bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antagonistic pleiotropy plays an important role in governing the evolution and genetic diversity of SARS-CoV-2
Authors: Lee Ding-Chin , Tai Jui-Hung , Lin Hsin-Fu , Chao Tai-Ling , Ruan Yongsen , Cheng Ya-Wen , Chou Yu-Chi , Lin You-Yu , Chang Sui-Yuan , Chen Pei-Jer , Yeh Shiou-Hwei , Wang Hurng-Yi 
Published: February 2023

AbstractAnalyses of the genomic diversity of SARS-CoV-2 found that some sites across the genome appear to have mutated independently multiple times with frequency significantly higher than four-fold sites, which can be either due to mutational bias, i.e., elevated mutation rate in some sites of the genome, or selection of the variants due to antagonistic pleiotropy, a condition where mutations increase some components of fitness at a cost to others. To examine how different forces shaped evolution of SARS-CoV-2 in 2020–2021, we analyzed a large set of genome sequences (~ 2 million). Here we show that while evolution of SARS-CoV-2 during the pandemic was largely mutation-driven, a group of nonsynonymous changes is probably maintained by antagonistic pleiotropy. To test this hypothesis, we studied the function of one such mutation, spike M1237I. Spike I1237 increases viral assembly and secretion, but decreases efficiency of transmissionin vitro. Therefore, while the frequency of spike M1237I may increase within hosts, viruses carrying this mutation would be outcompeted at the population level. We also discuss how the antagonistic pleiotropy might facilitate positive epistasis to promote virus adaptation and reconcile discordant estimates of SARS-CoV-2 transmission bottleneck sizes in previous studies.
The genomic landscape of swine influenza A viruses in Southeast Asia
Authors: Zeller Michael A , Ma Jordan , Wong Foong Ying , Tum Sothrya , Hidano Arata , Holt Hannah , Chhay Ty , San Sorn , Koeut Dina , Seng Bunnary , Chao Sovanncheypo , Ng Giselle GK , Yan Zhuang , Chou Monidarin , Rudge James W , Smith Gavin JD , Su Yvonne CF 
Published: February 2023

AbstractSwine are a primary source for the emergence of pandemic influenza A viruses. The intensification of swine production, along with global trade, has amplified the transmission and zoonotic risk of swine influenza virus (swIAV). Effective surveillance is essential to uncover emerging virus strains, however gaps remain in our understanding of the swIAV genomic landscape in Southeast Asia. By collecting more than 4,000 nasal swabs and 4,000 sera from pigs in Cambodia, we unmasked the co-circulation of multiple lineages of genetically diverse swIAV of pandemic concern. Genomic analyses revealed a novel European avian-like H1N2 swine reassortant variant with North American triple reassortant internal genes, that emerged approximately seven years before its first detection in pigs in 2021. Using phylogeographic reconstruction, we identified south central China as the dominant source of swine viruses disseminated to other regions in China and Southeast Asia. We also identified nine distinct swIAV lineages in Cambodia, which diverged from their closest ancestors between two to 15 years ago, indicating significant undetected diversity in the region, including reverse zoonoses of human H1N1/2009 pandemic and H3N2 viruses. A similar period of cryptic circulation of swIAVs occurred in the decades before the H1N1/2009 pandemic. The hidden diversity of swIAV observed here further emphasizes the complex underlying evolutionary processes present in this region, reinforcing the importance of genomic surveillance at the human-swine interface for early warning of disease emergence to avoid future pandemics.
Improving cell-free expression of membrane proteins by tuning ribosome co-translational membrane association and nascent chain aggregation
Authors: Steinküher Jan , Peruzzi Justin A. , Krüger Antje , Jacobs Miranda L. , Jewett Michael C. , Kamat Neha P. 
Published: February 2023

AbstractCell-free gene expression (CFE) systems are powerful tools for transcribing and translating genes outside of a living cell. Given their diverse roles in nature, synthesis of membrane proteins is of particular interest, but their yield in CFE is substantially lower than for soluble protein. In this paper, we study factors that affect the cell-free synthesis of membrane proteins and develop a quantitative kinetic model of their production. We identify that stalling of membrane protein translation on the ribosome is a strong predictor of membrane protein synthesis and creates a negative feedback loop in which stalled peptide sequences quench ribosome activity through aggregation between the ribosome nascent chains. Synthesis can be improved by the addition of lipid membranes which incorporate protein nascent chains and, therefore, kinetically competes with aggregation. Using both quantitative modeling and experiment, we show that the balance between peptide-membrane association and peptide aggregation rates determines the total yield of synthesized membrane protein. We then demonstrate that this balance can be shifted by altering membrane composition or the protein N-terminal domain sequence. Based on these findings, we define a membrane protein expression score that can be used to rationalize the engineering of N-terminal domain sequences both of a native and computationally designed membrane proteins produced through CFE.
Sema7A and Sema4D Heterodimerization is Essential for Membrane Targeting and Neocortical Wiring
Authors: Bessa Paraskevi , Newman Andrew G. , Yan Kuo , Schaub Theres , Dannenberg Rike , Lajkó Denis , Eilenberger Julia , Brunet Theresa , Textoris-Taube Kathrin , Kemmler Emanuel , Banerjee Priyanka , Ravindran Ethiraj , Mülleder Michael , Preissner Robert , Grosschedl Rudolf , Rosário Marta , Tarabykin Victor 
Published: February 2023

SUMMARYDisruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving intellectual disability, speech delay, epilepsy and craniofacial defects. We show that Satb2 controls neuronal migration and axonal outgrowth by inducing the expression of the GPI-anchored protein, Sema7A. We find that heterodimerization with Sema4D increases targeting of Sema4D to the membrane and is required for Sema7A function. Finally, we report that membrane localization and pos- translational modification of the Sema7A-Sema4D complex is disrupted by a novel de novo mutation in Sema4D (Q497P) that is associated with epilepsy in humans.GRAPHICAL ABSTRACTHIGHLIGHTSSema7A is a direct Satb2 target that drives neuronal migration and axon outgrowthSema7A exerts its effect by heterodimerizing with Sema4D at neurites and growth conesSema7A increases cell surface localization of Sema4DDe novohuman Sema4D-Q497P mutation causes epilepsy, inhibits post-translational processing & surface localizationeTOCSema7A is a direct target of the transcription factor Satb2. Sema7A promotes normal migration and axon outgrowth in cortical neurons by modulating reverse signaling via Sema4D. These processes are dependent on Sema7A-Sema4D heterodimerization and membrane localization; insufficient transcription of Sema7A or incomplete glycosylation of Sema4D inhibit this progression.
The yeast RNA methylation complex consists of conserved yet reconfigured components with m6A-dependent and independent roles
Authors: Ensinck Imke , Maman Alexander , Albihlal Waleed S. , Lassandro Michelangelo , Salzano Giulia , Sideri Theodora , Howell Steven , Calvani Enrica , Patel Harshil , Bushkin G. Guy , Ralser Markus , Snijders Ambrosius P. , Skehel Mark , Casañal Ana , Schwartz Schraga , van Werven Folkert J. 
Published: February 2023

AbstractN6-methyladenosine (m6A), the most abundant mRNA modification, is deposited in mammals/insects/plants by m6A methyltransferase complexes (MTC) comprising a catalytic subunit and at least five additional proteins. The yeast MTC is critical for meiosis and was known to comprise three proteins, of which two were conserved. We uncover three novel MTC components (Kar4/Ygl036w-Vir1/Dyn2). All MTC subunits, except for Dyn2, are essential for m6A deposition and have corresponding mammalian MTC orthologs. Unlike the mammalian bipartite MTC, the yeast MTC is unipartite, yet multifunctional. The mRNA interacting module, comprising Ime4, Mum2, Vir1, and Kar4, exerts the MTC’s m6A-independent function, while Slz1 enables the MTC catalytic function in m6A deposition. Both functions are critical for meiotic progression. Kar4 also has a mechanistically separate role from the MTC during mating. The yeast MTC constituents play distinguishable m6A-dependent, MTC-dependent and MTC-independent functions, highlighting their complexity and paving the path towards dissecting multi-layered MTC functions in mammals.
Age-associated changes in endothelial transcriptome and chromatin landscape correlate with elevated risk of hemorrhage
Authors: Mohan Kshitij , Gasparoni Gilles , Salhab Abdulrahman , Orlich Michael M. , Geffers Robert , Hoffmann Steve , Adams Ralf H. , Walter Jörn , Nordheim Alfred 
Published: February 2023

AbstractIntracerebral hemorrhage (ICH), a devastating form of stroke, is a leading global cause of human death and disability. The major risk factors for ICH include increasing age, hypertension and cerebral amyloid angiopathy. Despite high mortality and morbidity associated with ICH, the mechanisms leading to blood-brain barrier (BBB) dysfunction with age and development of hemorrhagic stroke is poorly understood. In the vasculature of the central nervous system, endothelial cells (ECs) constitute the core component of the BBB and provide a physical barrier due to tight junctions, adherens junctions, and basement membrane layers. In this study, we show in brains of mice that incidents of intracerebral bleeding increase with advancing age. After isolation of an enriched population of cerebral ECs, we studied gene expression in ECs isolated from murine brains of increasing ages of 2, 6, 12, 18, and 24 months. The study reveals agedependent dysregulation of 1388 genes in the ECs, including many involved in the maintenance of BBB and vascular integrity. Since epigenetic mechanisms regulate gene expression, we also investigated age-dependent changes at the levels of CpG methylation and accessible chromatin in cerebral ECs. Our study reveals correlations between age-dependent changes in chromatin structure and gene expression. We find significant age-dependent downregulation of the apelin receptor (Aplnr) gene along with an age-dependent reduction in chromatin accessibility of the promoter of this gene.Aplnris known to play a crucial role in positive regulation of vasodilation and is implicated in vascular health. Interestingly, we also observe an age-dependent reduction in the protein expression levels of the apelin receptor in the brain, potentially implicating the apelin receptor to be critical for the increased risk of intracerebral hemorrhage with ageing.
Effect of the SARS-CoV-2 Delta-associated G15U mutation on the s2m element dimerization and its interactions with miR-1307-3p
Authors: Cunningham Caylee L. , Frye Caleb J. , Makowski Joseph A. , Kensinger Adam H. , Shine Morgan , Milback Ella J. , Lackey Patrick E. , Evanseck Jeffrey D. , Mihailescu Mihaela-Rita 
Published: February 2023

AbstractThe stem loop 2 motif (s2m), a highly conserved 41-nucleotide hairpin structure in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, serves as an attractive therapeutic target that may have important roles in the virus life cycle or interactions with the host. However, the conserved s2m in Delta SARS-CoV-2, a previously dominant variant characterized by high infectivity and disease severity, has received relatively less attention than that of the original SARS-CoV-2 virus. The focus of this work is to identify and define the s2m changes between Delta and SARS-CoV-2 and subsequent impact of those changes upon the s2m dimerization and interactions with the host microRNA miR-1307-3p. Bioinformatics analysis of the GISAID database targeting the s2m element reveals a greater than 99% correlation of a single nucleotide mutation at the 15thposition (G15U) in Delta SARS-CoV-2. Based on1H NMR assignments comparing the imino proton resonance region of s2m and the G15U at 19°C, we find that the U15-A29 base pair closes resulting in a stabilization of the upper stem without overall secondary structure deviation. Increased stability of the upper stem did not affect the chaperone activity of the viral N protein, as it was still able to convert the kissing dimers formed by s2m G15U into a stable duplex conformation, consistent with the s2m reference. However, we find that the s2m G15U mutation drastically reduces the binding affinity of the host miR-1307-3p. These findings demonstrate that the observed G15U mutation alters the secondary structure of s2m with subsequent impact on viral binding of host miR-1307-3p, with potential consequences on the immune response.
RNA polymerase sliding on DNA can couple the transcription of nearby bacterial operons
Authors: Tenenbaum Debora , Inlow Koe , Friedman Larry , Cai Anthony , Gelles Jeff , Kondev Jane 
Published: February 2023

ABSTRACTDNA transcription initiates after an RNA polymerase (RNAP) molecule binds to the promoter of a gene. In bacteria, the canonical picture is that RNAP comes from the cytoplasmic pool of freely diffusing RNAP molecules. Recent experiments suggest the possible existence of a separate pool of polymerases, competent for initiation, which freely slide on the DNA after having terminated one round of transcription. Promoter-dependent transcription reinitiation from this pool of post-termination RNAP may lead to coupled initiation at nearby operons, but it is unclear whether this can occur over the distance- and time-scales needed for it to function widely on a bacterial genome in vivo. Here, we mathematically model the hypothesized reinitiation mechanism as a diffusion-to-capture process and compute the distances over which significant inter-operon coupling can occur and the time required. These quantities depend on previously uncharacterized molecular association and dissociation rate constants between DNA, RNAP and the transcription initiation factorσ70; we measure these rate constants using single-molecule experiments in vitro. Our combined theory/experimental results demonstrate that efficient coupling can occur at physiologically relevantσ70concentrations and on timescales appropriate for transcript synthesis. Coupling is efficient over terminator-promoter distances up to ∼ 1, 000 bp, which includes the majority of terminator-promoter nearest neighbor pairs in theE. coligenome. The results suggest a generalized mechanism that couples the transcription of nearby operons and breaks the paradigm that each binding of RNAP to DNA can produce at most one messenger RNA.SIGNIFICANCE STATEMENTAfter transcribing an operon, a bacterial RNA polymerase can stay bound to DNA, slide along it, and reini-tiate transcription of the same or a different operon. Quantitative single-molecule biophysics experiments combined with mathematical theory demonstrate that this reinitiation process can be quick and efficient over gene spacings typical of a bacterial genome. Reinitiation may provide a mechanism to orchestrate the transcriptional activities of groups of nearby operons.
Circular mitochondrial-encoded mRNAs are a distinct subpopulation of mitochondrial mRNA inTrypanosoma brucei
Authors: Smoniewski Clara M. , Borujeni Poorya Mirzavand , Petersen Austin , Hampton Marshall , Salavati Reza , Zimmer Sara L. 
Published: February 2023

AbstractSince the first identification of circular RNA (circRNA) in viral-like systems, reports of circRNAs and their functions in various organisms, cell types, and organelles have greatly expanded. Here, we report the first evidence of circular mRNA in the mitochondrion of the eukaryotic parasite,Trypanosoma brucei. While using a circular RT-PCR technique developed to sequence mRNA tails of mitochondrial transcripts, we found that some mRNAs are circularized without anin vitrocircularization step normally required to produce PCR products. Starting from totalin vitrocircularized RNA andin vivocircRNA, we high-throughput sequenced three transcripts from the 3’ end of the coding region, through the 3’ tail, to the 5’ start of the coding region. We found that fewer reads in the circRNA libraries contained tails than in the total RNA libraries. When tails were present on circRNAs, they were shorter and less adenine-rich than the total population of RNA tails of the same transcript. Additionally, using hidden Markov modelling we determined that enzymatic activity during tail addition is different for circRNAs than for total RNA. Lastly, circRNA UTRs tended to be shorter and more variable than those of the same transcript sequenced from total RNA. We propose a revised model of Trypanosome mitochondrial tail addition, in which a fraction of mRNAs is circularized prior to the addition of adenine-rich tails and may act as a new regulatory molecule or in a degradation pathway.
Fluctuations and entropy enable neural crest cell ingression
Authors: Pasiliao Clarissa C. , Thomas Evan C. , Yung Theodora , Zhu Min , Tao Hirotaka , Sun Yu , Goyal Sidhartha , Hopyan Sevan 
Published: February 2023

ABSTRACTThe second law of thermodynamics explains the dissipative nature of embryonic development as an exchange of energy-dependent order for proportionately greater output of heat and waste. Recent work on granular matter provides a path by which to define the roles of passive, stochastic mechanisms in nonequilibrium systems. Here, we apply such a framework to examine the role of thermodynamic parameters to cell ingression, the movement of cells from one tissue layer to another that has been attributed, in part, to directional cues. Using the murine neural crest as a model system, we provide evidence that a stochastic mechanism, rather than a proposed stiffness gradient, underlies cell ingression. Cortical fluctuations representing effective temperature and cell packing configurations generate an entropic trap that promotes cell ingression. The results imply dissipative mechanisms that transiently disorder tissue underlie some morphogenetic events.
Rationally designed protein bandpass filters for controlling cellular signaling with chemical inputs
Authors: Shui Sailan , Scheller Leo , Correia Bruno E. 
Published: February 2023

AbstractBiological mechanisms that rely on signal integration and processing are fundamental for cell function. These types of capabilities are analogous to those found in electronic circuits where individual components perform operations on input signals. In electronics, bandpass filters are crucial components to narrow frequencies within a specified range and reject frequencies outside of that range. However, no generalizable protein-based components are currently available to mimic such processes in engineered biological systems, representing an unmet need in controllable modules. Here, we propose a rational design approach to create protein-basedchemically responsive bandpass filters(CBP) which pass chemical concentrations within a range and reject concentrations outside of that range, showing an OFF-ON-OFF regulatory pattern. The CBPs were designed using structure-based approaches where we created a heterodimeric construct which the assembly is triggered by low concentration of a small-molecule, and this interaction is inhibited at high concentrations of the drug, effectively creating a bandpass filter. The CBPs have a multidomain architecture where we used known drug-receptors, a computationally designed protein binder and small-molecule inhibitors. Owing to the modularity of the system, each domain of the CBPs can be rationally fine-tuned to optimize its performance, including bandwidth, maximum response, cutoff concentration and fold changes. These CBPs were used to regulate cell surface receptor signaling pathways showing the capability to control cellular activities in engineered cells.
Development of an instrument to assess independent online learning readiness of high school students in Indonesia
Authors: Belawati Tian , Daryono Daryono , Sugilar Sugilar , Kusmawan Udan 
Published: February 2023

PurposeThe paper reports a study that was intended to develop a self-assessment instrument to measure high school students' readiness for pursuing independent online learning.Design/methodology/approachThe instrument was developed through the following steps: (1) developing the draft, (2) checking the instrument's face validity and (3) testing the instrument's validity, reliability and discriminant capacity using PLS analysis.FindingsThe study has developed a tool to self-assess high school students' readiness for independent online learning. The instrument consists of 36 statement items and is statistically proven to have good reliability, construct and indicator validity and a discriminating power.Research limitations/implicationsThe instrument items were designed to fit the context of Indonesian high school students. However, only responses from high school students in rather urban areas were used to test the validity and reliability of the instrument. This could imply that the instrument is only accurate in urban settings.Practical implicationsAs a result of the research, a tool to assess high school students' readiness for independent online learning has been created. To better prepare students for independent online learning endeavors, the school might use the results to enhance areas that need improvement.Originality/valueThe study succeeded in developing a contextualized self-assessment tool for measuring Indonesian students' independent online learning readiness.
The impact of audit data analytics on audit quality and audit review continuity in Thailand
Authors: Ditkaew Kanthana , Suttipun Muttanachai 
Published: February 2023

PurposeThe main objective of this study is to examine the impact of audit data analytics (ADA) on audit quality (AQ) and audit review continuity (ARC).Design/methodology/approachUsing 452 CPAs in Thailand as samples, mail questionnaires were used and sent to collect the data. Descriptive analysis, correlation matrix and path analysis were used to analyze the data.FindingsThe results of this study indicated that audit data analytics had a positive impact on AQ and ARC. Cybersecurity, used as a moderator in this study, was found to be the interaction between ADA, AQ and review continuity.Practical implicationsAuditors and audit firms can consider using big data in their data analytics to improve AQ and ARC.Originality/valueResource advantage theory has been used in this study to explain the impact of ADA on AQ and ARC in Thailand.