bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of enterovirus VP0 maturation cleavage based on the structure of a stabilised assembly intermediate
Authors: Kingston Natalie J , Snowden Joseph S , Grehan Keith , Hall Philippa K , Hietanen Eero V , Passchier Tim C , Polyak Stephen J , Filman David J , Hogle James M , Rowlands David J , Stonehouse Nicola J 
Published: April 2024

AbstractMolecular details of genome packaging are little understood for the majority of viruses. In enteroviruses (EVs), cleavage of the structural protein VP0 into VP4 and VP2 is initiated by the incorporation of RNA into the assembling virion and is essential for infectivity. We have applied a combination of bioinformatic, molecular and structural approaches to generate the first high-resolution structure of an intermediate in the assembly pathway, termed a provirion, which contains RNA and intact VP0. We have demonstrated an essential role of VP0 E096 in VP0 cleavage independent of RNA encapsidation and generated a new model of capsid maturation, supported by bioinformatic analysis. This provides a molecular basis for RNA-dependence, where RNA induces conformational changes required for VP0 maturation, but that RNA packaging itself is not sufficient to induce maturation. These data have implications for understanding production of infectious virions and potential relevance for future vaccine and antiviral drug design.
The structure of the monobactam-producing thioesterase domain of SulM forms a unique complex with the upstream carrier protein domain
Authors: Patel Ketan D. , Oliver Ryan A. , Lichstrahl Michael S. , Li Rongfeng , Townsend Craig A. , Gulick Andrew M. 
Published: April 2024

ABSTRACTNonribosomal peptide synthetases (NRPSs) are responsible for the production of important biologically active peptides. The large, multidomain NRPSs operate through an assembly line strategy in which the growing peptide is tethered to carrier domains that deliver the intermediates to neighboring catalytic domains. While most NRPS domains catalyze standard chemistry of amino acid activation, peptide bond formation and product release, some canonical NRPS catalytic domains promote unexpected chemistry. The paradigm monobactam antibiotic sulfazecin is produced through the activity of a terminal thioesterase domain that catalyzes an unusual β-lactam forming reaction in which the nitrogen of the C-terminalN-sulfo-2,3-diaminopropionate residue attacks its thioester tether to release the β-lactam product. We have determined the structure of the thioesterase domain as both a free-standing domain and a didomain complex with the upstreamholopeptidyl-carrier domain. The structure illustrates a constrained active site that orients the substrate properly for β-lactam formation. In this regard, the structure is similar to the β-lactone forming thioesterase domain responsible for the production of obafluorin. Analysis of the structure identifies features that are responsible for this four-membered ring closure and enable bioinformatic analysis to identify additional, uncharacterized β-lactam-forming biosynthetic gene clusters by genome mining.
The membrane-targeting-sequence motif is required for exhibition of recessive resurrection inEscherichia coliRNase E
Authors: Basak Papri , Ekka Manjula , Pandiyan Apuratha , Tandon Smriti , Gowrishankar Jayaraman 
Published: April 2024

AbstractThe essential homo-tetrameric endoribonuclease RNase E ofEscherichia coliparticipates in global RNA turnover as well as stable RNA maturation. The protomer’s N-terminal half (residues 1-529) bears the catalytic, allosteric and tetramerization domains, including the critical active site residues D303 and D346. The C-terminal half (CTH, residues 530-1061) is dispensable for viability. We have previously described a phenomenon of recessive resurrection in RNase E that requires the CTH, wherein the wild-type homo-tetramer apparently displays nearly identical activity in vivo as a hetero-tetramer comprised of three catalytically dead subunits (with D303A/D346A substitutions) and one wild-type subunit. Here we show that recessive resurrection is exhibited even in dimeric RNase E with the CTH, and that it is largely dependent on presence of the membrane-targeting-sequence motif (residues 565-582). A single F575E substitution also impaired recessive resurrection, whereas other CTH motifs (such as those for binding of RNA or of partner proteins) were dispensable. The phenomenon was independent of RNA 5’-monophosphate sensing by the enzyme. We propose that membrane-anchoring of RNase E renders it processive for endoribonucleolytic action, and that recessive resurrection and dominant negativity associated with mutant protomers are mutually exclusive manifestations of, respectively, processive and distributive catalytic mechanisms in a homo-oligomeric enzyme.
Nuclear release of eIF1 globally increases stringency of start-codon selection to preserve mitotic arrest physiology
Authors: Ly Jimmy , Xiang Kehui , Su Kuan-Chung , Sissoko Gunter B. , Bartel David P. , Cheeseman Iain M. 
Published: April 2024

AbstractRegulated start-codon selection has the potential to reshape the proteome through the differential production of uORFs, canonical proteins, and alternative translational isoforms. However, conditions under which start-codon selection is altered remain poorly defined. Here, using transcriptome-wide translation initiation site profiling, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This increased stringency of start-codon selection during mitosis results from increased interactions between the key regulator of start-codon selection, eIF1, and the 40S ribosome. We find that increased eIF1-40S ribosome interactions during mitosis are mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the changes to translational stringency during mitosis, resulting in altered mitotic proteome composition. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage following treatment with anti-mitotic chemotherapeutics. Thus, cells globally control translation initiation stringency with critical roles during the mammalian cell cycle to preserve mitotic cell physiology.
Structural plasticity of 2A proteins in the Parechovirus family
Authors: Zhu Ling , Pichon Marion , Pietras Zuzanna , Wang Xiangxi , Ren Jingshan , Fry Elizabeth E. , Stuart David. I. , Perrakis Anastassis , von Castelmur Eleonore 
Published: April 2024

AbstractParechoviruses, includingParechovirus Athat infects humans as well asParechovirus B(formerly Ljungan virus) andParechovirus C(formerly Sebokele virus) that infect rodents, belong to a group of picornaviruses whose 2A proteins, instead of being proteases, contain a conserved H-box and NC-motif and are homologous to a small cellular lipid-modifying enzyme (PLAAT3) that acts as a host factor, enabling the picornavirus life cycle. Despite the common evolutionary origin, 2AH/NCproteins and PLAAT3 have no conserved function, as the active site of the viral proteins cannot support catalysis. Here, we set out to find if allParechovirusspecies share the structural rearrangement that destroys the active site configuration of the cellular enzyme. This has revealed a remarkable structural plasticity of these 2AH/NCproteins that arises not only from sequence differences between species, but also from differences in the length of the recombinantly expressed proteins, resulting in large structural rearrangements. These include rerouting of a large internal loop and repositioning of the C-terminal helix with respect to the central β-sheet, and these in turn influence the oligomeric state of the protein. We discuss how this structural plasticity could correlate with the function of these proteins in the viral life cycle and how this could recapitulate the possible evolution of this protein from host factor to viral 2AH/NCprotein, with new independent functions in RNA replication.
The association between HDL-C and stroke in people over 40 years of age: A NHANES cross-sectional study
Authors: Patel Kevin 
Published: April 2024

1.AbstractBackgroundPreviously, studies have indicated that high-density cholesterol (HDL-C) levels are associated with lower risk of cardiovascular disease. However, this has been challenged in recent years.MethodThis cross-sectional study was conducted on data from the National Health and Nutrition Examination Survey 2011-2020. There were total of 15232 out of 45462 individuals who were age >40 years old, not missing HDL-C levels and not missing stroke data. The independent variable was HDL-Cholesterol. The outcome variable was stroke. We used multivariate logistic regression models to assess the relationship between stroke and HDL-C in three models consisting of the following explanatory variables: 1. HDL-C alone (unadjusted model), 2. HDL-C and non-modifiable risk factors (age, sex and race), 3. HDL-C, non-modifiable, and modifiable risk factors [hypertension, diabetes and smoking status] risk factors. We also conducted analyses stratified by sex and race.ResultsHDL-C categories 40-59 mg/dl (unadjusted model- 0.759, CI: 0.639, 0.901; non-modifiable risk factors adjusted- 0.668, CI: 0.558, 0.798) and 60-79 mg/dl (unadjusted model- 0.733, CI: 0.598, 0.898; non-modifiable risk factors adjusted- 0.565, CI: 0.455, 0.701) had significantly lower risk of stroke relative to HDL-C category <40 mg/dl. But when adjusted for modifiable risk factors, risk of stroke HDL-C categories 40-59 mg/dl and 60-79 mg/dl categories were not significantly different from the HDL-C <40 mg/dl category. The risk of stroke HDL-C categories 80-89 mg/dl and >90 mg/dl categories were not significantly different from the HDL-C <40 mg/dl category in all models. In stratified analyses, HDL-C was significantly inversely associated with the risk of stroke in male gender and in non-Hispanic White race.ConclusionOur study reveals various inverse relationship between HDL-C and risk of stroke. These findings suggest that relevant levels of HDL-C may be beneficial in preventing stroke in the absence of modifiable risk-factors.
Soft-lithographically defined template for arbitrarily patterned acoustic bioassembly
Authors: Chen Sihan , Wang Jibo , Jiang Shanqing , Fan Yuhang , Zhao Yang , Zhao Wen , Wan Zian , Zhou Qin , Chen Yun , Chen Pu 
Published: April 2024

AbstractAcoustic bioassembly is recently regarded as a highly efficient biofabrication tool to generate functional tissue mimics. Despite their capacity of directly patterning live cells with close intercellular proximity, most acoustic bioassembly techniques are currently limited to generate some specific simple types of periodic and symmetric patterns, which represents an urgent challenge to emulate geometrically complex cytoarchitecture in human tissue. To address this challenge, we herein demonstrate a soft-lithographically defined acoustic bioassembly (SLAB) technique that enables to assemble live cells into geometrically defined arbitrary multicellular structures. Particularly, we employed a widely accessible soft lithography technique to fabricate a PDMS construct that works as an amplitude modulation template to define the pressure distribution of near-field acoustic waves. We found that zero pressure areas of the near-field acoustic waves at the PDMS surface distribute above the air-filling regions of the PDMS construct when both the PDMS top layer and air layer are approximately one-tenth of the acoustic wavelength. Using this technique, bioparticles can be assembled into symmetrical or asymmetrical patterns. Specifically, we have demonstrated the SLAB of endothelial spheroids and hepatic cells into liver tissue mimics (LTMs). The functional analysis further indicates that the formed LTMs displayed liver-specific functions, including albumin secretion, urea synthesis, glucose metabolism, and lipid storage. We expect this SLAB technique will be broadly used to construct complex functional tissues for tissue engineering and regenerative medicine.
Differential Causal Effects of Type 1 and Type 2 Diabetes on Osteomyelitis Risk: Insights from Mendelian Randomization Analysis
Authors: Li YanHui , Zhou Chuanyang , Yang Liming , Tan Lei 
Published: April 2024

AbstractBackgroundOsteomyelitis (OM) poses a significant clinical challenge, especially among individuals with diabetes mellitus (DM). While both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have been linked to an elevated risk of OM, the precise causal relationships remain uncertain.MethodsWe conducted Mendelian randomization (MR) analyses using summary statistics from genome-wide association studies (GWAS) to explore the causal effects of T1DM, T2DM, their complications, and glycemic traits on OM risk. The study utilized the inverse variance weighted (IVW) method, along with weighted median and MR-Egger for causal estimation, and performed various sensitivity analyses to ensure robustness. Multivariable MR (MVMR) analysis assessed direct effects, while two-step mediation MR analyses investigated the mediating role of DM between rheumatoid arthritis (RA) and OM.ResultsThe MR analysis unveiled distinct causal effects of T1DM and T2DM on OM risk. Genetically determined T2DM, rather than its complications, significantly increased OM risk (primary dataset: IVW: OR = 1.13, 95% CI 1.056–1.209,p= 4E-04; validation dataset: IVW: OR = 1.317, 95% CI 1.14–1.522,p=2E-04; Meta-analysis: OR=1.206; 95% CI 1.037–1.402;p=0.014), with no observable heterogeneity or horizontal pleiotropy. MVMR analysis confirmed the robustness of the causal association between T2DM and OM, even after adjusting for potential confounders such as body mass index. Conversely, T1DM and its complications showed no significant causal link with OM in either the primary dataset (IVW:p= 0.071), the validation dataset (IVW:p= 0.276), or the meta-analysis (IVW:p= 0.242). Additionally, there was no robust evidence supporting the causal risk of glycemic traits on OM. Mediation MR analysis underscored T2DM as a pivotal contributor to the differential effects of RA on OM.ConclusionsMendelian randomization analysis provides compelling evidence of a significant causal relationship between genetically determined T2DM and increased OM risk, while T1DM exhibits distinct causal effects. Additionally, our findings highlight the role of T2DM in mediating the association between RA and OM. Further research is warranted to elucidate the underlying mechanisms and guide targeted interventions for OM prevention and management in diabetic populations.
State of affairs: the US platelet supply and the role of whole blood–derived platelets
Authors: Razatos Anna , King Aspen 
Published: April 2024

PurposeThe US platelet supply is almost exclusively dependent on apheresis donors who are “aging out.” As a result, blood centers and hospitals have been experiencing spot shortages and have resorted to transfusing low-dose platelets. This paper explores using whole blood–derived platelets (WB-PLTs) to supplement the apheresis platelet (APH-PLT) supply.Design/methodology/approachThis paper reviews the history leading to the current state of the US platelet supply and includes the impact of recent events such as the COVID-19 pandemic and the implementation of the US Food and Drug Administration (FDA)-mandated bacterial mitigation strategies.FindingsWB-PLTs represent a viable source of platelets that can be used to supplement the APH-PLT supply. Whole blood automation represents a new methodology to more easily prepare WB-PLTs. Advances in donor testing and screening as well as pre-storage leukoreduction have improved the safety of WB-PLTs to the same level as APH-PLTs. Blood services in the US and abroad transfuse WB-PLTs interchangeably in all patient populations.Originality/valueThis paper highlights how the US blood industry is essentially “sole-sourced” in terms of APH-PLTs. In this post-COVID-19 period, when most industries are building redundancies in their supply chains, blood centers should consider WB-PLTs as an additional source of platelets to bolster the US platelet supply.
Measuring learning agility: a review and critique of learning agility measures
Authors: Smith Brandon A. , Watkins Karen E. 
Published: April 2024

PurposeThe purpose of this review is to evaluate existing learning agility measures and offer recommendations for their use in organizational and scholarly contexts.Design/methodology/approachThis is a general review paper assessing the psychometric qualities of prevalent learning agility measures. Measures were selected based on their predominance and use in the learning agility literature and organizational settings.FindingsLearning agility measurement is an area requiring further research. Multiple conceptualizations of learning agility exist, making the true structure of learning agility unclear. The learning agility measures in the academic literature deviate from learning agility’s traditional conceptualization and require further validation and convergent validity studies. Commercial measures of learning agility exist, but their development procedures are not subjected to peer review and are not widely used in academic research, given the cost associated with their use.Practical implicationsLearning agility is prevalently used in organizational settings and is receiving increased scholarly attention. Various conceptualizations and measurement tools exist, and it is unclear how these theories and measures relate and differ. This paper contributes to practice by providing practical guidelines and limitations for measuring learning agility.Originality/valueLearning agility was initially conceived as a multidimensional construct comprising people agility, results agility, change agility and mental agility. As the construct has evolved, the dimension structure of the measure has evolved as well. This study addresses a gap in our current understanding of how to conceptualize and measure learning agility.
Two‐dimensional SH‐wave and acoustic P‐wave full waveform inversion: A Midland Basin case study
Authors: Liu Youfang , Simmons James 
Published: April 2024

AbstractBuilding a reliable S‐wave velocity model remains challenging from P‐wave land seismic data as multi‐parameter elastic full waveform inversion which updates P‐ and S‐wave velocities simultaneously is not yet widely adopted due to its computational cost, highly nonlinear nature and noise contamination from land seismic data. To overcome this challenge, we propose implementing the SH‐wave full waveform inversion to obtain the S‐wave velocity model. The value of this approach has been examined by applying two‐dimensional time‐domain SH‐ and P‐wave acoustic full waveform inversion to a nine‐component three‐dimensional seismic survey acquired in the Midland Basin. The nine‐component seismic survey was acquired by using both vertical and horizontal component vibrators and receivers, which enables us to apply both SH‐ and P‐wave full waveform inversion to the raw and preprocessed shot gathers along a two‐dimensional line. The SH‐ and P‐wave full waveform inversion applied to the raw shot gathers provide more detailed P‐ and S‐wave velocities compared to the velocities from the stacking velocity analysis. Additionally, there are no problematic artefacts in the inverted S‐wave velocity model, which shows the stability of the SH‐wave inversion. Through the SH‐wave full waveform inversion from the preprocessed shot gathers, we reveal the lateral velocity variations in the Grayburg–San Andres interval, which coincides with the depositional environment changes suggested by the previous regional study mainly based on well log and cores. These variations demonstrate that SH‐wave full waveform inversion can identify additional geological features that are not observed in the inverted P‐wave velocity model. The inverted P‐ and SH‐wave velocities are validated by the flattening of the events observed in the common image gathers after Kirchhoff depth migration. The SH‐wave migration image further reveals the irregular geometries of carbonates in the Spraberry formation. Vp/Vs ratios calculated from the independently inverted P‐ and S‐wave velocity models show strong lateral variations in the Wolfcamp interval (key‐producing interval), which could be caused by the organic content variations between the reservoir and non‐reservoir rocks. The inversion results demonstrate that the SH‐wave full waveform inversion can be used to provide an S‐wave velocity model that is comparable to the P‐wave velocity model derived from acoustic full waveform inversion, which is widely used for P‐wave velocity model building from P‐wave land seismic data.
Optimizing myocardial cell protection with xanthine derivative KMUP‐3 potentiates autophagy through the PI3K/Akt/eNOS axis
Authors: Huang Shang‐En , Hsu Jong‐Hau , Shiau Bo‐Wen , Liu Yi‐Ching , Wu Bin‐Nan , Dai Zen‐Kong , Liu Chung‐Pin , Yeh Jwu‐Lai 
Published: April 2024

AbstractBackgroundAutophagy can have either beneficial or detrimental effects on various heart diseases. Pharmacological interventions improve cardiac function, which is correlated with enhanced autophagy. To assess whether a xanthine derivative (KMUP‐3) treatment coincides with enhanced autophagy while also providing cardio‐protection, we investigated the hypothesis that KMUP‐3 treatment activation of autophagy through PI3K/Akt/eNOS signalling offered cardioprotective properties.MethodsThe pro‐autophagic effect of KMUP‐3 was performed in a neonatal rat model targeting cardiac fibroblasts and cardiomyocytes, and by assessing the impact of KMUP‐3 treatment on cardiotoxicity, we used antimycin A‐induced cardiomyocytes.ResultsAs determined by transmission electron microscopy observation, KMUP‐3 enhanced autophagosome formation in cardiac fibroblasts. Furthermore, KMUP‐3 significantly increased the expressions of autophagy‐related proteins, LC3 and Beclin‐1, both in a time‐ and dose‐dependent manner; moreover, the pro‐autophagy and nitric oxide enhancement effects of KMUP‐3 were abolished by inhibitors targeting eNOS and PI3K in cardiac fibroblasts and cardiomyocytes. Notably, KMUP‐3 ameliorated cytotoxic effects induced by antimycin A, demonstrating its protective autophagic response.ConclusionThese findings enable the core pathway of PI3K/Akt/eNOS axis in KMUP‐3‐enhanced autophagy activation and suggest its principal role in safeguarding against cardiotoxicity.