bluuebunny/crossref_metadata_2025 huggingface dataset:
Excess Mortality in the Vaccination Era in the United States, By State and 6-Month Period
Authors: Faust Jeremy Samuel , Renton Benjamin , Du Chengan , Chen Alexander Junxiang , Li Shu-Xia , Lin Zhenqiu , Krumholz Harlan M.
Published: March 2023

Introduction

The US continued to record all-cause excess mortality after the rollout of vaccines. We sought to quantify excess mortality by state and compare these rates to primary series vaccination completion levels.

Methods

Observational cohort, US and state-level data. Expected monthly deaths were modeled using pre-pandemic US and state-level data (2015-2020). Mortality data was accessed from CDC public reporting.

Results

We find that in a two-year period since the rollout of vaccines, the US recorded >874,000 excess deaths. Vaccination rates and excess mortality were most strongly correlated in first two periods before the Omicron variant.

Conclusion

The association between vaccination and lower excess mortality rates was strongest in 2021 and early 2022, prior to high population rates of infection-acquired immunity. The findings underscore the benefits of the rapid vaccination rollout campaign and the continued need to boost at-risk populations.
The neutrophil-to-lymphocyte ratio, as an emerging marker, is an important indicator predicting spontaneous reperfusion and clinical prognosis in patients with ST-segment elevation myocardial infarction
Authors: Li Bing , Zhang Mingyou , Zhang Yaoting , Zheng Yang , Cai He
Published: March 2023

Background

Neutrophil to lymphocyte ratio (NLR) has emerged as a new inflammation marker, which plays a major role in plaque instability, rupture, and erosion, and facilitates its progression, leading to acute myocardial infarction. The study aims to explore the role of NLR in predicting spontaneous reperfusion (SR) and prognosis in patients with ST-segment elevation myocardial infarction (STEMI).

Methods

This was a retrospective analysis including 506 STEMI patients undergoing primary percutaneous coronary intervention treatment, who were divided into two groups according to the thrombolysis in myocardial infarction (TIMI) flow: SR group (69 patients, initial TIMI flow 3) and No-SR group (437 patients, initial TIMI flow 0-2).

Results

The incidence of SR was 13.6%. SR group was associated with a remarkably lower level of NLR [5.14 (2.97, 7.02) vs. 8.03 (4.54, 10.92), P<0.001], more proportions of final TIMI 3 flow (98.6% vs. 91.5%, P < 0.05), lower incidence of congestive heart failure (8.7% vs. 18.5%, P < 0.05), and significantly better outcomes. Using multivariate logistic regression analysis, NLR (OR: 0.799, 95% CI: 0.730-0.874, P < 0.001) and fasting blood glucose were the independent predictors of SR. On multivariate Cox regression analysis, NLR (HR: 1.035, 95% CI: 1.001-1.071, P < 0.05) was the independent predictor of MACEs during follow-up.

Conclusions

NLR had the ability in predicting SR in STEMI patients and SR flow was associated with a favorable outcome. We also revealed an association between NLR and increased risk of MACEs during follow-up.

Clinical Perspective

What Is New?

The incidence of spontaneous reperfusion was 13.6%. Patients with spontaneous reperfusion had a remarkably low level of NLR [5.14 (2.97, 7.02) versus 8.03 (4.54, 10.92), P<0.001], more proportions of final TIMI 3 flow (98.6% versus 91.5%, P < 0.05), lower incidence of congestive heart failure (8.7% versus 18.5%, P < 0.05), and favorable outcomes.

NLR was not only an independent predictor of spontaneous reperfusion, but also was the independent predictor of major adverse cardiac events during follow-up (HR: 1.035, 95% CI: 1.001-1.071, P < 0.05) in patients with ST-segment elevation myocardial infarction.

What Are the Clinical Implications?

The level of neutrophil to lymphocyte ratio in patients with ST-segment elevation myocardial infarction is associated with low occurrence of spontaneous reperfusion and adverse outcomes, although, the patients received primary percutaneous coronary intervention.

Neutrophil to lymphocyte ratio the plays a major role in the risk classification of patients with ST-segment elevation myocardial infarction.
ACRC/GCNA is an essential protease for the repair of DNA-protein crosslinks during vertebrate development
Authors: Otten Cecile , Supina-Pavic Christine , Kutnjak Marin , Anticevic Ivan , Medved Vanna , Popovic Marta
Published: March 2023

DNA-protein crosslinks (DPCs) are frequent DNA lesions associated with cancer, neurodegeneration and premature aging. These bulky lesions are an obstacle to all DNA transactions, but the mechanisms of DPC repair (DPCR) at the organism level are largely unknown. Because proteases play a central role in DPCR, we investigate the function of the putative protease ACRC/GCNA (ACidic Repeat Containing/Germ Cell Nuclear Antigen) which has recently been linked to DPCR, in a zebrafish model. Using a newly created fish line with a mutation in the protease core, we show for the first time that the proteolytic function of Acrc is critical for DPCR during early vertebrate development and that Acrc deficiency leads to DPC accumulation and embryonic death. We also show that Sprt domain rather than IDR domain of Acrc is essential and that Sprtn protease cannot compensate for the absence of Acrc. We identified histone H3-DPC as a novel Acrc substrate.
Traction Force and Mechanosensing can be Functionally Distinguished Through the Use of Specific Domains of the Calpain Small Subunit
Authors: Hao Bingqing , Beningo Karen A.
Published: March 2023

Cell migration is a fundamental process pertaining to many critical physiological events. The ability to form and release adhesion structures is necessary for cell migration. The Calpain family of cysteine proteases are known to target adhesion proteins as their substrates and modulate adhesion dynamics. The two best studied Calpains, Calpain 1 and Calpain 2 form catalytically active holoenzymes through heterodimerization with a common non-catalytic regulatory small subunit known as Calpain 4. In previous studies, we determined that calpains are important in the production of traction forces and in the sensing of localized mechanical stimulation from the external environment. We found that perturbation of either Calpain 1 or 2 had no effect on the generation of traction forces. However, traction forces were weak when Calpain 4 was silenced. On the other hand, silencing of Calpain 1, 2, or 4 resulted in deficient sensing of external mechanical stimuli. These results together suggest that Calpain 4 functions independent of the catalytic large subunits in the generation of traction forces but functions together with either catalytic subunit in sensing external mechanical stimuli. The small subunit Calpain 4 contains 268 a.a. and is composed of 2 domains, the N-terminal domain V and C-terminal domain VI. Domain VI is a calmodulinlike domain containing five consecutive EF-hand motifs, of which the fifth one heterodimerizes with a large subunit. Moreover, domain V contains the common sequence GTAMRILGGVI that suggests cell membrane interactions. Given these attributes of domain V and VI of Calpain 4, we speculated that an individual domain might provide the functional properties for either traction or sensing. Therefore, each domain was cloned and expressed individually inCapn4−/−cells and assayed for traction and sensing. Results revealed that over-expression of domain V was sufficient to rescue the traction forces defect inCapn4−/−cells while overexpression of domain VI did not rescue the traction force. Consistent with our hypothesis, overexpression of domain VI rescued the sensing defect inCapn4−/−cells while overexpression of domain V had no effect. These results suggest that individual domains of Calpain 4 do indeed function independently to regulate either traction force or the sensing of external stimuli. We speculate that membrane association of Calpain 4 is required for the regulation of traction force and its association with a catalytic subunit is necessary for mechanosensing.
Functional analysis of flavivirus replicase by deep mutational scanning of dengue NS5
Authors: Suphatrakul Amporn , Posiri Pratsaneeyaporn , Srisuk Nittaya , Nantachokchawapan Rapirat , Onnome Suppachoke , Mongkolsapaya Juthathip , Siridechadilok Bunpote
Published: March 2023

Flavivirus NS5 is multi-functional viral protein that play critical roles in virus replication, evolution, and immune antagonism against the hosts. Its error-prone replicase activity copies viral RNA for progeny virus particles and shapes virus evolution. Its methyltransferase activity and STAT2-targeting activity compromise type-I interferon signalling, dampening protective immune response during infection. It interacts with several host factors to shape the host-cell environment for virus replication. Thus, NS5 represents a critical target for both vaccine and antiviral drug development. Here, we performed deep mutational scanning (DMS) on the NS5 of dengue virus serotype 2 in mammalian cells. In combination with available structural and biochemical data, the comprehensive single amino-acid mutational data corroborated key residues and interactions involved in enzymatic functions of the replicase and suggested potential plasticity in NS5 guanylyl transferase. Strikingly, we identified that a set of strictly conserved residues in the motifs lining the replicase active site could tolerate mutations, suggesting additional roles of the priming loop in viral RNA synthesis and possible strategies to modulate the error rate of viral replicase activity through active-site engineering. Our DMS dataset and NS5 libraries could provide a framework and a resource to investigate molecular, evolutionary, and immunological aspects of NS5 functions, with relevance to vaccine and antiviral drug development.
Temporal landscape and translational regulation of A-to-I editing in mouse retina development
Authors: Yang Ludong , Yi Liang , Yang Jiaqi , Zhang Rui , Xie Zhi , Wang Hongwei
Published: March 2023

The significance of A-to-I RNA editing in neurological development is widely recognized, however, its influence on retina development remains to be thoroughly understood. In this study, we aimed to characterize the temporal landscape of A-to-I editing in mouse retina development using total RNA-seq and Ribosome profiling, with a specific emphasis on its effect on gene translation. Our findings revealed that the editing underwent plastic changes and distinct editing contents facilitated stage-specific functions. Further analysis showed a dynamic interplay between A-to-I editing and alternative splicing, with A-to-I editing having a significant impact on splicing efficiency and increasing the quantity of splicing events. A-to-I editing held the potential of enhancing the translatome’s diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated regulatory effect on translatome dynamics. Overall, our study presents a temporally resolved atlas of A-to-I editing, connecting its dynamic changes with the regulatory impact on splicing and translation.
How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-formTrypanosoma bruceicell
Authors: Nascimento Janaina F. , Souza Rodolpho O. O. , Alencar Mayke B. , Marsiccobetre Sabrina , Murillo Ana M. , Damasceno Flávia S. , Girard Richard B. M. M. , Marchese Letícia , Luévano-Martinez Luis A. , Achjian Renan W. , Haanstra Jurgen R. , Michels Paul A. M. , Silber Ariel M.
Published: March 2023

ATP hydrolysis is required for the synthesis, transport and polymerization of monomers for macromolecules as well as for the assembly of the latter into cellular structures. Other cellular processes not directly related to synthesis of biomass, such as maintenance of membrane potential and cellular shape, also require ATP. The unicellular flagellated parasiteTrypanosoma bruceihas a complex digenetic life cycle. The primary energy source for this parasite in its bloodstream form (BSF) is glucose, which is abundant in the host’s bloodstream. Here, we made a detailed estimation of the energy budget during the BSF cell cycle. As glycolysis is the source of most produced ATP, we calculated that a single parasite produces 6×1011molecules of ATP/cell cycle. Biomass production accounts for ∼62% of the total energy budget, with translation being the most expensive process. Flagellar motility, variant surface glycoprotein recycling, transport and maintenance of transmembrane potential account for less than 30% of the consumed ATP. Finally, there is still ∼9% available in the budget that is being used for other cellular processes of unknown cost. These data put a new perspective on the assumptions about the relative energetic weight of the processes a BSF trypanosome undergoes during its cell cycle.

Abstract Importance

Cells use ATP as the main energy currency for the synthesis, organization and maintenance of their macromolecules and cellular structures, in order to stay alive and proliferate. For this purpose, ATP is produced from external nutrients, and is spent by cells in the many processes that are necessary for maintenance and building up new cells. Despite its relevance and the impressive quantity of biological data available, very little is known about how much ATP is required for maintaining and duplicating a cell. In this paper, we present a calculation on how much of the ATP produced by catabolism of the nutrient glucose is used to energize the different processes known to occur during the cell cycle of the infective form of the trypanosomatid parasite that causes human sleeping sickness, the bloodstream form ofTrypanosoma brucei.
Naturally-acquired and Vaccine-induced Human Monoclonal Antibodies toPlasmodium vivaxDuffy Binding Protein Inhibit Invasion ofPlasmodium knowlesi(PvDBPOR) Transgenic Parasites
Authors: Watson Quentin D. , Carias Lenore L. , Malachin Alyssa , Redinger Karli R. , Bosch Jürgen , Bardelli Martino , Moon Robert W. , Draper Simon J. , Zimmerman Peter A. , King Christopher L.
Published: March 2023

The Duffy antigen receptor for chemokines (DARC) expressed on erythrocytes is central toPlasmodium vivax(Pv) invasion of reticulocytes. Pv expresses a Duffy binding protein (PvDBP) on merozoites, a DARC ligand, and their protein-protein interaction is central to vivax blood stage malaria. Here we compared the functional activity of humAbs derived from naturally exposed and vaccinated individuals for the first time using easily culturedP. knowlesi(Pk) that had been genetically modified to replace its endogenous PkDBP orthologue with PvDBP to create a transgenic parasite, PkPvDBPOR. This transgenic parasite requires DARC to invade human erythrocytes but is not reticulocyte restricted. Using this model, we evaluated the invasion inhibition potential of 12 humAbs (9 naturally acquired; 3 vaccine-induced) targeting PvDBP individually and in combinations using growth inhibition assays (GIAs). The PvDBP-specific humAbs demonstrated 70-100% inhibition of PkPvDBPOR invasion with the IC50values ranging from 51 to 338 μg/mL for the 9 naturally acquired (NA) humAbs and 33 to 99 μg/ml for the 3 vaccine-induced (VI) humAbs. To evaluate antagonistic, additive, or synergistic effects, six pairwise combinations were performed using select humAbs. Of these combinations tested, one NA/NA (099100/094083) combination demonstrated relatively strong additive inhibition between 10-100 μg/mL; all combinations of NA and VI humAbs showed additive inhibition at concentrations below 25 μg/mL and antagonism at higher concentrations. None of the humAb combinations showed synergy. This PkPvDBPOR model system enables efficient assessment of NA and VI humAbs individually and in combination.

IMPORTANCE

Given the importance of Duffy blood group antigen andP. vivaxDuffy binding protein (PvDBP) interaction leading to blood stage vivax malaria, development of vaccines or therapeutic human monoclonal antibodies (humAbs) targeting PvDBP are key strategies for treating and controlling Pv. TheP. knowlesi-based PkPvDBPOR transgenic model system enables efficient assessment of NA and VI humAbs individually and in combination. As such, this model could prioritize specific humAb combinations ahead of clinical trials of these reagents.
Adhesion-based capture stabilizes nascent microvilli at epithelial cell junctions
Authors: Cencer Caroline S. , Silverman Jennifer B. , Meenderink Leslie M. , Krystofiak Evan S. , Millis Bryan A. , Tyska Matthew J.
Published: March 2023

Differentiated transporting epithelial cells present an extensive apical array of microvilli – a “brush border” – where neighboring microvilli are linked together by intermicrovillar adhesion complexes (IMACs) composed of protocadherins CDHR2 and CDHR5. Although loss-of-function studies provide strong evidence that IMAC function is needed to build a mature brush border, how the IMAC contributes to the stabilization and accumulation of nascent microvilli remains unclear. We found that, early in differentiation, the apical surface exhibits a marginal accumulation of microvilli, characterized by higher packing density relative to medial regions of the surface. While medial microvilli are highly dynamic and sample multiple orientations over time, marginal protrusions exhibit constrained motion and maintain a vertical orientation. Unexpectedly, we found that marginal microvilli span the junctional space and contact protrusions on neighboring cells, mediated by complexes of CDHR2/CDHR5. FRAP analysis indicated that thesetransjunctionalIMACs are highly stable relative to adhesion complexes between medial microvilli, which explains the restricted motion of protrusions in the marginal zone. Finally, long-term live imaging revealed that the accumulation of microvilli at cell margins consistently leads to accumulation in medial regions of the cell. Collectively, our findings suggest that nascent microvilli are stabilized by a capture mechanism that is localized to cell margins and enabled by the transjunctional formation of IMACs. These results inform our understanding of how apical specializations are assembled in diverse epithelial systems.
The syntax-meter interface in spoken language and music: Same, different, or individually variable?
Authors: Harding Eleanor E. , Sammler Daniela , Kotz Sonja A.
Published: March 2023

Considerable debate surrounds syntactic processing similarities in language and music. Yet few studies have investigated how syntax interacts with meter considering that metrical regularity varies across domains. Furthermore, there are reports on individual differences in syntactic and metrical structure processing in music and language. Thus, a direct comparison of individual variation in syntax and meter processing across domains is warranted. In a behavioral (Experiment 1) and EEG study (Experiment 2), participants engaged in syntactic processing tasks with sentence- and melody stimuli that were more or less metrically regular, and followed a preferred or non-preferred (but correct) syntactic structure. We further employed a range of cognitive diagnostic tests, parametrically indexed verbal- and musical abilities using a principal component analysis, and correlated cognitive factors with the behavioral and ERP results (Experiment 3). Based on previous results in the language domain, we expected that a regular meter would facilitate the syntactic integration of non-preferred syntax. While syntactic discrimination was better in regular than irregular meter conditions in both domains (Experiment 1), a P600 effect indicated different integration costs during the processing of syntactic complexities in the two domains (Experiment 2). Metrical regularity altered the P600 response to preferred syntax in language while it modulated non-preferred syntax processing in music. Moreover, experimental results yielded within-domain individual differences, and identified continuous metrics of musical ability more beneficial than grouping musicians or non-musicians (Experiment 3). These combined results suggest that the meter-syntax interface differs uniquely in how it forms syntactic preferences in language and music.
The endosymbiont ofEpithemia clementinais specialized for nitrogen fixation within a photosynthetic eukaryote
Authors: Moulin Solène L.Y. , Frail Sarah , Doenier Jon , Braukmann Thomas , Yeh Ellen
Published: March 2023

Epithemiaspp. diatoms contain obligate, nitrogen-fixing endosymbionts, or “diazoplasts”, derived from cyanobacteria. These algae are a rare example of photosynthetic eukaryotes that have successfully coupled oxygenic photosynthesis with oxygen-sensitive nitrogenase activity. Here, we report a newly-isolated species,E. clementina, as a model to investigate endosymbiotic acquisition of nitrogen fixation. To detect the metabolic changes associated with endosymbiotic specialization, we compared nitrogen fixation, associated carbon and nitrogen metabolism, and their regulatory pathways in theEpithemiadiazoplast with its close, free-living cyanobacterial relative,Crocosphaera subtropica. UnlikeC. subtropica, we show that nitrogenase activity in the diazoplast is concurrent with, and even dependent on, host photosynthesis and no longer associated with cyanobacterial glycogen storage suggesting carbohydrates are imported from the host diatom. Carbohydrate catabolism in the diazoplast indicates that the oxidative pentose pathway and oxidative phosphorylation, in concert, generates reducing equivalents and ATP and consumes oxygen to support nitrogenase activity. In contrast to expanded nitrogenase activity, the diazoplast has diminished ability to utilize alternative nitrogen sources. Upon ammonium repletion, negative feedback regulation of nitrogen fixation was conserved, however ammonia assimilation showed paradoxical responses in the diazoplast compared withC. subtropica. The altered nitrogen regulation likely favors nitrogen transfer to the host. Our results suggest that the diazoplast is specialized for endosymbiotic nitrogen fixation. Altogether, we establish a new model for studying endosymbiosis, perform the first functional characterization of this diazotroph endosymbiosis, and identify metabolic adaptations for endosymbiotic acquisition of a critical biological function.
Tracking live-cell single-molecule dynamics enables measurements of heterochromatin-associated protein-protein interactions
Authors: Chen Ziyuan , Seman Melissa , Farhat Ali , Fyodorova Yekaterina , Biswas Saikat , Levashkevich Alexander , Freddolino P. Lydia , Biteen Julie S. , Ragunathan Kaushik
Published: March 2023

Visualizing and measuring molecular-scale interactions in living cells represents a major challenge, but recent advances in microscopy are bringing us closer to achieving this goal. Single-molecule super-resolution microscopy enables high-resolution and sensitive imaging of the positions and movement of molecules in living cells. HP1 proteins are important regulators of gene expression because they selectively bind and recognize H3K9 methylated (H3K9me) histones to form heterochromatin-associated protein complexes that silence gene expression. Here, we extended live-cell single-molecule tracking studies in fission yeast to determine how HP1 proteins interact with their binding partners in the nucleus. We measured how genetic perturbations that affect H3K9me alter the diffusive properties of HP1 proteins and each of their binding partners based on which we inferred their most likely interaction sites. Our results indicate that H3K9me promotes specific complex formation between HP1 proteins and their interactors in a spatially restricted manner, while attenuating their ability to form off-chromatin complexes. As opposed to being an inert platform or scaffold to direct HP1 binding, our studies propose a novel function for H3K9me as an active participant in enhancing HP1-associated complex formation in living cells.
Label-free proteomic comparison reveals ciliary and non-ciliary phenotypes of IFT-A mutants
Authors: Leggere Janelle C. , Hibbard Jaime V.K. , Papoulas Ophelia , Lee Chanjae , Pearson Chad G. , Marcotte Edward M. , Wallingford John B.
Published: March 2023

DIFFRAC is a powerful method for systematically comparing proteome content and organization between samples in a high-throughput manner. By subjecting control and experimental protein extracts to native chromatography and quantifying the contents of each fraction using mass spectrometry, it enables the quantitative detection of alterations to protein complexes and abundances. Here, we applied DIFFRAC to investigate the consequences of genetic loss of Ift122, a subunit of the intraflagellar transport-A (IFT-A) protein complex that plays a vital role in the formation and function of cilia and flagella, on the proteome ofTetrahymena thermophila. A single DIFFRAC experiment was sufficient to detect changes in protein behavior that mirrored known effects of IFT-A loss and revealed new biology. We uncovered several novel IFT-A-regulated proteins, which we validated through live imaging inXenopusmulticiliated cells, shedding new light on both the ciliary and non-ciliary functions of IFT-A. Our findings underscore the robustness of DIFFRAC for revealing proteomic changes in response to genetic or biochemical perturbation.
The long non-coding RNA MALAT1 modulates NR4A1 expression through a downstream regulatory element in specific cancer-cell-types
Authors: Wernig-Zorc Sara , Schwartz Uwe , Martínez Paulina , Inalef Josefa , Pavicic Francisca , Ehrenfeld Pamela , Längst Gernot , Maldonado Rodrigo
Published: March 2023

Chromatin-associated long non-coding RNAs (lncRNAs) have been shown to define chromatin density, regulate gene expression, and are involved in the initiation and progression of various cancer types. Despite the wealth of studies describing transcriptome changes upon lncRNA modulation, little data is showing the direct effects of lncRNA on regulatory elements (REs) that drive gene expression. Here we explored the molecular mechanism of the chromatin-interacting lncRNA, MALAT1, through RNA- and ATAC-seq, using HeLa cells as a model system. Time-resolved MALAT1 knock-down assays revealed its direct regulation of a limited number of protein-coding genes. Loss of MALAT1 resulted in a substantial loss of chromatin accessibility downstream of theNR4A1gene, associated with its down-regulation. CRISPR-i assays revealed that this region corresponds to a new downstream RE. Next, using TCGA data, we identified a direct correlation between the expression of NR4A1 and the accessibility of the downstream RE in breast cancer. The molecular mechanism was validated on estrogen receptor (ER) positive breast cancer cells (MCF7) and Pancreatic Duct Epithelioid Carcinoma (PANC1) cells, not showing this effect according to TCGA data. Indeed, MALAT1 regulates the expression of NR4A1 in a cell type-specific manner by changing the accessibility of the downstream RE. MALAT1 exhibits a molecular mechanism that fine-tunes the expression of cancer drivers, like NR4A1, in ER-positive breast cancer cells, but not in other cell types.
AMSTNDel273Cmutation withFGF5knockout sheep by CRISPR/Cas9 promotes skeletal muscle myofiber hyperplasia
Authors: Chen Ming-Ming , Zhao Yue , Xu Xue-Ling , Zhang Xiao-Sheng , Zhang Jin-Long , Wu Su-Jun , Liu Zhi-Mei , Yuan Yi-Ming , Guo Xiao-Fei , Qi Shi-Yu , Yi Guang , Wang Shu-Qi , Li Huang-Xiang , Wu Ao-Wu , Liu Guo-Shi , Yu Kun , Deng Shoulong , Han Hong-Bing , Lv Feng-Hua , Li Yan , Lian Zheng-Xing
Published: March 2023

Mutations in the well-known Myostatin (MSTN) produce a “double-muscle” phenotype, which makes it commercially invaluable for improving livestock meat production and providing high-quality protein for humans. However, mutations at different loci of theMSTNoften produce a variety of different phenotypes. In the current study, we increased the delivery ratio of Cas9 mRNA to sgRNA from the traditional 1:2 to 1:10, which improves the efficiency of the homozygous mutation of biallelic gene. Here, aMSTNDel273Cmutation withFGF5knockout sheep, in which theMSTNandFGF5dual-gene biallelic homozygous mutations were produced via the deletion of 3-base pairs of AGC in the third exon ofMSTN, resulting in cysteine-depleted at amino acid position 273, and theFGF5double allele mutation led to inactivation ofFGF5gene. TheMSTNDel273Cmutation withFGF5knockout sheep highlights a dominant “double-muscle” phenotype, which can be stably inherited. Both F0 and F1 generation mutants highlight the excellent trait of high-yield meat with a smaller cross-sectional area and higher number of muscle fibers per unit area. Mechanistically, theMSTNDel273Cmutation withFGF5knockout mediated the activation ofFOSL1via the MEK-ERK-FOSL1 axis. The activatedFOSL1promotes skeletal muscle satellite cell proliferation and inhibits myogenic differentiation by inhibiting the expression of MyoD1, and resulting in smaller myotubes. In addition, activated ERK1/2 may inhibit the secondary fusion of myotubes by Ca2+-dependent CaMKII activation pathway, leading to myoblasts fusion to form smaller myotubes.
Localization ofKif1cmRNA to cell protrusions dictates binding partner specificity of the encoded protein
Authors: Norris Megan L. , Mendell Joshua T.
Published: March 2023

Subcellular localization of messenger RNA (mRNA) is a widespread phenomenon that can impact the regulation and function of the encoded protein. In nonneuronal cells, specific mRNAs localize to cell protrusions, and proper mRNA localization is required for cell migration. However, the mechanisms by which mRNA localization regulates protein function in this setting remain unclear. Here, we examined the functional consequences of localization of the mRNA encoding KIF1C. KIF1C is a kinesin motor protein required for cell migration and mRNA trafficking, including trafficking of its own mRNA. We show thatKif1cmRNA localization does not regulate KIF1C's protein abundance, distribution, or ability to traffic other mRNAs. Conversely,Kif1cmRNA localization to protrusions is required for directed cell migration. We used mass spectrometry to identify binding partners of endogenous KIF1C, which revealed dramatic dysregulation of the number and identity of KIF1C interactors in response toKif1cmRNA mislocalization. These results therefore uncovered a mechanistic connection between mRNA localization to cell protrusions and the specificity of protein–protein interactions. We anticipate that this mechanism is not limited toKif1cand is likely to be a general principle that impacts the functions of proteins encoded by protrusion-enriched mRNAs in nonneuronal cells.
Defining the separation landscape of topological domains for decoding consensus domain organization of the 3D genome
Authors: Dang Dachang , Zhang Shao-Wu , Duan Ran , Zhang Shihua
Published: March 2023

Topologically associating domains (TADs) have emerged as basic structural and functional units of genome organization and have been determined by many computational methods from Hi-C contact maps. However, the TADs obtained by different methods vary greatly, which makes the accurate determination of TADs a challenging issue and hinders subsequent biological analyses about their organization and functions. Obvious inconsistencies among the TADs identified by different methods indeed make the statistical and biological properties of TADs overly depend on the chosen method rather than on the data. To this end, we use the consensus structural information captured by these methods to define the TAD separation landscape for decoding the consensus domain organization of the 3D genome. We show that the TAD separation landscape could be used to compare domain boundaries across multiple cell types for discovering conserved and divergent topological structures, decipher three types of boundary regions with diverse biological features, and identify consensus TADs (ConsTADs). We illustrate that these analyses could deepen our understanding of the relationships between the topological domains and chromatin states, gene expression, and DNA replication timing.
Assessing conformations of small molecules with crystallographic databases
Authors: McCabe Patrick , Cole Jason
Published: March 2023

In this work, libraries of crystallographically determined bond lengths, valence angles and torsion angles derived from the Cambridge Structural Database (CSD) are used to generate a score to validate an individual bond length, valence angle or torsion angle. A single score can also be derived for each ensemble of bond lengths, ensemble of valence angles and ensemble of torsion angles in the molecule. The data used to compute the score for the individual parts of the molecule are also used to compute a single value assessing the specific conformation relative to the geometric molecular data contained in the CSD. Such a single-number summary may be used, for example, to validate geometries of modelled molecules or molecular conformations in experimentally or computationally determined crystal structures. An example of how the score can be applied to an individual conformation is provided. Validation of the new score is performed by comparison with existing software for validating molecular geometries (Mogul) and a comparison with the CSD Conformer Generator scores is also carried out. Further application to the experimental standard deviation of C—C bonds of CSD entries is demonstrated, and the Platinum diverse data set is also studied.
Revisited relativistic Dirac–Hartree–Fock X-ray scattering factors. II. Chemically relevant cations and selected monovalent anions for atoms with Z = 3–112
Authors: Olukayode Shiroye , Froese Fischer Charlotte , Volkov Anatoliy
Published: March 2023

The previously described approach for determination of the relativistic atomic X-ray scattering factors (XRSFs) at the Dirac–Hartree–Fock level [Olukayode et al. (2023). Acta Cryst. A79, 59–79] has been used to evaluate the XRSFs for a total of 318 species including all chemically relevant cations [Greenwood & Earnshaw (1997). Chemistry of the Elements], six monovalent anions (O−, F−, Cl−, Br−, I−, At−), the ns
1
np
3 excited (valence) states of carbon and silicon, and several exotic cations (Db5+, Sg6+, Bh7+, Hs8+ and Cn2+) for which the chemical compounds have been recently identified, thus significantly extending the coverage relative to all the earlier studies. Unlike the data currently recommended by the International Union of Crystallography (IUCr) [Maslen et al. (2006). International Tables for Crystallography, Vol. C, Section 6.1.1, pp. 554–589], which originate from different levels of theory including the non-relativistic Hartree–Fock and correlated methods, as well as the relativistic Dirac–Slater calculations, the re-determined XRSFs come from a uniform treatment of all species within the same relativistic B-spline Dirac–Hartree–Fock approach [Zatsarinny & Froese Fischer (2016). Comput. Phys. Comm.
202, 287–303] that includes the Breit interaction correction and the Fermi nuclear charge density model. While it was not possible to compare the quality of the generated wavefunctions with that from the previous studies due to a lack (to the best of our knowledge) of such data in the literature, a careful comparison of the total electronic energies and the estimated atomic ionization energies with experimental and theoretical values from other studies instils confidence in the quality of the calculations. A combination of the B-spline approach and a fine radial grid allowed for a precise determination of the XRSFs for each species in the entire 0 ≤ sin θ/λ ≤ 6 Å−1 range, thus avoiding the necessity for extrapolation in the 2 ≤ sin θ/λ ≤ 6 Å−1 interval which, as was shown in the first study, may lead to inconsistencies. In contrast to the Rez et al. work [Acta Cryst. (1994), A50, 481–497], no additional approximations were introduced when calculating wavefunctions for the anions. The conventional and extended expansions were employed to produce interpolating functions for each species in both the 0 ≤ sin θ/λ ≤ 2 Å−1 and 2 ≤ sin θ/λ ≤ 6 Å−1 intervals, with the extended expansions offering a significantly better accuracy at a minimal computational overhead. The combined results of this and the previous study may be used to update the XRSFs for neutral atoms and ions listed in Vol. C of the 2006 edition of International Tables for Crystallography.
Food entrepreneurship and self-employment in an island context
Authors: Rytkönen Paulina Ines , Oghazi Pejvak , Mostaghel Rana
Published: March 2023

Purpose

The aim is to advance the conceptualisation of island entrepreneurship by investigating how the island context, for example, industry characteristics, social context and formal and informal institutions, influences the development of artisan food businesses in that context.

Design/methodology/approach

An applied, qualitative and participatory research approach was implemented. Data were collected during a business development process focusing on food artisans in the Åland Islands. In total, 19 business owners participated in the process. Key informants and public officers were interviewed, and the literature was reviewed. Interviews were analysed using phenomenography to identify representative categories, and the literature was analysed using content analysis.

Findings

Island characteristics and context, local institutions, the quality of social capital and gendered institutions influence business activities positively and negatively. Island entrepreneurship entails mobilising agencies to find innovative solutions that enable businesses to overcome obstacles. Most previous research treats business activities as entrepreneurship; however, as self-employment is essential in the island context, it should be highlighted in future studies.

Research limitations/implications

This study illustrates how the island context influences the business development of small firms. Results indicate that local policies (1) benefitting female entrepreneurs, (2) supporting local businesses and (3) promoting locally produced artisan food could generate benefits for the entire artisan food businesses.

Practical implications

Local policies that (1) benefit female entrepreneurs, (2) support local businesses and (3) promote locally produced artisan food have the potential to generate benefits for the entire trade. Policies can benefit from an understanding of the role played by different ecosystem actors. Promoting self-employment can generate benefits for the local entrepreneurial ecosystem by providing agglomeration and helping to solve some challenges caused by the characteristics of islands.

Originality/value

Empirically, this research enhances the knowledge of post-productive responses in the island context. Theoretically, the study advances the conceptualisation of research on the island entrepreneurship context and the local food debate.
Effects of social media empowerment on COVID-19 preventive behaviors in China
Authors: Lu Jiandong , Wang Xiaolei , Fei Liguo , Chen Guo , Feng Yuqiang
Published: March 2023

Purpose

During the coronavirus disease 2019 (COVID-19) pandemic, ubiquitous social media has become a primary channel for information dissemination, social interactions and recreational activities. However, it remains unclear how social media usage influences nonpharmaceutical preventive behavior of individuals in response to the pandemic. This paper aims to explore the impacts of social media on COVID-19 preventive behaviors based on the theoretical lens of empowerment.

Design/methodology/approach

In this paper, survey data has been collected from 739 social media users in China to conduct structural equation modeling (SEM) analysis.

Findings

The results indicate that social media empowers individuals in terms of knowledge seeking, knowledge sharing, socializing and entertainment to promote preventive behaviors at the individual level by increasing each person's perception of collective efficacy and social cohesion. Meanwhile, social cohesion negatively impacts the relationship between collective efficacy and individual preventive behavior.

Originality/value

This study provides insights regarding the role of social media in crisis response and examines the role of collective beliefs in the influencing mechanism of social media. The results presented herein can be used to guide government agencies seeking to control the COVID-19 pandemic.
Non-performing loans and bank performance: what role does corporate social responsibility play? A system GMM analysis for European banks
Authors: Boussaada Rim , Hakimi Abdelaziz , Karmani Majdi
Published: March 2023

Purpose

This research investigated whether corporate social responsibility (CSR) can alleviate the negative effect of non-performing loans (NPLs) on bank performance.

Design/methodology/approach

The research employed a sample of European banks over the 2008–2017 period. To resolve endogeneity and heterogeneity problems, the system generalized method of moments (SGMM) model was employed.

Findings

First, bank NPLs were negatively and significantly associated with bank performance as measured by the Q-Tobin ratio and the return on assets (ROA). Second, CSR scores exerted a negative and significant effect on the level of NPLs. Finally, the results indicated that bank performance could benefit from the interactional effect of CSR and NPLs.

Research limitations/implications

This study fills the gap in the debate over the mediating role of CSR in the NPLs – bank performance interrelation. In addition, our SGMM analysis yielded more robust and efficient results while resolving endogeneity and heterogeneity problems concerning CSR and bank performance or risk in corporate finance.

Practical implications

CSR practices can play an essential mediating role in the NPLs–bank performance relationship. CSR activities in the European context may reduce the level of NPLs and increase bank performance.

Originality/value

To the best of the authors’ knowledge, studies of the implications of CSR activities on the banking sector are very limited. Indeed, this paper shows that CSR mediates the relationship between CSR practices and NPLs. The results suggest that bank performance could benefit from the interactional effect of CSR and NPLs.
Nicotine‐ and tar‐removed cigarette smoke extract modulates the antigen presentation function of mouse bone marrow‐derived dendritic cells
Authors: Furuta Kazuyuki , Yoshioka Takehiro , Nishikaze Kana , Yoshikawa Noriko , Nakamura Kazuki , Kaito Chikara
Published: March 2023

Dendritic cells (DCs) take up antigens derived from pathogens such as bacteria and viruses, and from tumor cells and induce the activation of antigen‐specific T cells through major histocompatibility complex (MHC)‐mediated antigen presentation. Mainstream cigarette smoke extract (CSE) has various effects, and the effects of its major components, nicotine and tar, have been analyzed extensively. Recently, the physiological effects of nicotine‐ and tar‐removed CSE (cCSE) have also been reported. However, the effects of cCSE on DC‐mediated immune responses remain unknown. In this study, we found that cCSE enhanced lipopolysaccharide (LPS)‐stimulated induction of the expression of MHC‐I and MHC‐II on the cell surface of mouse bone marrow‐derived DCs (BMDCs). In contrast, cCSE suppressed the induction of CD86 induced by stimulation with curdlan and interferon‐γ (IFN‐γ). In addition, cCSE suppressed the production of IL‐12, IL‐23, and IL‐10 by LPS and curdlan stimulation. In the presence of cCSE, LPS‐stimulated BMDCs showed enhanced activation of CD4 and CD8 T cells and increased IL‐2 production from T cells by antigen presentation in a mixed‐leukocyte reaction assay. In contrast, cCSE did not affect the activation of T cells by curdlan‐ or IFN‐γ‐stimulated BMDCs, and curdlan‐stimulated BMDCs suppressed IL‐17 production from T cells and enhanced IFN‐γ production. These results suggest that cCSE has different effects on the activation signals induced by LPS, curdlan, and IFN‐γ in BMDCs and modulates the antigen presentation function of BMDCs.
Recent advances in studies on magnetosome‐associated proteins composing the bacterial geomagnetic sensor organelle
Authors: Taoka Azuma , Eguchi Yukako , Shimoshige Rino , Fukumori Yoshihiro
Published: March 2023

Magnetotactic bacteria (MTB) generate a membrane‐enclosed subcellular compartment called magnetosome, which contains a biomineralized magnetite or greigite crystal, an inner membrane–derived lipid bilayer membrane, and a set of specifically targeted associated proteins. Magnetosomes are formed by a group of magnetosome‐associated proteins encoded in a genomic region called magnetosome island. Magnetosomes are then arranged in a linear chain–like positioning, and the resulting magnetic dipole of the chain functions as a geomagnetic sensor for magneto‐aerotaxis motility. Recent metagenomic analyses of environmental specimens shed light on the sizable phylogenetical diversity of uncultured MTB at the phylum level. These findings have led to a better understanding of the diversity and conservation of magnetosome‐associated proteins. This review provides an overview of magnetosomes and magnetosome‐associated proteins and introduces recent topics about this fascinating magnetic bacterial organelle.
Soil protist functional composition shifts with atmospheric nitrogen deposition in subtropical forests
Authors: Wang Jianqing , Zheng Chengyang , Lucas‐Borja Manuel Esteban , Shi Xiuzhen
Published: March 2023

Soil protists play a key role in driving ecological functions through predation and parasitism. However, little is known about how nitrogen (N) deposition and seasonal variation influence soil protist functions in forest soils.

Here, we assessed first the impacts of N deposition (control, 50, 100 and 150 kg N ha−1 year−1) on the functional composition of the soil protist community in summer and winter, using amplicon sequencing of environmental DNA from a subtropical natural forest.

We found that soil protists were dominated by consumers (42.6%–51.6%), followed by parasites (32.9%–40.9%) and phototrophs (3.2%–13.1%), implying a predominant role of consumers and potential top‐down effects on the other trophic groups in subtropical forest soils. The functional composition of soil protists was greatly influenced by N deposition, but these responses were dependent on seasonal variation. The diversity of phototrophs was lower in summer than in winter. Instead, an opposite pattern was observed for consumers, resulting in a significantly higher protist diversity in summer than in winter. Furthermore, low and high N deposition simplified the structural complexity of soil protist communities, suggesting a nonlinear response of protist structural stability to N deposition.

Synthesis and applications. This study provides unprecedented evidence that seasonal variation plays an important role in regulating responses of soil protist functional composition to N deposition, and highlights the nonlinear effects of rising N deposition on the soil food web.
Lactantius's “Modern” Conception of Religio*
Authors: Alimi Toni
Published: March 2023

Scholars of religion sometimes argue that a distinctively modern conception of religion takes religion to be a trans‐cultural category, divisible into “true” and “false” versions, of which Christianity is the core type. Thus, according to the so‐called modern conception of religion, every culture has its own religion. Some are true (paradigmatically Christianity), some are false. This paper argues that these ideas were present in Lactantius's (c. 250–325) conception of religio. It shows this by presenting Lactantius's development of a theory of religio. This theory was the product of Lactantius combining one Ciceronian conception of religio and a Christian origin‐story about where religio comes from. Lactantius used this theory to analyse Christianity and what he took to be its competitors.