bluuebunny/crossref_metadata_2025_split huggingface dataset:
The cell cycle inhibitor RB is diluted in G1 and contributes to controlling cell size in the mouse liver
Authors: Zhang Shuyuan , Zatulovskiy Evgeny , Arand Julia , Sage Julien , Skotheim Jan M. 
Published: June 2022

AbstractEvery type of cell in an animal maintains a specific size, which likely contributes to its ability to perform its physiological functions. While some cell size control mechanisms are beginning to be elucidated through studies of cultured cells, it is unclear if and how such mechanisms control cell size in an animal. For example, it was recently shown that RB, the retinoblastoma protein, was diluted by cell growth in G1 to promote size-dependence of the G1/S transition. However, it remains unclear to what extent the RB-dilution mechanism controls cell size in an animal. We therefore examined the contribution of RB-dilution to cell size control in the mouse liver. The RB-dilution model has two requirements. First, manipulations changing RB concentration drive corresponding changes in cell size, and second, the endogenous RB concentration decreases with cell size in G1. We found that both these requirements were met. Genetic perturbations decreasing RB protein concentrations through inducible shRNA expression or through liverspecific Rb1 knockout reduced hepatocyte size, while perturbations increasing RB protein concentrations in an Fah−/− mouse model increased hepatocyte size. Moreover, RB concentration decreased in larger G1 hepatocytes while the concentrations of the cell cycle activators Cyclin D1 and E2f1 remained relatively constant. Lastly, we tested how Rb1 manipulations affected G1/S cell size control in primary hepatocytes using live cell imaging. Loss of Rb1 weakened cell size control, i.e., reduced the inverse correlation between how much cells grew in G1 and how large they were at birth. Taken together, our results show that an RB- dilution mechanism contributes to cell size control in the mouse liver by linking cell growth to the G1/S transition.
A pan-genome approach to decipher variants in the highly complex tandem repeat ofLPA
Authors: Chin Chen-Shan , Behera Sairam , Metcalf Ginger A. , Gibbs Richard A. , Boerwinkle Eric , Sedlazeck Fritz J. 
Published: June 2022

AbstractLp(a) is an important factor in Coronary Heart disease risk, and its expression is correlated with the length of theLPAgene. The KIV-2 region ofLPAconsists of variable tandem repeats whose number is highly variable across individuals. Little is known about the inner diversity of the KIV-2 repeats themselves. Here we utilize a pan-genome graph approach across 47 haplotype resolved assemblies to identify unexpected variation across KIV-2.
NSUN2-mediated mRNA m5C Modification Regulates the Progression of Hepatocellular Carcinoma
Authors: Song Dan , An Ke , Zhai Wen-Long , Feng Lu-Yao , Xu Ying-Jie , Sun Ran , Wang Yue-Qin , Yang Yun-Gui , Kan Quan-Cheng , Tian Xin 
Published: June 2022

AbstractRNA modification affects many biological processes and physiological diseases. The 5-methylcytosine (m5C) modification regulates the progression of multiple tumors. However, its characteristics and functions in hepatocellular carcinoma (HCC) remain largely unknown. Here, we found that HCC tissues had a higher m5C methylation level than the adjacent normal tissues. Transcriptome analysis revealed that a major fraction of the hypermethylated genes participated in the phosphokinase signaling pathways, such as the Ras and PI3K-Akt pathways. The m5C methyltransferase NSUN2 was highly expressed in HCC tissues consistently. Interestingly, the expression of many oncogenes was positively correlated with the expression of NSUN2, including GRB2, RNF115, AATF, ADAM15, RTN3, and HDGF. Real-time PCR assays further revealed that the expression of the mRNA of GRB2, RNF115, and AATF decreased significantly with the depletion of NSUN2 in HCC cells. Furthermore, NSUN2 could regulate the cellular sensitivity of HCC cells to sorafenib via modulating the Ras signaling pathway. Moreover, knocking down NSUN2 caused cell cycle arrest. Our study demonstrated a vital role of NSUN2 in the progression of HCC.
An atypical F-actin capping protein modulates cytoskeleton behaviors crucial to colonization of Trichomonas vaginalis
Authors: Wang Kai-Hsuan , Chang Jing-Yang , Li Fu-An , Chen Yen-Ju , Wu Kuan-Yi , Chu Tse-Ling , Lin Jessica , Hsu Hong-Ming 
Published: June 2022

AbstractCytoadherence and consequential migration are crucial for pathogens to establish colonization in the host. In contrast to the nonadherent isolate of Trichomonas vaginalis, the adherent one expresses more actin-related machinery proteins with more active flagellate-amoeboid morphogenesis, amoeba migration, and cytoadherence, activities that were abrogated by an actin assembly blocker. By immunoprecipitation coupled with label-free quantitative proteomics, an F-actin capping protein (TvFACPα) was identified from the actin-centric interactome, with an atypically greater binding preference to G-actin than F-actin. TvFACPα partially colocalized with F-actin at the parasite pseudopodia protrusion and formed the protein complexes with α-actin through its c-terminal domain. Meanwhile, TvFACPα overexpression suppresses F-actin polymerization, amoeboid morphogenesis, and cytoadherence in this parasite. Ser2 phosphorylation of TvFACPα enriched in the amoeboid stage of adhered trophozoites was reduced by a CKII inhibitor. The site-directed mutagenesis and CKII inhibitor treatment revealed that Ser2 phosphorylation acts as a switching signal to alter TvFACPα actin-binding activity and consequent actin cytoskeleton behaviors. Through CKII signaling, TvFACPα also controls the conversion of adherent trophozoite from amoeboid migration to flagellate form with axonemal motility. Together, CKII-dependent Ser2 phosphorylation regulates TvFACPα binding actin to fine-tune cytoskeleton dynamics and drive crucial behaviors underlying host colonization of T. vaginalis.
Non-standard viral genome-derived RNA activates TLR3 and type I IFN signaling to induce cDC1-dependent CD8+ T-cell responses during vaccination in mice
Authors: Fisher Devin G. , Holthausen David J. , López Carolina B. 
Published: June 2022

ABSTRACTThere is a critical need to develop vaccine adjuvants that induce robust immune responses able to protect against intracellular pathogens, including viruses. Previously, we described the virus-derived adjuvant, defective viral genome-derived oligonucleotide (DDO), as a strong inducer of type 1 immune responses, including protective Th1 CD4+ T-cells and effector CD8+ T-cells in mice. Here we unravel the early innate response required for this type 1 immunity induction. Upon DDO subcutaneous injection, type 1 conventional dendritic cells (cDC1s) accumulate rapidly in the draining lymph node in a type I interferon (IFN)-dependent manner. cDC1 accumulation in the lymph node is required for antigen-specific CD8+ T-cell responses. Notably, in contrast to poly I:C, DDO administration resulted in type I IFN expression at the injection site, but not in the draining lymph node. Additionally, DDO induced an inflammatory cytokine profile distinct from that induced by poly I:C. Therefore, DDO represent a powerful new adjuvant to be used during vaccination against intracellular pathogens.IMPORTANCEThere is a paucity of vaccine adjuvants able to trigger effective and safe protective responses to many intracellular pathogens. Defining the minimal requirements to achieve type 1 immunity, which includes antigen specific CD8+ T cells capable of eliminating infected cells, is essential for the development of adjuvants that lead to optimal protective immune responses during vaccination against intracellular pathogens. We use a virus-derived immunostimulatory molecule, defective viral genome-derived oligonucleotide (DDO), to provide insights into how type 1 immune responses are triggered during vaccination using an inactivated influenza vaccine model. Understanding the mechanism of action of vaccine adjuvants not only aids in the advancement of vaccine development, but also in understanding specific immune pathways required for efficient induction of adaptive immune responses to infections.
Intracellular mechanics and TBX3 expression jointly dictate the spreading mode of melanoma cells in 3D environments
Authors: Higgins Ghodeejah , Higgins Faatiemah , Peres Jade , Lang Dirk M , Abdalrahman Tamer , Zaman Muhammad H. , Prince Sharon , Franz Thomas 
Published: June 2022

AbstractCell stiffness and T-box transcription factor 3 (TBX3) expression have been identified as biomarkers of melanoma metastasis in 2D environments. This study aimed to determine how mechanical and biochemical properties of melanoma cells change during cluster formation in 3D environments. Vertical growth phase (VGP) and metastatic (MET) melanoma cells were embedded in 3D collagen matrices of 2 and 4 mg/ml collagen concentrations, representing low and high matrix stiffness. Mitochondrial fluctuation, intracellular stiffness, and TBX3 expression were quantified before and during cluster formation. In isolated cells, mitochondrial fluctuation decreased and intracellular stiffness increased with increase in disease stage from VGP to MET and increased matrix stiffness. TBX3 was highly expressed in soft matrices but diminished in stiff matrices for VGP and MET cells. Cluster formation of VGP cells was excessive in soft matrices but limited in stiff matrices, whereas for MET cells it was limited in soft and stiff matrices. In soft matrices, VGP cells did not change the intracellular properties, whereas MET cells exhibited increased mitochondrial fluctuation and decreased TBX3 expression. In stiff matrices, mitochondrial fluctuation and TBX3 expression increased in VGP and MET, and intracellular stiffness increased in VGP but decreased in MET cells. The findings suggest that soft extracellular environments are more favourable for tumour growth, and high TBX3 levels mediate collective cell migration and tumour growth in the earlier VGP disease stage but play a lesser role in the later metastatic stage of melanoma.Symbols
The restriction factor pastrel is associated with host vigor, viral titer, and variation in disease tolerance during Drosophila C Virus infection
Authors: Kutzer Megan A.M. , Gupta Vanika , Neophytou Kyriaki , Doublet Vincent , Monteith Katy M. , Vale Pedro F. 
Published: June 2022

AbstractGenetic variation for both resistance and disease tolerance has been described in a range of species infected with bacterial, viral and fungal pathogens. In Drosophila melanogaster, genetic variation in mortality following systemic Drosophila C Virus (DCV) infection has been shown to be driven by large effect polymorphisms in the viral restriction factor pastrel (pst). However, it is unclear if pst impacts variation in DCV titres (i.e. resistance), or if it also contributes to disease tolerance. We investigated systemic infection across a range of DCV challenge doses spanning nine orders of magnitude, in males and females of ten Drosophila Genetic Reference Panel (DGRP) lines carrying either a susceptible (S) or resistant (R) pst allele. Our results uncover among-line variation in fly survival, viral titers, and disease tolerance measured both as the ability to maintain survival (mortality tolerance) and reproduction (fecundity tolerance). We confirm the role of pst in resistance, as fly lines with the resistant (R) pst allele experienced lower viral titers, and we uncover novel effects of pst on host vigor, as flies carrying the R allele exhibited higher survival and fecundity even in the absence of infection. Finally, we found significant variation in the expression of the JAK-STAT ligand upd3 and the epigenetic regulator of JAK-STAT G9a. While G9a has been previously shown to mediate tolerance of DCV infection, we found no correlation between the expression of either upd3 or G9a on fly tolerance or resistance. Our work highlights the importance of both resistance and tolerance in viral defence.
Chiral growth of adherent filopodia
Authors: Li Wenhong , Chung Wen-Lu , Kozlov Michael M. , Medalia Ohad , Geiger Benjamin , Bershadsky Alexander D. 
Published: June 2022

AbstractAdherent filopodia are elongated finger-like membrane protrusions, extending from the edges of diverse cell types and participating in cell adhesion, spreading, migration and environmental sensing. The formation and elongation of filopodia are driven by the polymerization of parallel actin filaments, comprising the filopodia cytoskeletal core. Here, we report that adherent filopodia, formed during the spreading of cultured cells on galectin-8-coated substrates, tend to change the direction of their extension in a chiral fashion, acquiring a left-bent shape. Cryo-electron tomography examination indicated that turning of the filopodia tip to the left is accompanied by the displacement of the actin core bundle to the right of the filopodia midline. Reduction of the adhesion to galectin-8 by treatment with thiodigalactoside abolished the filopodia chirality. By modulating the expression of a variety of actin-associated filopodia proteins, we identified myosin-X and formin DAAM1 as major filopodia chirality promoting factors. Formin mDia1, actin filament elongation factor VASP, and actin filament crosslinker fascin were also shown to be involved. Thus, the simple actin cytoskeleton of filopodia, together with a small number of associated proteins are sufficient to drive a complex navigation process, manifested by the development of left-right asymmetry in these cellular protrusions.
Deep thermal proteome profiling for detection of proteoforms and drug sensitivity biomarkers
Authors: Kurzawa Nils , Stahl Matthias , Leo Isabelle , Kunold Elena , Becher Isabelle , Audrey Anastasia , Mermelekas Georgios , Huber Wolfgang , Mateus André , Savitski Mikhail M. , Jafari Rozbeh 
Published: June 2022

AbstractThe complexity of the functional proteome extends significantly beyond the protein coding genome resulting in millions of proteoforms. Investigation of proteoforms and their functional roles is important to understand cellular physiology and its deregulation in diseases, but challenging to perform systematically. Here, we apply thermal proteome profiling with deep peptide coverage to detect functional proteoforms in acute lymphoblastic leukemia cell lines with different cytogenetic aberrations. We detect 15,846 proteoforms, capturing differently spliced, post-translationally modified, and cleaved proteins expressed from 9,290 genes. We identify differential coaggregation of proteoform pairs and establish links to disease biology. Moreover, we systematically make use of measured biophysical proteoform states to find specific biomarkers of drug sensitivity. Our approach thus provides a powerful and unique tool for systematic detection and functional annotation of proteoforms.
Keap1-resistant ΔN-Nrf2 isoform does not translocate to the nucleus upon electrophilic stress
Authors: Mikac Sara , Dziadosz Alicja , Padariya Monikaben , Kalathiya Umesh , Fahraeus Robin , Marek-Trzonkowska Natalia , Chruściel Elżbieta , Urban-Wójciuk Zuzanna , Papak Ines , Arcimowicz Łukasz , Marjanski Tomasz , Rzyman Witold , Sznarkowska Alicja 
Published: June 2022

AbstractThe Nrf2 pathway is an essential defense pathway in a cell. It responds to oxidative and electrophilic stress via derepression of Nrf2 from Keap1-Cul3-mediated degradation, accumulation of Nrf2 in the nucleus and transcriptional activation of a number of detoxifying and cell protective Nrf2 target genes. Here we report that normal and cancer cells also express the N-terminally truncated Nrf2 isoform (ΔN-Nrf2), which originates from an alternative promoter. Co-immunoprecipitation together with molecular dynamics simulation showed that the binding between ΔN-Nrf2 and Keap1 is impaired, resulting in the much higher stability of this form. ΔN-Nrf2 is retained in the cytoplasm in response to electrophilic stress, indicating that it does not regulate transcription under the same stress stimuli as the full-length Nrf2. Altogether this data suggests that Nrf2 has other functions in cells than transcriptional activation of genes, which most probably rely on the protein-protein interactions in the cytoplasm. The regulation between these functions takes place on the level of transcription.Significance StatementThis work signifies the importance of alternative transcription in assigning the function to the produced protein. Nrf2 transcripts produced from the second promoter of the Nrf2 gene give rise to the N-terminally truncated Nrf2 form (ΔN-Nrf2), which is retained in the cytoplasm upon stress, thus it has a different role in cells than transcriptional regulation. ΔN-Nrf2 is resistant to the Keap1-Cul3 degradation pathway and is highly expressed in all tested cell types. This work points to the new, cytoplasmic role of Nrf2 in cells, determined at the level of transcription.
The effects of workplace resources on employees’ decision to provide instrumental help to their colleagues
Authors: Zampetakis Leonidas A. 
Published: June 2022

PurposeThe purpose of this research is to establish a hierarchy among different workplace resources in terms of their relative contribution to employee decision to provide instrumental help.Design/methodology/approachA within-person survey experiment was conducted and the data were analyzed using multilevel regression. The data are based on a random sample of 94 employees working in medium-sized companies in Crete, Greece.FindingsResults suggest that for employees’ decision to provide instrumental help, some job resources are perceived as more important than others. Workplace resources that are closer to employees (i.e. coworkers’ social support and manager–subordinate relationship) are perceived as more important compared to leadership style and the manager use of humor.Practical implicationsFindings suggest that organizations can successfully improve instrumental helping through interventions primarily aimed at building group-level resources.Originality/valueThe study highlights the importance of workplace resources for employees’ decision to provide instrumental help. However not all job resources are perceived as equally important. Theoretically, the study extends influential resource-based theories.
The role of artificial intelligence in effective business operations during COVID-19
Authors: Chen Yasheng , Biswas Mohammad Islam , Talukder Md. Shamim 
Published: June 2022

PurposeThe pressure to survive in a highly competitive market by using artificial intelligence (AI) has further demonstrated the need for automation in business operations during a crisis, such as COVID-19. Prior research finds managers' mixed perceptions about the use of technology in business, which underscores the need to better understand their perceptions of adopting AI for automation in business operations during COVID-19. Based on social exchange theory, the authors investigated managers' perceptions of using AI in business for effective operations during the COVID-19 pandemic.Design/methodology/approachThis study collected data through a survey conducted in China (N = 429) and ran structural equation modeling to examine the proposed research model and structural relationships using Smart PLS software.FindingsThe results show that using AI in supply chain management, inventory management, business models, and budgeting are positively associated with managers' satisfaction. Further, the relationship between managers' satisfaction and effective business operations was found to be positively significant. In addition, the findings suggest that top management support and the working environment have moderating effects on the relationship between managers' satisfaction and effective business operations.Practical implicationsThe results of this study can guide firms to adopt an AI usage policy and execution strategy, according to managers' perceptions and psychological responses to AI.Social implicationsThe study can be used to manage the behavior of managers within organizations. This will ultimately improve society's perception of the employment of AI in business operations.Originality/valueThe study's outcomes provide valuable insights into business management and information systems with AI application as a business response to any crisis in the future.
TMT's decision-making on adoption of management innovation
Authors: Li Ruida , Zheng Li , Yuan Ling 
Published: June 2022

PurposeExternal environment drives established enterprises to employ management innovation. Drawing on dual-process theories, this paper purports to investigate TMT's intuitive and rational decision-making styles as mediating roles between perceived environmental turbulences and management innovation, and explain how organizational slack play an critical moderating role.Design/methodology/approachSPSS 25 is used to test 120 established enterprises' top management team (TMT) samples in China, and the moderated mediation model is empirically tested by using hierarchical regression analysis and conditional process analysis.FindingsPerceived environmental turbulences promotes management innovation. Organizational slack as contextual variable influences the relationship between technology turbulence and TMT's decision-making styles. Interestingly, only perceived technology turbulence indirectly affects management innovation through TMT's intuitive decision-making when moderated by organizational slack. However, the indirect effect from perceived market turbulence to management innovation through TMT's rational decision-making is not significant when moderated by organizational slack.Originality/valueBased on management innovation's human agency perspective, TMT's decision-making styles have not been discussed in research on management innovation. This paper sheds light on TMT's decision-making styles as mediating role.
Justice as fairness: a Rawlsian perspective in compensating regulatory land takings
Authors: Ti Edward S.W. 
Published: June 2022

Purpose
The purpose of this paper is to articulate the inherent unfairness in compensation outcomes between landowners whose land is physically taken versus those whose land is regulated. Using Rawlsian theory as the normative standard of “fairness as justice”, the paper argues that both physical and regulatory takings should be compensated.

Design/methodology/approach
Most jurisdictions invariably provide market price compensation when land is physically acquired. When land is not physically taken but merely subject to regulation, however, there is no corresponding need to compensate, even where the economic loss suffered by the landowner is the same. Adopting Rawlsian theory, this paper explains why justice and fairness in land use planning require both physical takings and regulatory takings to be equally compensable.

Findings
Applying Rawlsian theory to compare compensable compulsory purchase with non-compensable regulatory takings of land show that the latter is not compatible with an ethical planning praxis.

Originality/value
While Rawlsian theory has been applied in urban planning research before, this would be its first application in highlighting the apparent justice paradox which now distinguishes a physical and regulatory taking of land.