bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defective transfer of parental histone decreases frequency of homologous recombination in budding yeast
Authors: Karri Srinivasu , Yang Yi , Zhou Jiaqi , Dickson Quinn , Wang Zhiquan , Gan Haiyun , Yu Chuanhe 
Published: January 2023

AbstractRecycling of parental histones is an important step in epigenetic inheritance. During DNA replication, DNA polymerase epsilon subunit DPB3/DPB4 and DNA replication helicase subunit MCM2 are involved in the transfer of parental histones to the leading and lagging DNA strands, respectively. SingleDpb3deletion (dpb3Δ) orMcm2mutation (mcm2-3A), which each disrupt one parental histone transfer pathway, leads to the other’s predominance. However, the impact of the two histone transfer pathways on chromatin structure and DNA repair remains elusive. In this study, we used budding yeastSaccharomyces cerevisiaeto determine the genetic and epigenetic outcomes from disruption of parental histone H3-H4 tetramer transfer. We found that adpb3Δ/mcm2-3Adouble mutant did not exhibit the singledpb3Δandmcm2-3Amutants’ asymmetric parental histone patterns, suggesting that the processes by which parental histones are transferred to the leading and lagging strands are independent. Surprisingly, the frequency of homologous recombination was significantly lower indpb3Δ, mcm2-3A, anddpb3Δ/mcm2-3Amutants relative to the wild-type strain, likely due to the elevated levels of free histones detected in the mutant cells. Together, these findings indicate that proper transfer of parental histones to the leading and lagging strands during DNA replication is essential for maintaining chromatin structure and that high levels of free histones due to parental histone transfer defects are detrimental to cells.
The QseB response regulator imparts tolerance to positively charged antibiotics by controlling metabolism and minor changes to LPS
Authors: Hurst Melanie N. , Beebout Connor J. , Hollingsworth Alexis , Guckes Kirsten R. , Purcell Alexandria , Bermudez Tomas A. , Williams Diamond , Reasoner Seth A. , Trent M. Stephen , Hadjifrangiskou Maria 
Published: January 2023

ABSTRACTThe modification of lipopolysaccharide (LPS) inEscherichia coliandSalmonella spp. is primarily controlled by the two-component system PmrAB. LPS modification allows bacteria to avoid killing by positively charged antibiotics like polymyxin B. We previously demonstrated that in uropathogenicE. coli(UPEC), the sensor histidine kinase PmrB also activates a non-cognate transcription factor, QseB, and this activation somehow augments polymyxin B tolerance in UPEC. Here, we demonstrate – for the first time – that in the absence of the canonical LPS transcriptional regulator, PmrA, QseB can direct some modifications on the LPS. In agreement with this observation, transcriptional profiling analyses demonstrate regulatory overlaps between PmrA and QseB in terms of regulating LPS modification genes. However, both PmrA and QseB must be present for UPEC to mount robust tolerance to polymyxin B. Transcriptional and metabolomic analyses also reveal that QseB transcriptionally regulates the metabolism of glutamate and 2-oxoglutarate, which are consumed and produced during the modification of lipid A. We show that deletion ofqseBalters glutamate levels in the bacterial cells. TheqseBdeletion mutant, which is susceptible to positively charged antibiotics, is rescued by exogenous addition of 2-oxoglutarate. These findings uncover a previously unknown mechanism of metabolic control of antibiotic tolerance that may be contributing to antibiotic treatment failure in the clinic.IMPORTANCEAlthough antibiotic prescriptions are guided by well-established susceptibility testing methods, antibiotic treatments oftentimes fail. The presented work is significant, because it uncovers a mechanism by which bacteria transiently avoid killing by antibiotics. This mechanism involves two closely related transcription factors, PmrA and QseB, which are conserved across Enterobacteriaceae. We demonstrate that PmrA and QseB share regulatory targets in lipid A modification pathway and prove that QseB can orchestrate modifications of lipid A inE. coliin the absence of PmrA. Finally, we show that QseB controls glutamate metabolism during the antibiotic response. These results suggest that rewiring of QseB-mediated metabolic genes can lead to stable antibiotic resistance in subpopulations within the host, thereby contributing to antibiotic treatment failure.
COVID-19 NFL Injury Prevalence Analysis, A Follow-Up Study
Authors: Puga Troy B , Schafer Josh , Thiel Grace , Scigliano Nicholas , Ruan Tiffany , Toledo Andres , Agbedanu Prince N , Treffer Kevin 
Published: January 2023

AbstractBackgroundIn 2020, COVID-19 spread across the world and brought the world to a halt, causing the shutdown of nearly everything in order to prevent its spread. The NFL experienced the same effects of the shutdowns leaving athletes unable to train in some of the most advanced facilities with many of the best trainers in the world. Through a previous study,COVID-19 Return to Sport Injury Prevalence Analysis, it was determined that there was increased injury prevalence during the 2020 season likely due to decreased physiological adaptations within athletes bodies that resulted from facility shutdowns. Understanding injury epidemiology is vital in the prevention of injuries and the development of return-to-play protocols.ObjectiveThe objective of this study is to perform a follow up study toCOVID-19 Return to Sport Injury Prevalence Analysisin order to to examine the longitudinal effects of the COVID-19 pandemic on injury epidemiology. This study will examine if there was a recovery to baseline or lingering effects from the COVID-19 pandemic-induced spike in injuries.MethodsInjury tallies collected from the 17-week-long 2020 NFL regular season, played after COVID-19 restrictions, were compared with the injury tallies collected from the 18-week-long NFL regular seasons (2021, 2022), in order to determine if there was a change in injury prevalence. An unpaired t-test was conducted to compare the mean injuries per team per week between each of the 2020, 2021, and 2022 regular seasons.ResultsThe 2022 and 2021 NFL regular seasons produced lower numbers of total injuries than the 2020 NFL regular season that was impacted by COVID-19. The comparison of the mean number of injuries per team per week of the 2020 season compared with the 2021 regular season was statistically significant (P=.03). The comparison of the 2020 and 2022 regular seasons was also statistically significant (P=.02).ConclusionsThe results of this follow-up study and our previous study show that extended training interruptions have the ability to induce detraining and lead to increased injuries.Additionally, the results of this study show that retraining can occur and lead to injury protective factors. This is the first large scale opportunity to demonstrate the effects of these principles and how they are important to understanding injury epidemiology.
Personalized virtual brains of Alzheimer’s Disease link dynamical biomarkers of fMRI with increased local excitability
Authors: Yalçınkaya Bahar Hazal , Ziaeemehr Abolfazl , Fousek Jan , Hashemi Meysam , Lavanga Mario , Solodkin Ana , McIntosh Anthony R. , Jirsa Viktor K. , Petkoski Spase 
Published: January 2023

AbstractAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of abnormal beta-amyloid (Aβ) and hyperphosphorylated Tau (pTau). These proteinopathies disrupt neuronal activity, causing, among others, an excessive and hypersynchronous neuronal firing that promotes hyperexcitability and leads to brain network dysfunction and cognitive deficits. In this study, we used computational network modeling to build a causal inference framework to explain AD-related abnormal brain activity. We constructed personalized brain network models with a set of working points to enable maximum dynamical complexity for each brain. Structural brain topographies were combined, either with excitotoxicity, or postsynaptic depression, as two leading mechanisms of the Aβ and pTau on neuronal activity. By applying various levels of these putative mechanisms to the limbic regions that typically present, with the earliest and largest protein burden, we found that the excitotoxicity is sufficient and necessary to reproduce empirical biomarkers two biometrics associated with AD pathology: homotopic dysconnectivity and a decrease in limbic network dynamical fluidity. This observation was shown not only in the clinical groups (aMCI and AD), but also in healthy subjects that were virtually-diseased with excitotoxicity as these abnormal proteins can accumulate before the appearance of any cognitive changes. The same findings were independently confirmed by a mechanistic deep learning inference framework. Taken together, our results show the crucial role of protein burden-induced hyperexcitability in altering macroscopic brain network dynamics, and offer a mechanistic link between structural and functional biomarkers of cognitive dysfunction due to AD.
T7 phage-assisted evolution of riboswitches using error-prone replication and dual selection
Authors: Goicoechea Eduardo , Jaramillo Alfonso 
Published: January 2023

AbstractLeveraging riboswitches, non-coding mRNA fragments pivotal to gene regulation, poses a challenge in effectively selecting and enriching these functional genetic sensors, which can toggle between ON and OFF states in response to their cognate inducers. Here, we show our engineered phage T7, enabling the evolution of a theophylline riboswitch. We have replaced T7’s DNA polymerase with a transcription factor controlled by a theophylline riboswitch and have created two types of host environments to propagate the engineered phage. Both types host an error-prone T7 DNA polymerase regulated by a T7 promoter along with another critical gene - either cmk or pifA, depending on the host type. The cmk gene is necessary for T7 replication and is used in the first host type for selection in the riboswitch’s ON state. Conversely, the second host type incorporates the pifA gene, leading to abortive T7 infections and used for selection in the riboswitch’s OFF state. This dual-selection system, termed T7AE, was then applied to a library of 65,536 engineered T7 phages, each carrying randomized riboswitch variants. Through successive passage in both host types with and without theophylline, we observed an enrichment of phages encoding functional riboswitches that conferred a fitness advantage to the phage in both hosts. The T7AE technique thereby opens new pathways for the evolution and advancement of gene switches, including non-coding RNA-based switches, setting the stage for significant strides in synthetic biology.
Pathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2’s nuclease activity
Authors: Broderick Ronan , Cherdyntseva Veronica , Nieminuszczy Jadwiga , Dragona Eleni , Kyriakaki Maria , Evmorfopoulou Theodora , Gagos Sarantis , Niedzwiedz Wojciech 
Published: January 2023

SUMMARYTelomerase-independent cancer proliferationviathe alternative lengthening of telomeres (ALT) relies upon two distinct, largely uncharacterized, break-induced-replication (BIR) processes. How cancer cells initiate and regulate these terminal repair mechanisms is unknown. Here, we establish that the EXD2 nuclease is recruited to ALT telomeres to direct their productive repair. We demonstrate that EXD2 loss leads to telomere shortening, elevated telomeric sister chromatid exchanges, C-circle formation as well as BIR-mediated telomeric replication. We discover that EXD2 fork-processing activity triggers a switch between RAD52-dependent and -independent ALT-associated BIR. The latter is suppressed by EXD2 but depends specifically on the fork remodeler SMARCAL1 and the MUS81 nuclease. Thus, our findings suggest that processing of stalled replication forks orchestrates elongation pathway choice at ALT telomeres. Finally, we show that co-depletion of EXD2 with BLM, DNA2 or POLD3 confers synthetic lethality in ALT cells, identifying EXD2 as a potential druggable target for ALT-reliant cancers.
Single-cell response to Wnt activation in human embryonic stem cells reveals uncoupling of Wnt target gene expression
Authors: Söderholm Simon , Jauregi-Miguel Amaia , Pagella Pierfrancesco , Ghezzi Valeria , Zambanini Gianluca , Nordin Anna , Cantù Claudio 
Published: January 2023

AbstractWnt signaling drives nuclear translocation of β-catenin and its subsequent association with the DNA-bound TCF/LEF transcription factors, which dictate target gene specificity by recognizing Wnt responsive elements across the genome. β-catenin target genes are therefore thought to be collectively activated upon Wnt pathway stimulation. However, this appears in contrast with the non-overlapping patterns of Wnt target gene expression in several contexts, including early mammalian embryogenesis. Here we followed Wnt target gene expression in human embryonic stem cells after Wnt pathway stimulation at a single-cell resolution. Cells changed gene expression program over time consistent with three key developmental events: i) loss of pluripotency, ii) induction of Wnt target genes, and iii) mesoderm specification. Contrary to our expectation, not all cells displayed equal amplitude of Wnt target gene activation; rather, they distributed in a continuum from strong to weak responders when ranked based on the expression of the targetAXIN2. Moreover, highAXIN2did not always correspond to elevated expression of other Wnt targets, which were activated in different proportions in individual cells. This uncoupling of Wnt target gene expression, which was also identified in single colorectal cancer cells with hyper-activated Wnt signaling, underlines the necessity to identify additional mechanisms that explain the heterogeneity of the Wnt/β-catenin-mediated transcriptional outputs in single cells.
Natural selection differences detected in key protein domains between non-pathogenic and pathogenic Feline Coronavirus phenotypes
Authors: Zehr Jordan D. , Kosakovsky Pond Sergei L. , Millet Jean K. , Olarte-Castillo Ximena A. , Lucaci Alexander G. , Shank Stephen D. , Ceres Kristina M. , Choi Annette , Whittaker Gary R. , Goodman Laura B. , Stanhope Michael J. 
Published: January 2023

AbstractFeline Coronaviruses (FCoVs) commonly cause mild enteric infections in felines worldwide (termed Feline Enteric Coronavirus [FECV]), with around 12% developing into deadly Feline Infectious Peritonitis (FIP; Feline Infectious Peritonitis Virus [FIPV]). Genomic differences between FECV and FIPV have been reported, yet the putative genotypic basis of the highly pathogenic phenotype remains unclear. Here, we used state-of-the-art molecular evolutionary genetic statistical techniques to identify and compare differences in natural selection pressure between FECV and FIPV sequences, as well as to identify FIPV and FECV specific signals of positive selection. We analyzed full length FCoV protein coding genes thought to contain mutations associated with FIPV (Spike, ORF3abc, and ORF7ab). We identified two sites exhibiting differences in natural selection pressure between FECV and FIPV: one within the S1/S2 furin cleavage site, and the other within the fusion domain of Spike. We also found 15 sites subject to positive selection associated with FIPV within Spike, 11 of which have not previously been suggested as possibly relevant to FIP development. These sites fall within Spike protein subdomains that participate in host cell receptor interaction, immune evasion, tropism shifts, host cellular entry, and viral escape. There were 14 sites (12 novel) within Spike under positive selection associated with the FECV phenotype, almost exclusively within the S1/S2 furin cleavage site and adjacent C domain, along with a signal of relaxed selection in FIPV relative to FECV, suggesting that furin cleavage functionality may not be needed for FIPV. Positive selection inferred in ORF7b was associated with the FECV phenotype, and included 24 positively selected sites, while ORF7b had signals of relaxed selection in FIPV. We found evidence of positive selection in ORF3c in FCoV wide analyses, but no specific association with the FIPV or FECV phenotype. We hypothesize that some combination of mutations in FECV may contribute to FIP development, and that is unlikely to be one singular “switch” mutational event. This work expands our understanding of the complexities of FIP development and provides insights into how evolutionary forces may alter pathogenesis in coronavirus genomes.
Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection
Authors: Vaca Gabriela Baldeon , Meyer Michelle , Cadete Ana , Hsiao Chiaowen Joyce , Golding Anne , Jeon Albert , Jacquinet Eric , Azcue Emily , Guan Chenxia Monica , Sanchez-Felix Xavier , Pietzsch Colette A. , Mire Chad E. , Hyde Matthew A. , Comeaux Margaret E. , Williams Julie M. , Sung Jean C. , Carfi Andrea , Edwards Darin K. , Bukreyev Alexander , Bahl Kapil 
Published: January 2023

AbstractIntranasal vaccination represents a promising approach for preventing disease caused by respiratory pathogens by eliciting a mucosal immune response in the respiratory tract that may act as an early barrier to infection and transmission. This study investigated immunogenicity and protective efficacy of intranasally administered messenger RNA (mRNA)–lipid nanoparticle (LNP) encapsulated vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Syrian golden hamsters. Intranasal mRNA-LNP vaccination systemically induced spike-specific binding (IgG and IgA) and neutralizing antibodies with similar robustness to intramuscular controls. Additionally, intranasal vaccination decreased viral loads in the respiratory tract, reduced lung pathology, and prevented weight loss after SARS-CoV-2 challenge. This is the first study to demonstrate successful immunogenicity and protection against respiratory viral infection by an intranasally administered mRNA-LNP vaccine.
Mitotic events depend on regulation of PLK-1 levels by the mitochondrial protein SPD-3
Authors: Chen Yu-Zen , Zimyanin Vitaly , Redemann Stefanie 
Published: January 2023

AbstractIn metazoans, Polo Kinase (Plk1) controls several mitotic events including nuclear envelope breakdown, centrosome maturation and kinetochore assembly. Here we show that mitotic events regulated by Polo Like Kinase (PLK-1) in earlyC. elegansembryos depend on the mitochondrial-localized protein SPD-3.spd-3mutant one-cell embryos contain abnormally positioned mitotic chromosomes and prematurely and asymmetrically disassemble the nuclear lamina. Nuclear envelope breakdown (NEBD) inC. elegansrequires direct dephosphorylation of lamin by PLK-1. Inspd-3mutants PLK-1 levels are ~6X higher in comparison to control embryos and PLK-1::GFP was highly accumulated at centrosomes, the nuclear envelope, nucleoplasm, and chromosomes prior to NEBD. Partial depletion ofplk-1inspd-3mutant embryos rescued mitotic chromosome and spindle positioning defects indicating that these phenotypes result from higher PLK-1 levels and thus activity. Our data suggests that the mitochondrial SPD-3 protein controls NEBD and chromosome positioning by regulating the endogenous levels of PLK-1 during early embryogenesis inC. elegans. This finding suggests a novel link between mitochondria and mitotic events by controlling the amount of a key mitotic regulator, PLK-1 and thus may have further implications in the context of cancers or age-related diseases and infertility as it provides a novel link between mitochondria and mitosis.
The natural tannins oligomeric proanthocyanidins and punicalagin are potent inhibitors of infection by SARS-CoV-2 in vitro
Authors: Chen Hsiao-Fan , Wang Wei-Jan , Chen Chung-Yu , Chang Wei-Chao , Hsueh Po-Ren , Peng Shin-Lei , Wu Chen-Shiou , Chen Yeh , Huang Hsin-Yu , Shen Wan-Jou , Wang Shao-Chun , Hung Mien-Chie 
Published: January 2023

AbstractThe COVID-19 pandemic continues to infect people worldwide. While the vaccinated population has been increasing, the rising breakthrough infection persists in the vaccinated population. For living with the virus, the dietary guidelines to prevent virus infection are worthy of and timely to develop further. Tannic acid has been demonstrated to be an effective inhibitor of coronavirus and is under clinical trial. Here we found that two other members of the tannins family, oligomeric proanthocyanidins (OPCs) and punicalagin, are also potent inhibitors against SARS-CoV-2 infection with different mechanisms. OPCs and punicalagin showed inhibitory activity against omicron variants of SARS-CoV-2 infection. The water extractant of the grape seed was rich in OPCs and also exhibited the strongest inhibitory activities for viral entry of wild-type and other variants in vitro. Moreover, we evaluated the inhibitory activity of grape seed extractants (GSE) supplementation against SARS-CoV-2 viral entry in vivo and observed that serum samples from the healthy human subjects had suppressive activity against different variants of SARS-CoV-2 vpp infection after taking GSE capsules. Our results suggest that natural tannins acted as potent inhibitors against SARS-CoV-2 infection, and GSE supplementation could serve as healthy food for infection prevention.HighlightsOPCs and Punicalagin had inhibitory activity against omicron variants of SARS-CoV-2 infection.OPCs serve as a dual inhibitor of the viral Mpro and the cellular TMPRSS2 protease.Punicalagin possesses the most potent activity to suppress the Mpro and block the interaction of the viral spike protein and human ACE2.OPCs-enriched grape seed extractant exhibited inhibitory activities for viral entry of wild-type and other variants of SARS-CoV-2.The daily intake of grape seed extractants may be able to prevent SARS-CoV-2 infection.
Do national culture and board attributes influence corporate investment decisions?
Authors: Agyei-Mensah Ben Kwame 
Published: January 2023

Purpose
The purpose of this paper is to study the relationship between board attributes and national culture on firms’ investment decisions.

Design/methodology/approach
The study used data from listed firms from seven Sub-Saharan Africa countries. Descriptive analysis was performed to provide the background statistics of the variables examined. This was followed by regression analysis, which constitutes the main data analysis.

Findings
The multiple regression analysis results indicate a negative relationship between uncertainty avoidance (UAI) and corporate investment decisions. The study also found that there is a negative relationship between the interaction between UAI and the number of independent board members and corporate investment decisions.

Originality/value
This study is one of the few to measure the influence of governance variables and national culture on corporate investment decisions in Sub-Sahara Africa.