structural material for thermal energy storage systems with mPCM.
Structural evolution of Lu2‐xCexTi2O7 pyrochlores under 400 keV Ne irradiation
Authors: Xia Yue , Yang Dongyan , Chen Chien‐Hung , Hao Yan , Ewing Rodney C. , Li Yuhong
Published: June 2020

Lu2‐xCexTi2O7 (LCTO) pyrochlores were irradiated by 400 keV Ne2+ with fluences (dose) of up to 5 × 1015 ions/cm2 (1.875 dpa). The detailed damage process was investigated by combining grazing incident angle X‐ray diffraction (GIXRD) and transmission electron microscopy (TEM). Subsequent to the 2% volume swelling at a fluence of 1 × 1014 ions/cm2 (0.037 dpa), the initially swollen LCTO pyrochlore formed both a disordered fluorite phase and a nanocrystalline pyrochlore phase at a fluence of 5 × 1014 ions/cm2 (0.185 dpa). At higher fluences, the fluorite phase diminished as amorphous domains increased in volume when the dose reached a fluence of 1 × 1015 ions/cm2 (0.371 dpa), while the nanocrystalline pyrochlore phase persisted. At the highest fluence of 5 × 1015 ions/cm2 (1.854 dpa), the amorphous fraction decreased, meanwhile the degree of crystallinity of nanocrystalline pyrochlore phase was enhanced, as evidenced by the increased intensity of superlattice diffraction maxima. The phase transformation and recrystallization can be explained by the release of strain in irradiation‐induced swollen pyrochlore crystallites. The evolution of the damage process is mainly driven by the differences in the Gibb's free energies of fluorite phase as compared with the pyrochlore phase as a function of grain size. We have demonstrated that ion beam techniques can be used to manipulate the phase stability and crystallite size of pyrochlore. These results provide the basis for tailoring the mechanical strength and response of pyrochlores to extreme radiation environments.
Microsporidia Can Acquire Lamin‐like Intermediate Filaments and Cell Adhesion Catenin‐cadherin Complexes from the Host (?)
Authors: Weidner Earl , Sokolova Yuliya Y. , Overstreet Robin M.
Published: June 2020

On their spore surfaces, Microsporidia often develop a canopy of filaments with characteristics of intermediate filaments (IF), as we demonstrated in previous studies on Thelohania sp., Ameson michaelis, and Spraguea lophii. Genomic studies indicate that among invertebrates, lamins that may localize in the cytoplasm or nucleus, are the only known IF type. These IFs can bind to the substrate containing cell adhesion molecules (CAMs) cadherins, associated with β and γ catenins. The objects of this study were to determine whether microsporidia have CAMs with the attached IFs on their envelopes and to find out if these proteins are provided by the host. An examination was made for localization of lamins and CAMs on the spores of the mentioned above species and Anncaliia algerae, plus in the host animals. Then, we determined whether the spores of A. michaelis and A. algerae could bind vertebrate nuclear lamin onto the spore surface. We also tested transgenic Drosophila melanogaster stocks bearing cadherin‐GFP to see whether developing A. algerae parasites in these hosts could acquire host CAMs. The tests were positive for all these experiments. We hypothesize that microsporidia are able to acquire host lamin IFs and cell adhesion catenin–cadherin complexes from the host.
Perspectives from Ten Years of Protist Studies by High‐Throughput Metabarcoding
Authors: Santoferrara Luciana , Burki Fabien , Filker Sabine , Logares Ramiro , Dunthorn Micah , McManus George B.
Published: June 2020

During the last decade, high‐throughput metabarcoding became routine for analyzing protistan diversity and distributions in nature. Amid a multitude of exciting findings, scientists have also identified and addressed technical and biological limitations, although problems still exist for inference of meaningful taxonomic and ecological knowledge based on short DNA sequences. Given the extensive use of this approach, it is critical to settle our understanding on its strengths and weaknesses and to synthesize up‐to‐date methodological and conceptual trends. This article summarizes key scientific and technical findings, and identifies current and future directions in protist research that uses metabarcoding.
Feasibility of brief distress screening for family caregivers of adults diagnosed with schizophrenia in Changsha, Hunan, China
Authors: Guan Ziyao , Cross Wendy , Lam Louisa , Wiley James A. , Sun Mei , Bai Xiaoling , Tang Siyuan
Published: June 2020

What is known on the subject?

Distress screening amongst FGs is emphasized in worldwide studies, but existing general tools were found time‐consuming and sometimes inconvenient when using them amongst FGs of patients diagnosed with schizophrenia.

The DT, a single‐item scale, was widely used to detect distress amongst FGs of cancer patients, showing good reliability, validity and discrimination power.

The 21‐item Depression Anxiety and Stress Scale (DASS21) can identify distress in the general population and serve as a criterion to determine an optimal cut‐off score of the DT.

What does the paper add to existing knowledge?

The DT presented good reliability, validity and discriminatory power amongst FGs of adults diagnosed with schizophrenia. A cut‐off score of six maximized sensitivity (77%) and specificity (76%). Over half of the FGs of adults diagnosed with schizophrenia reached this cut‐off score and experienced significant distress. Distress was higher in FGs of male patients, when FGs were parents, and for FGs whose educational background was primary school or below.

What are the implications for practice?

The DT is an effective alternative to existing instruments in identifying distressed FGs of adults diagnosed with schizophrenia. It is important to provide FGs with distress screening programmes and interventions (e.g. skill‐building psychoeducation) to identify and relieve distress. In addition, future research could explore brief measures to simultaneously recognize potential negative and positive impacts of caregiving in FGs.