bluuebunny/crossref_metadata_2025 huggingface dataset:
The Liexi fauna: a new Lagerstätte from the Lower Ordovician of South China
Authors: Fang Xiang , Mao Yingyan , Liu Qi , Yuan Wenwei , Chen Zhongyang , Wu Rongchang , Li Lixia , Zhang Yuchen , Ma Junye , Wang Wenhui , Zhan Renbin , Peng Shanchi , Zhang Yuandong , Huang Diying
Published: July 2022

The Ordovician Lagerstätten record substantial amounts of excellent preservation and soft-bodied fossils during the Great Ordovician Biodiversification Event (GOBE). However, few Lagerstätten are known from the Lower Ordovician, most of which are preserved in restricted environments and high-latitude regions. Here, we report on a new tropical Lagerstätte, Liexi fauna, which has been recently discovered from a carbonate succession within the Lower Ordovician Madaoyu Formation in western Hunan, South China. It contains a variety of soft tissues, as well as rich shelly fossils, including palaeoscolecidan worms, possible
Ottoia
, trilobites, echinoderms, sponges, graptolites, polychaetes, bryozoans, conodonts and other fossils. The fauna includes taxa that are not only Cambrian relics, but also taxa originated during the Ordovician, constituting a complex and complete marine ecosystem. The coexistence of the Cambrian relics and Ordovician taxa reveals the critical transition between the Cambrian and Palaeozoic Evolutionary faunas. The unusual Liexi fauna provides new evidence for understanding Ordovician macroevolution and the onset of the GOBE.
Message in a bottle: mRNA vaccination for influenza
Authors: Shartouny Jessica R. , Lowen Anice C.
Published: July 2022

Current influenza vaccines, while being the best method of managing viral outbreaks, have several major drawbacks that prevent them from being wholly-effective. They need to be updated regularly and require extensive resources to develop. When considering alternatives, the recent deployment of mRNA vaccines for SARS-CoV-2 has created a unique opportunity to evaluate a new platform for seasonal and pandemic influenza vaccines. The mRNA format has previously been examined for application to influenza and promising data suggest it may be a viable format for next-generation influenza vaccines. Here, we discuss the prospect of shifting global influenza vaccination efforts to an mRNA-based system that might allow better control over the product and immune responses and could aid in the development of a universal vaccine.
High-resolution Spatiotemporal Changes in Dominant Frequency and Structural Organization During Persistent Atrial Fibrillation
Authors: Pong Terrence , Aparicio-Valenzuela Joy , Obafemi Oluwatomisin Olurotimi , Cyr Kevin J. , Carlton Cody , Taylor Calvin , Lee Anson M.
Published: July 2022

Objective

Analyze changes in frequency activity and structural organization that occur over time with persistent atrial fibrillation (AF)

Background

Little is known about the frequency characteristics of the epicardium during transition from paroxysmal to persistent AF. Accurate identification of areas of high dominant frequency (DF) is often hampered by limited spatial resolution. Improvements in electrode arrays provide high spatiotemporal resolution, allowing for characterization of the changes that occur during this transition.

Methods

AF was induced in adult Yorkshire swine by atrial tachypacing. DF mapping was performed using personalized mapping arrays. Histological analysis and late gadolinium enhanced magnetic resonance imaging were performed to determine structural differences in fibrosis.

Results

The left atrial epicardium was associated with a significant increase in DF in persistent AF (6.5 ± 0.2 vs. 7.4 ± 0.5 Hz, P = 0.03). The organization index (OI) significantly decreased during persistent AF in both the left atria (0.3 ± 0.03 vs. 0.2 ± 0.03, P = 0.01) and right atria (0.33 ± 0.04 vs. 0.23 ± 0.02, P = 0.02). MRI analysis demonstrated increased ECV values in persistent AF (0.19 vs 0.34, paroxysmal vs persistent, P = 0.05). Tissue sections from the atria showed increase in fibrosis in pigs with persistent AF compared to paroxysmal AF. Staining demonstrated decreased myocardial fiber alignment and loss of anisotropy in persistent AF tissue.

Conclusions

Changes in tissue organization and fibrosis are observed in the porcine model of persistent AF. Alterations in frequency activity and organization index can be captured with high resolution using flexible electrode arrays.
Anion efflux mediates transduction in hair cells of zebrafish lateral line
Authors: Lunsford Elias T. , Bobkov Yuriy V. , Ray Brandon C. , Liao James C. , Strother James A.
Published: July 2022

Hair cells are the principal sensory receptors of the vertebrate auditory system, and transduce sounds with mechanically-gated ion channels that permit cations to flow from the surrounding endolymph into the cells. The lateral line of zebrafish has served as a key model system for understanding hair cell physiology and development, and it has often been speculated that these hair cells employ a similar transduction mechanism. In this study, we demonstrate that the hair cells are exposed to an unregulated external environment with cation concentrations that are too low to support transduction. Instead, our results indicate that hair cell excitation is mediated by a fundamentally different mechanism involving the outward flow of anions.
BepiPred-3.0: Improved B-cell epitope prediction using protein language models
Authors: Clifford Joakim , Høie Magnus Haraldson , Nielsen Morten , Deleuran Sebastian , Peters Bjoern , Marcatili Paolo
Published: July 2022

B-cell epitope prediction tools are of great medical and commercial interest due to their practical applications in vaccine development. The introduction of protein language models (LM) trained on unprecedented large datasets of protein sequences and structures, tap into a powerful numeric representation that can be exploited to accurately predict local and global protein structural features from amino acid sequences only. In this paper, we present BepiPred 3.0, a sequence-based epitope prediction tool that, by exploiting LM embeddings, greatly improves the prediction accuracy for both linear and conformational epitope prediction on several independent test sets. Furthermore, by carefully selecting additional input variables and epitope residue annotation strategy, performance can be further improved, thus achieving extraordinary results. Our tool can predict epitopes across hundreds of sequences in mere minutes. It is freely available as a web server with a user-friendly interface to navigate the results, as well as a standalone downloadable package.
Delivery of loaded MR1 monomer results in efficient ligand exchange to host MR1 and subsequent MR1T cell activation
Authors: Kulicke Corinna A. , Swarbrick Gwendolyn M. , Ladd Nicole A. , Cansler Meghan , Null Megan , Worley Aneta , Lemon Chance , Ahmed Tania , Bennett Joshua , Lust Taylor N. , Heisler Chelsea M. , Huber Megan E. , Krawic Jason R. , Ankley Laurisa M. , McBride Savannah K. , Tafesse Fikadu G. , Olive Andrew J. , Hildebrand William H. , Lewinsohn Deborah A. , Adams Erin J. , Lewinsohn David M. , Harriff Melanie J.
Published: July 2022

MR1-restricted T cells have been implicated in microbial infections, sterile inflammation, wound healing and cancer. Similar to other antigen presentation molecules, evidence supports multiple, complementary MR1 antigen presentation pathways. To investigate ligand exchange pathways for MR1, we used MR1 monomers and tetramers loaded with 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) to deliver the antigen. Using MR1-deficient cells reconstituted with wild-type MR1 or MR1 molecules that cannot bind 5-OP-RU, we show that presentation of monomer-delivered 5-OP-RU is dependent on cellular MR1 and requires the transfer of ligand from the soluble molecule onto MR1 expressed by the antigen presenting cell. This mode of antigen delivery strengthens the evidence for post-ER ligand exchange pathways for MR1, which could represent an important avenue by which MR1 acquires antigens derived from endocytosed pathogens.
Wide-pulse electrical stimulation of the quadriceps femoris allows greater maximal evocable torque than conventional stimulation
Authors: Espeit Loïc , Lapole Thomas , Millet Guillaume Y , Rozand Vianney , Maffiuletti Nicola A
Published: July 2022

Purpose

The effectiveness of a neuromuscular electrical stimulation (NMES) program has been shown to be proportional to the maximal evocable torque (MET), which is potentially influenced by pulse characteristics such as duration and frequency. The aim of this study was to compare MET between conventional and wide-pulse NMES at two different frequencies.

Methods

MET - expressed as a percentage of maximal voluntary contraction (MVC) torque - and maximal tolerable current intensity (MTCI) were quantified on 71 healthy subjects. The right quadriceps femoris muscle was stimulated with three NMES protocols using different pulse duration/frequency combinations: conventional NMES (0.2 ms/50 Hz; CONV), wide-pulse NMES at 50 Hz (1 ms/50 Hz; WP50) and wide-pulse NMES at 100 Hz (1 ms/100 Hz; WP100). The proportion of subjects reaching the maximal stimulator output (100 mA; MSO) before attaining MTCI was also quantified for each NMES protocol.

Results

The proportion of subjects attaining MSO was higher for CONV than WP50 and WP100 (30%, 3% and 4%, respectively; p < 0.001). In subjects who did not attain MSO in any protocol, MET was higher for both WP50 and WP100 than for CONV (45% vs 43% vs 39% MVC; p < 0.001). MTCI was lower for both WP50 and WP100 than for CONV (45, 42, and 77 mA, respectively; p < 0.001) and was also lower for WP100 than for WP50.

Conclusion

When compared to conventional NMES, wide-pulse protocols resulted in greater MET, lower MTCI and consequently in a lower proportion of subjects attaining MSO. Overall, this may lead to better NMES training/rehabilitation effectiveness and less practical issues associated with MSO limitations.
Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies
Authors: Venkatesan Vigneshwaran , Christopher Abisha Crystal , Babu Prathibha , Azhagiri Manoj Kumar K , Walavalkar Kaivalya , Saravanan Bharath , Srinivasan Saranya , Karuppusamy Karthik V , Jacob Annlin , Rangaraj Sumathi , Bagchi Abhirup , Pai Aswin Anand , Nakamura Yukio , Balasubramanian Poonkuzhali , Pai Rekha , Marepally Srujan Kumar , Mohankumar Kumarasamypet Murugesan , Velayudhan Shaji R , Notani Dimple , Srivastava Alok , Thangavel Saravanabhavan
Published: July 2022

Reactivation of fetal hemoglobin (HbF) is the commonly adapted strategy to ameliorate β-hemoglobinopathies. However, the continued production of defective adult hemoglobin (HbA) limits the HbF tetramer production affecting the therapeutic benefits. Here, we tested various deletional hereditary persistence of fetal hemoglobin (HPFH) mutations and identified a 11 kb sequence, encompassing Putative Repressor Region (PRR) to β-globin Exon-1 (βE1), as the core deletion that ablates HbA and exhibit superior production of HbF compared to HPFH or other well-established targets. The PRR-βE1 edited hematopoietic stem and progenitor cells (HSPCs) retained engraftment potential to repopulate for long-term hematopoiesis in immunocompromised mice generating HbF+ cells in vivo. Importantly, the editing induces therapeutically relevant levels of HbF to reverse the phenotypes of both sickle cell disease and β-thalassemia major. These results indicate that the PRR-βE1 gene editing in patient HSPCs can potentially lead to superior therapeutic outcomes for β-hemoglobinopathies gene therapy.
Self-cyclisation as a general and efficient platform for peptide and protein macrocyclisation
Authors: Jia Xinying , Chin Yanni K.-Y. , Zhang Alan , Crawford Theo , Zhu Yifei , Fletcher Nicholas L. , Zhou Zihan , Hamilton Brett R. , Stroet Martin , Thurecht Kristofer J. , Mobli Mehdi
Published: July 2022

Macrocyclisation of proteins and peptides results in a remarkable increase in structural stability, making cyclic peptides and proteins of great interest in drug discovery—either directly as drug leads or as in the case of cyclised nanodiscs (cNDs), as tools for studies of trans-membrane receptors and membrane-active peptides. Various biological methods have been developed that are capable of yielding head-to-tail macrocyclised products. Such enzymatic methods require careful optimisation of cyclisation over polymerisation. Here, we describe the engineering of self-cyclising “autocyclase” proteins, where an intramolecular rearrangement can be triggered to yield a monomeric cyclic product in high yields. We characterise the self-cyclisation reaction mechanism and demonstrate how the unimolecular reaction path can circumvent existing challenges of enzymatic cyclisation. We use the method to produce several notable cyclic peptides and proteins, demonstrating how autocyclases offer a simple and scalable way to access a vast diversity of macrocyclic biomolecules.
Structure of the NuA4 acetyltransferase complex bound to the nucleosome
Authors: Qu Keke , Chen Kangjing , Wang Hao , Li Xueming , Chen Zhucheng
Published: July 2022

DNA in eukaryotes wraps around the histone octamer to form nucleosomes1, the fundamental unit of chromatin. The N-termini of histone H4 interact with nearby nucleosomes, and play an important role in the formation of high order chromatin structure and heterochromatin silencing2-4. NuA4 in yeast and its homolog Tip60 complex in mammalian cells are the key enzymes that catalyze H4 acetylation, which in turn regulate chromatin packaging, and function in transcription activation and DNA repair5-10. Here we report the cryo-EM structure of NuA4 from Saccharomyces cerevisiae bound to the nucleosome. NuA4 comprises two major modules: the catalytic histone acetyltransferase (HAT) module and the transcription activator-binding TRA module. The nucleosome is mainly bound by the HAT module, and positioned close to a polybasic surface of the TRA module, which is important for the optimal activity of NuA4. The nucleosomal linker DNA carrying the upstream activation sequence is oriented towards the conserved, transcription-activator-binding surface of the Tra1 subunit, which suggests a potential mechanism of NuA4 to act as a transcription co-activator. The HAT module recognizes the disk face of the nucleosome through the H2A-H2B acidic patch and the nucleosomal DNA, projecting the catalytic pocket of Esa1 to the N-terminal tail of H4, supporting its function in selective acetylation of H4. Together, our findings illustrate how NuA4 is assembled, and provide mechanistic insights into nucleosome recognition and transcription coactivation by a histone acetyltransferase.
Genome-Wide Association Study in a Rat Model of Temperament Identifies Multiple Loci for Exploratory Locomotion and Anxiety-Like Traits
Authors: Chitre Apurva S. , Hebda-Bauer Elaine K. , Blandino Peter , Bimschleger Hannah , Nguyen Khai-Minh , Maras Pamela , Li Fei , Ozel A. Bilge , Polysskaya Oksana , Cheng Riyan , Flagel Shelly B. , Watson Stanley J. , Li Jun , Akil Huda , Palmer Abraham A
Published: July 2022

Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment (bred High Responders (bHR) vs. Low Responders (bLR)). To identify genes underlying the response to selection, we phenotyped and genotyped 558 rats from an F2cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait.

Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which thePik3c3gene is located. There were no significant loci for PavCA. We identified a missense variant in thePlekhf1gene on the chromosome 1:95 Mb QTL andFancfandGas2as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing thePkhd1l1andTrhrgenes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats.

The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders.
Noncovalent antibody catenation on a target surface drastically increases the antigen-binding avidity
Authors: Song Jinyeop , Jeong Bo-Seong , Kim Seong-Woo , Im Seong-Bin , Cho Wonki , Ahn Myung-Ju , Oh Byung-Ha
Published: July 2022

Immunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface where target antigen molecules are abundant, and that it could be an effective way to greatly enhance the antigen-binding avidity. A thermodynamic simulation shows that quite low homodimerization affinity of a catenator, e.g. dissociation constant of 100 μM, can enhance nanomolar antigen-binding avidity to a picomolar level, and that the fold enhancement sharply depends on the density of the antigen. In a proof-of-concept experiment where antigen molecules are immobilized on a biosensor tip, C-terminal fusion of a weakly homodimerizing protein to two different antibodies enhanced the antigen-binding avidity by at least 210 to 5,120 folds from the intrinsic binding avidity. Thus, the homodimerization-induced antibody catenation would be a simple, powerful and general approach to improve many antibody applications, including the detection of scarce biomarkers and targeted anticancer therapies.
Study on endogenous inhibitors against PD-L1: cAMP as a potential candidate
Authors: Huang Qiuyang , Zang Xiaoling , Zhang Zhiwei , Zhang Xin , Ali Mustafa R. K. , Lv Zhihua
Published: July 2022

The discovery of new anticancer drugs targeting the PD-1/PD-L1 pathway has been research hotspots. In this study, a combination of biological affinity ultrafiltration (BAU), UPLC-HRMS, molecular dynamic (MD) simulations and molecular docking methods were applied to search for endogenous active compounds that can inhibit the binding of PD-L1 and PD-1. We screened dozens of potential cancer related endogenous compounds. The results showed that cyclic adenosine monophosphate (cAMP) had a direct inhibition effect on the PD-1/PD-L1 binding with an in vitro IC50 value of about 2.7 µM determined by homogeneous time-resolved fluorescence (HTRF) assay. The binding mode analyses for the cAMP - dimeric/monomeric PD-L1 complex indicated that cAMP was likely to bind to the dimeric PD-L1, since the binding free energies of the cAMP - dimeric and monomeric PD-L1 complex were about 23.6 and 15.1 kcal/mol, respectively, from MD simulations. The direct binding assay using surface plasmon resonance (SPR) method showed that cAMP could also bind to monomeric PD-L1 fixed on the sensor chip surface with a KD value of about 1.72 mM. Our findings suggested that cAMP may directly inhibit the PD-1/PD-L1 interaction.
Interpreting the molecular mechanisms of disease variants in human transmembrane proteins
Authors: Tiemann Johanna Katarina Sofie , Zschach Henrike , Lindorff-Larsen Kresten , Stein Amelie
Published: July 2022

Next-generation sequencing of human genomes reveals millions of missense variants, some of which may lead to loss of protein function and ultimately disease. We here investigate missense variants in membrane proteins — key drivers in cell signaling and recognition. We find enrichment of pathogenic variants in the transmembrane region across 19,000 functionally classified variants in human membrane proteins. To accurately predict variant consequences, one fundamentally needs to understand the reasons for pathogenicity. A key mechanism underlying pathogenicity in missense variants of soluble proteins has been shown to be loss of stability. Membrane proteins though are widely understudied. We here interpret for the first time on a larger scale variant effects by performing structure-based estimations of changes in thermodynamic stability under the usage of a membrane-specific force-field and evolutionary conservation analyses of 15 transmembrane proteins. We find evidence for loss of stability being the cause of pathogenicity in more than half of the pathogenic variants, indicating that this is a driving factor also in membrane-protein-associated diseases. Our findings show how computational tools aid in gaining mechanistic insights into variant consequences for membrane proteins. To enable broader analyses of disease-related and population variants, we include variant mappings for the entire human proteome.

SIGNIFICANCE

Genome sequencing is revealing thousands of variants in each individual, some of which may increase disease risks. In soluble proteins, stability calculations have successfully been used to identify variants that are likely pathogenic due to loss of protein stability and subsequent degradation. This knowledge opens up potential treatment avenues. Membrane proteins form about 25% of the human proteome and are key to cellular function, however calculations for disease-associated variants have not systematically been tested on them. Here we present a new protocol for stability calculations on membrane proteins under the usage of a membrane specific force-field and its proof-of-principle application on 15 proteins with disease-associated variants. We integrate stability calculations with evolutionary sequence analysis, allowing us to separate variants where loss of stability is the most likely mechanism from those where other protein properties such as ligand binding are affected.
Soil chemistry and soil history significantly structure oomycete communities in Brassicaceae crop rotations
Authors: Blakney Andrew J.C. , Bainard Luke D. , St-Arnaud Marc , Hijri Mohamed
Published: July 2022

Oomycetes are critically important soil microbial communities, especially for agriculture where they are responsible for major declines in yields. Unfortunately, oomycetes are vastly understudied compared to bacteria and fungi. As such, our understanding of how oomycete biodiversity and community structure varies through time in the soil remains poor. Soil history established by previous crops is one factor known to structure other soil microbes, but has not been investigated for its influence on oomycetes. In this study, we established three different soil histories in field trials; the following year these plots were planted with five different Brassicaceae crops. We hypothesized that the previously established soil histories would structure different oomycete communities, regardless of their current Brassicaceae crop host, in both the roots and rhizosphere. We used a nested-ITS amplicon strategy incorporated with MiSeq metabarcoding, where the sequencing data was used to infer amplicon sequence variants (ASVs) of the oomycetes present in each sample. This allowed us to determine the impact of different soil histories on the structure and biodiversity of the oomycete root and rhizosphere communities from the five different Brassicaceae crops. We found that each soil history structured distinct oomycete rhizosphere communities, regardless of different Brassicaceae crop hosts, while soil chemistry structured the oomycete communities more during a dry year. Interestingly, soil history appeared specific to oomycetes, but was less influential for bacterial communities previously identified from the same samples. These results advance our understanding of how different agricultural practices and inputs can alter edaphic factors to impact future oomycete communities. Examining how different soil histories endure and impact oomycete biodiversity will help clarify how these important communities may be assembled in agricultural soils.

Highlights

Crop rotations model how soil history impacts subsequent microbial communities

Brassicaceae oilseed crops might mitigate pathogenic oomycetes

Soil history significantly structures oomycete communities

Oomycetes are significantly affected by soil chemistry

Brassicaceae crop hosts weakly influence oomycete communities
RGG motif-containing Scd6/LSM14A proteins regulate the translation of specific mRNAs in response to hydroxyurea-induced genotoxic stress
Authors: Mohanan Gayatri , Roy Raju , Malka-Mahieu Hélène , Lamba Swati , Fabbri Lucilla , Biswas Anusmita , Martineau Sylvain , Labbé Céline M. , Vagner Stéphan , Rajyaguru Purusharth I
Published: July 2022

Genotoxic stress response (GSR) mediated by mRNA translation and decay regulation remains poorly explored. Here, we identify a unique role of yeast RGG-motif protein Scd6 and its human ortholog LSM14A in mRNA translation control upon hydroxyurea (HU)-mediated GSR. Scd6/LSM14A, but not all tested RGG-containing proteins, localize to HU-induced cytoplasmic puncta in an RGG-dependent manner. The absence of Scd6 increases HU tolerance but sensitizes the cells to HU upon overexpression of SRS2, a known dampener of the DNA- damage response. Scd6 bindsSRS2mRNA to repress its translation in cytoplasmic granules upon HU stress. Scd6-SRS2 interaction is modulated by arginine methylation (AM) and the LSm-domain, which acts as acis-regulator of Scd6 AM. Polysome-profiling experiments indicate that LSM14A regulates the translation of NHEJ factor mRNAs such asLIG4(DNL4 homolog) andRTEL1(SRS2 functional homolog), and the NHEJ activity in response to HU. Overall, this report unveils the role of AM and Scd6/LSM14A in the GSR by determining the translation status of specific mRNAs.
Protein Structure Prediction with Expectation Reflection
Authors: Cresswell-Clay Evan , Hoang Danh-Tai , McKenna Joe , Yang Chris , Zhang Eric , Periwal Vipul
Published: July 2022

Sequence covariation in multiple sequence alignments of homologous proteins has been used extensively to obtain insights into protein structure. However, global statistical inference is required in order to ascertain direct relationships between amino acid positions in these sequences that are not simply secondary correlations induced by interactions with a third residue. Methods for statistical inference of such covariation have been developed to exploit the growing availability of sequence data. These hints about the folded protein structure provide critical a priori information for more detailed 3D predictions by neural networks. We present a novel method for protein structure inference using an iterative parameter-free model estimator which uses the formalism of statistical physics. With no tunable learning rate, our method scales to large system sizes while providing improved performance in the regime of small sample sizes. We apply this method to 40974 PDB structures and compare its performance to that of other methods. Our method outperforms existing methods for 76% of analysed proteins.
Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells
Authors: Romero-Moreno Ricardo , Czowski Brandon , Harris Lindsey , Kuehn Jessamine F. , White Katharine A.
Published: July 2022

Intracellular pH (pHi) dynamics regulate normal cell function, and dysregulated pHi dynamics is an emerging hallmark of cancer (constitutively increased pHi) and neurodegeneration (constitutively decreased pHi). However, the molecular mechanisms by which pHi dynamics regulate cell biology are poorly understood. Here, we discovered that altering pHi in normal human breast epithelial cells triggers global transcriptional changes. We identified 176 genes differentially regulated by pHi, with pHi-dependent genes clustering in signaling and glycolytic pathways. Using various normal epithelial cell models, we showed pH-dependent Notch1 expression, with increased protein abundance at high pHi. This resulted in pH-dependent downstream signaling, with increased Notch1 signaling at high pHi. We also found that high pHi increased the expression of glycolytic enzymes and regulators of pyruvate fate, including lactate dehydrogenase and pyruvate dehydrogenase kinase. These transcriptional changes were sufficient to alter lactate production, with high pHi shifting these normal epithelial cells toward a glycolytic metabolism and increasing lactate production. Thus, pHi dynamics transcriptionally regulate signaling and metabolic pathways in normal epithelial cells. Our data reveal new molecular regulators of pHi-dependent biology and a role for increased pHi in driving the acquisition of cancer-associated signaling and metabolic changes in normal human epithelial cells.
Allosteric inhibition of Staphylococcus aureus MenD by 1,4-dihydroxy naphthoic acid: A feedback inhibition mechanism of the menaquinone biosynthesis pathway
Authors: Stanborough Tamsyn , Ho Ngoc Anh Thu , Bulloch Esther M. M. , Bashiri Ghader , Dawes Stephanie S. , Akazong Etheline W. , Titterington James , Allison Timothy M. , Jiao Wanting , Johnston Jodie M.
Published: July 2022

Menaquinones (MKs) are electron carriers in bacterial respiratory chains. In Staphylococcus aureus (Sau), MKs are essential for aerobic and anaerobic respiration. As MKs are redox-active, their biosynthesis likely requires tight regulation to prevent disruption of cellular redox balance. We recently found that the Mycobacterium tuberculosis MenD, the first committed enzyme of the MK biosynthesis pathway, is allosterically inhibited by the downstream metabolite 1,4-dihydroxy-2-naphthoic acid (DHNA). To understand if this is a conserved mechanism in phylogenetically distant genera that also utilize MK, we investigated whether the Sau-MenD is allosterically inhibited by DHNA. Our results show that DHNA binds to and inhibits SEPHCHC synthase activity of Sau-MenD enzymes. We identified residues in the DHNA binding pocket that are important for catalysis (Arg98, Lys283, Lys309) and inhibition (Arg98, Lys283). Furthermore, we show that exogenous DHNA inhibits growth of Sau, an effect that can be rescued by supplementing the growth media with MK-4. Our results demonstrate that despite a lack of strict conservation of the DHNA-binding pocket between Mtb-MenD and Sau-MenD, feedback inhibition by DHNA is a conserved mechanism in Sau-MenD and hence the Sau MK biosynthesis pathway. These findings may have implications for the development of anti-staphylococcal agents targeting MK biosynthesis
Genomic surveillance of SARS-CoV-2 during the first year of the pandemic in the Bronx enabled clinical and epidemiological inference
Authors: Fels J. Maximilian , Khan Saad , Forster Ryan , Skalina Karin A. , Sirichand Surksha , Fox Amy S. , Bergman Aviv , Mitchell William B. , Wolgast Lucia R. , Szymczak Wendy , Bortz Robert H. , Dieterle M. Eugenia , Florez Catalina , Haslwanter Denise , Jangra Rohit K. , Laudermilch Ethan , Wirchnianski Ariel S. , Barnhill Jason , Goldman David L. , Khine Hnin , Goldstein D. Yitzchak , Daily Johanna P. , Chandran Kartik , Kelly Libusha
Published: July 2022

The Bronx was an early epicenter of the COVID-19 pandemic in the United States. We conducted temporal genomic surveillance of 104 SARS-CoV-2 genomes across the Bronx from March to October 2020. Although the local structure of SARS-CoV-2 lineages mirrored those of New York City and New York State, temporal sampling revealed a dynamic and changing landscape of SARS-CoV-2 genomic diversity. Mapping the trajectories of mutations, we found that although some became “endemic” to the Bronx, other, novel mutations rose in prevalence in the late summer/early fall. Geographically resolved genomes enabled us to distinguish between cases of reinfection and persistent infection in two pediatric patients. We propose that limited, targeted, temporal genomic surveillance has clinical and epidemiological utility in managing the ongoing COVID pandemic.
Public relations ethics in the 21st century: a state-of-the-field review
Authors: Jackson Michaela , Chorazy Ella , Sison Marianne D. , Wise Deborah
Published: July 2022

Purpose

To conduct a systematic review of public relations ethics (PRE) research and scholarship in the 21st century and suggest future research directions. The study is prompted by macro-level phenomena that have impacted societies since the beginning of the 21st century—notably globalisation 4.0 and the fourth industrial revolution.

Design/methodology/approach

A systematic review was used to search academic literature. Articles discussing PRE in nine leading English-language public relations and business ethics journals between 2000 and 2019 were reviewed. A code-frame facilitated data extraction and subsequent quantitative analysis; qualitative analysis identified key themes.

Findings

The review identified 288 articles, with discussions involving PRE increasing over time. Most works approached the topic generally, rather than from a specific sub-disciplinary perspective, and drew from professional settings. Works were dominated by authors from North American institutions and North American samples. Research became increasingly empirical and intra-disciplinary and discussion about ethics was broadly categorised as part of public relations practice or from the perspective of the “academy”. Overall, the field can be described as of notable size, maturing, yet unbalanced in some regards.

Originality/value

The review helps to identify whether PRE research reflects major changes in the 21st century and augments the sparse recent reviews of PRE research.
A bibliometric analysis and future research opportunities in Multinational Business Review
Authors: Jain Rajesh , Oh Chang Hoon , Shapiro Daniel
Published: July 2022

Purpose

This paper aims to evaluate the past contributions of Multinational Business Review (MBR), identify research gaps and opportunities and provide a research agenda that addresses several sustainability-related and other contemporary challenges.

Design/methodology/approach

This study analyzes 400 papers published between 2003 and 2021 to map the MBR’s intellectual and conceptual structure using advanced bibliometric techniques.

Findings

The bibliographic coupling technique identifies core clusters in MBR papers, and subsequent content analysis of these clusters reveals the following five research fronts: internalization theory and the future of international business (IB) research; internationalization and firm performance; regionalization versus globalization debate; internationalization by emerging market firms; and global dynamic capabilities and firm internationalization.

Originality/value

To the best of the authors’ knowledge, this is the first comprehensive analysis of past contributions of MBR to research on IB and suggests a way for MBR to play a seminal role in addressing contemporary challenges in IB.
Examining sources of post‐acute care inequities with layered target matching
Authors: Niknam Bijan A. , Zubizarreta Jose R.
Published: July 2022

Objective

To examine factors associated with racial inequities in discharge location, skilled nursing facility (SNF) utilization, and readmissions.

Data Sources

A 20% sample of longitudinal Medicare claims from 2016 to 2018.

Study Design

We present layered target matching, a method for studying sources of inequities. Layered target matching examines a fixed target population profile representing any race, ethnicity, or vulnerable population, sequentially adjusting for sets of characteristics that may contribute to inequities these groups endure. We use the method to study racial inequities in post‐acute care use and readmissions.

Data Collection/Extraction Methods

We studied Black and non‐Hispanic White fee‐for‐service Medicare beneficiaries aged 66+ admitted to short‐term acute‐care hospitals for qualifying diagnoses or procedures between January 1, 2016 and November 30, 2018.

Principal Findings

Admitted Black patients tended to be younger, had significantly higher rates of risk factors such as diabetes, stroke, or renal disease, and were much more frequently admitted to large or academic hospitals. Relative to demographically similar White patients, Black patients were significantly more likely to be discharged to SNFs (21.8% vs. 19.3%, difference = 2.5%, p < 0.0001) and to receive any SNF care within 30 days of discharge (25.3% vs. 22.4%, difference = 2.9%, p < 0.0001). Black patients were also significantly more likely to experience 30‐day readmission (18.7% vs. 14.5%, difference = 4.2%, p < 0.0001). Differences in reasons for hospitalization and risk factors explained most of the differences in discharge location, post‐acute care use, and readmission rates, while additional adjustment for differences in hospital characteristics and complications made little difference for any of the measures studied.

Conclusions

We found significant Black–White differences in discharge to SNFs, SNF utilization, and readmission rates. Using layered target matching, we found that differences in risk factors and reasons for hospitalization explained most of these differences, while differences in hospitals did not materially impact the differences.
SNAP work requirements increase mental health care use
Authors: Allen Lindsay , Henry Diana , Atwood Alicia
Published: July 2022

Objective

We measured the impact of Supplemental Nutrition Assistance Program (SNAP) work requirements on mental health care use.

Data Sources and Study Setting

We used 2015–2018 West Virginia Medicaid and SNAP data.

Study Design

Nine counties were exposed to SNAP work requirements. Using an event study framework, we assessed how this changed the probability and number of visits for depression and anxiety in the treatment versus the control group.

Data Collection/Extraction Methods

The sample included individuals aged 18–49, enrolled in both SNAP and Medicaid at the start of the study. Dually eligible individuals were excluded.

Principal Findings

At baseline, the probability of having a mood disorder visit was 6.1% among women and 5.3% among men, rising by 0.9 percentage points (SE 0.4, relative change +14.1%) among women and 0.7 percentage points (SE 0.3, relative change +13.0%) among men after exposure to work requirements. The probability of having an anxiety visit rose by 1.0 (SE 0.4) percentage points among women, a 17.8% relative increase over the baseline of 5.8%. Among men, the likelihood of having an anxiety visit increased by 1.0 percentage points (SE 0.5), a relative change of 24.3% over a baseline probability of 5.0%, though this effect occurred much more gradually compared to women.

Conclusions

Exposure to SNAP work requirements was associated with increases in health care use for mood disorders and anxiety among enrollees. The policy's effect differed between men and women.
Determining the effects of tencha‐ro drying on key volatile compounds in tencha (Camellia sinensis) through gas chromatography–mass spectrometry
Authors: Xiao Zhipeng , Zhang Wenjun , Guo Wenli , Zhang Lan , Huang Ai , Tao Meng , Li Meiqin , Su Rui , Liu Zhengquan
Published: July 2022

Drying is the key process through which the aroma of tencha forms. However, the effects of drying method on volatiles are unknown. We compared tencha‐ro drying with regular drying. Volatiles in tencha infusions were extracted using headspace solid‐phase microextraction and solvent‐assisted flavor evaporation combined with gas chromatography–mass spectrometry. Partial least squares (PLS), odor activity value (OAV), and heat map analyses were performed to identify the optimal drying method for creating a seaweed‐like aroma. Changes in the key volatile compounds of the samples were investigated. The tencha infusions contained 125 volatiles with nine chemical structures. According to the sensory evaluation, tencha‐ro drying was the optimal method for producing high‐quality tencha with an intense and consistent seaweed‐like aroma. The PLS model accurately distinguished among the types of tencha. By combining OAVs with screening through multivariate statistical analysis, six volatile compounds were revealed to contribute substantially to tencha's seaweed‐like aroma: 2‐ethyl‐3,5‐dimethylpyrazine, 2‐ethyl‐6‐methylpyrazine, 2‐ethyl‐5‐methylpyrazine, dimethyl sulfide, β‐ionone, and 2‐formyl‐1‐methylpyrrole. The findings provide a theoretical basis and technical guidance for the processing of high‐quality tencha with a strong seaweed‐like aroma.

Practical Application

This study demonstrated that tencha‐ro drying contributes to the formation of a seaweed‐like aroma in tencha and provides theoretical guidance for tea factories to use the appropriate drying methods for high‐quality tencha.
Self‐control impacts symptoms defining Internet gaming disorder through dorsal anterior cingulate–ventral striatal pathway
Authors: Gong Liangyu , Zhou Hui , Su Conghui , Geng Fengji , Xi Wan , Teng Binyu , Yuan Kai , Zhao Min , Hu Yuzheng
Published: July 2022

Self‐control is important for long‐term success and could be a protective factor against maladaptive behaviours such as excessive gaming activity or Internet gaming disorder (IGD). However, the neurobiological basis of self‐control and its relationship to IGD remain elusive. Using resting‐state fMRI data from 89 participants aged from 18 to 26, we found that self‐control and the number of IGD symptoms (IGD‐S) were positively and negatively correlated with functional connectivity between right ventral striatum (rVS) and dorsal anterior cingulate cortex (dACC), respectively. A mediation analysis indicated that self‐control influenced IGD‐S partially through the rVS‐dACC connectivity. In addition, step‐wise regression analyses revealed that the rVS connectivity in a reward‐anticipation limbic pathway contributed to IGD‐S but not self‐control, independent of the dACC pathway. These results suggest that the cingulate–ventral striatal functional connectivity may serve as an important neurobiological underpinning of self‐control to regulate maladaptive behaviours such as these manifesting IGD through striatal circuitry balance.
Percreta score to differentiate between placenta accreta and placenta percreta with ultrasound and MR imaging
Authors: Pain Flore‐Anne , Dohan Anthony , Grange Gilles , Marcellin Louis , Uzan‐Augui Joëlle , Goffinet François , Soyer Philippe , Tsatsaris Vassilis
Published: July 2022

Introduction

The objective of this study was to assess the performance of ultrasound and magnetic resonance imaging (MRI) features in helping to classify the type of placenta accreta spectrum (PAS; accreta/increta vs percreta), alone or combined in a predictive score.

Material and Methods

We conducted a retrospective study in 82 pregnant women with PAS who underwent ultrasound and MRI examination of the pelvis before delivery (from an initial cohort of 185 women with PAS). We estimated the sensitivity, specificity and accuracy of MRI and ultrasound in the diagnosis of the type of PAS. We analyzed cesarean and imaging features using univariable logistic regression analysis. We constructed a nomogram to predict the risk of placenta percreta and validated it with bootstrap resampling, then used receiver operating characteristic curves to assess the performance of the model in distinguishing between placenta percreta and placenta accreta/increta.

Results

Among the 82 patients, 29 (35%) had placenta accreta/increta and 53 (65%) had placenta percreta. The best features to discriminate between placenta accreta/increta and placenta percreta with ultrasound were increased vascularization at the uterine serosa–bladder wall interface (odds ratio [OR] 7.93; 95% confidence interval [CI] 2.78–24.99; p < 0.01) and the number of lacunae without a hyperechogenic halo (OR 1.36; 95% CI 1.14–1.67; p = 0.012). Concerning MRI markers, heterogeneous placenta (OR 12.89; 95% CI 3.05–89.16; p = 0.002), dark intraplacental bands (OR 12.89; 95% CI 3.05–89.16; p = 0.002) and bladder wall interruption (OR 15.89; 95% CI 4.78–73.33; p < 0.001) had a higher OR in discriminating placenta accreta/increta from placenta percreta. The nomogram yielded areas under the curve of 0.841 (95% CI 0.754–0.927) and 0.856 (95% CI 0.767–0.945), after bootstrap resampling, for the accurate prediction of placenta percreta.

Conclusions

The nomogram we developed to predict the risk of placenta percreta among patients with PAS had good discriminative capabilities. This performance and its impact on maternal morbidity should be confirmed by future prospective studies.
miR‐21, miR‐125b, and let‐7b contribute to the involution of atretic follicles and corpus lutea in Tibetan sheep ovaries
Authors: Zhang Taojie , Huo Shengdong , Wei Suocheng , Cui Sheng
Published: July 2022

Follicular granulosa cells (FGCs) are crucial for ovarian follicle functions, and miRNAs are differentially expressed at various stages of follicular developments. In this study, we confirmed that miR‐21, miR‐125b, and let‐7b were located in FGCs/luteal cells by in situ hybridization experiments. Moreover, miR‐21 and miR‐125b expressions were upregulated in late corpus lutea (CL) and atretic follicles (AF); let‐7b expression was increased in early AF. After transfected with inhibitor or mimic of miRNAs in FGCs, we found that FGCs apoptosis was decreased in the miR‐21‐mi group but increased in the miR‐125b‐mi group using flow cytometry. mRNA and protein expression levels were determined for apoptosis‐related factors (e.g., Bcl‐2 and Bax), the potential target genes of miRNAs (e.g., SMAD7, SP1, and STAT3), hormone receptors (e.g., FSHR and LHR), and genes related to hormone secretion (e.g., CYP19, CYP11, and 3βHSD). The protein levels of SMAD7 were decreased in the miR‐21‐mi group but opposite to SP1 and FSHR. In the let‐7b‐mi group, Bcl‐2, SMAD7, and FSHR were suppressed but not Bax, CYP11, and 3βHSD. However, hormone secretion was not changed in the supernatant of transfected FGCs. This study provides information about ovarian miRNAs to improve the fertility in Tibetan sheep.
Effects of intergroup contact on explicit and implicit outgroup attitudes: A longitudinal field study with majority and minority group members
Authors: Vezzali Loris , Lolliot Simon , Trifiletti Elena , Cocco Veronica Margherita , Rae James Richard , Capozza Dora , Hewstone Miles
Published: July 2022

A longitudinal field study tested the long‐term effects (three years) of intergroup contact on both explicit and implicit outgroup attitudes. Participants were majority (Italian) and minority (immigrant) high‐school students, who were tested at four waves from the beginning of their first year in high‐school to the end of the third school year. Results revealed, first, a longitudinal association of quantity (but not quality) of contact with lower intergroup anxiety and more positive explicit attitudes, as well as bidirectional effects over time between explicit attitudes and intergroup anxiety, on the one hand, and quantity and quality of contact, on the other. Second, reduced intergroup anxiety mediated the association between quantity of contact and improved explicit attitudes over time. Third, the product of quantity and quality of contact longitudinally predicted more positive implicit outgroup attitudes over school years. We discuss the theoretical and practical implications of findings.