bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombospondin 2 is a key determinant of fibrogenesis in NAFLD
Authors: Kimura Takefumi , Iwadare Takanobu , Wakabayashi Shun-ichi , Kuldeep Seema , Nakajima Tomoyuki , Yamazaki Tomoo , Aomura Daiki , Zafar Hamim , Iwaya Mai , Uehara Takeshi , Pydi Sai P , Tanaka Naoki , Umemura Takeji 
Published: June 2023

AbstractHepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. The current study aimed to identify the specific cells expressing THBS2/TSP2 in non-alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 up-regulation. Comprehensive NAFLD liver gene datasets, including single-cell RNA sequencing (scRNA-seq), in-house NAFLD liver tissue, and LX-2 cells derived from human hepatic stellate cells (HSCs), were analyzed using a combination of computational biology, genetic, immunological, and pharmacological approaches. Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r=0.349, p<0.001). In support of this, scRNA-seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGFβ) pathway and collagen gene activation. Moreover, the activation of LX-2 cells with TGFβ increased THBS2/TSP2 and collagen expression independently of the TGFβ-SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX-2 cells. In conclusion, THBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti-fibrotic therapy in NAFLD. (241 words)One-sentence summaries:Thrombospondin 2 represent a potential target for anti-fibrotic therapy in NAFLD.
Estimating multiplicity of infection, allele frequencies, and prevalences accounting for incomplete data
Authors: Hashemi Meraj , Schneider Kristan A. 
Published: June 2023

AbstractBackgroundMolecular surveillance of infectious diseases allows the monitoring of pathogens beyond the granularity of traditional epidemiological approaches and is well-established for some of the most relevant infectious diseases such as malaria. The presence of genetically distinct pathogenic variants within an infection, referred to as multiplicity of infection (MOI) or complexity of infection (COI) is common in malaria and similar infectious diseases. It is an important metric that scales with transmission intensities, potentially affects the clinical pathogenesis, and a confounding factor when monitoring the frequency and prevalence of pathogenic variants. Several statistical methods exist to estimate MOI and the frequency distribution of pathogen variants. However, a common problem is the quality of the underlying molecular data. If molecular assays fail not randomly, it is likely to underestimate MOI and the prevalence of pathogen variants.Methods and findingsA statistical model is introduced which explicitly addresses data quality, by assuming a probability by which a pathogen variant remains undetected in a molecular assay. This is different from the assumption of missing at random, for which a molecular assay either performs perfectly or fails completely. The method is applicable to a single molecular marker and allows to estimate allele-frequency spectra, the distribution of MOI, and the probability of variants to remain undetected (incomplete information). Based on the statistical model, expressions for the prevalence of pathogen variants are derived and differences between frequency and prevalence are discussed. The usual desirable asymptotic properties of the maximum-likelihood estimator (MLE) are established by rewriting the model into an exponential family. The MLE has promising finite sample properties in terms of bias and variance. The covariance matrix of the estimator is close to the Cramér-Rao lower bound (inverse Fisher information). Importantly, the estimator’s variance is larger than that of a similar method which disregards incomplete information, but its bias is smaller.ConclusionsAlthough the model introduced here has convenient properties, in terms of the mean squared error it does not outperform a simple standard method that neglects missing information. Thus, the new method is recommendable only for data sets in which the molecular assays produced poor quality results. This will be particularly true if the model is extended to accommodate information from multiple molecular markers at the same time, and incomplete information at one or more markers leads to strong depletion of sample size.
AGILE Platform: A Deep Learning-Powered Approach to Accelerate LNP Development for mRNA Delivery
Authors: Xu Yue , Ma Shihao , Cui Haotian , Chen Jingan , Xu Shufen , Wang Kevin , Varley Andrew , Ze Lu Rick Xing , Wang Bo , Li Bowen 
Published: June 2023

AbstractIonizable lipid nanoparticles (LNPs) have seen widespread use in mRNA delivery for clinical applications, notably in SARS-CoV-2 mRNA vaccines. Despite their successful use, expansion of mRNA therapies beyond COVID-19 is impeded by the absence of LNPs tailored to different target cell types. The traditional process of LNP development remains labor-intensive and cost-inefficient, relying heavily on trial and error. In this study, we present theAI-GuidedIonizableLipidEngineering (AGILE) platform, a synergistic combination of deep learning and combinatorial chemistry. AGILE streamlines the iterative development of ionizable lipids, crucial components for LNP-mediated mRNA delivery. This approach brings forth three significant features: efficient design and synthesis of combinatorial lipid libraries, comprehensive in silico lipid screening employing deep neural networks, and adaptability to diverse cell lines. Using AGILE, we were able to rapidly design, synthesize, and evaluate new ionizable lipids for mRNA delivery in muscle and immune cells, selecting from a library of over 10,000 candidates. Importantly, AGILE has revealed cell-specific preferences for ionizable lipids, indicating the need for different tail lengths and head groups for optimal delivery to varying cell types. These results underscore the potential of AGILE in expediting the development of customized LNPs. This could significantly contribute to addressing the complex needs of mRNA delivery in clinical practice, thereby broadening the scope and efficacy of mRNA therapies.One Sentence SummaryAI and combinatorial chemistry expedite ionizable lipid creation for mRNA delivery.
Deep Phenotyping of the Lipidomic Response in COVID and non-COVID Sepsis
Authors: Meng Hu , Sengupta Arjun , Ricciotti Emanuela , Mrčela Antonijo , Mathew Divij , Mazaleuskaya Liudmila L. , Ghosh Soumita , Brooks Thomas G. , Turner Alexandra P. , Schanoski Alessa Soares , Lahens Nicholas F. , Tan Ai Wen , Woolfork Ashley , Grant Greg , Susztak Katalin , Letizia Andrew G. , Sealfon Stuart C. , Wherry E. John , Laudanski Krzysztof , Weljie Aalim M. , Meyer Nuala B. , FitzGerald Garret A. 
Published: June 2023

AbstractLipids may influence cellular penetrance by pathogens and the immune response that they evoke. Here we find a broad based lipidomic storm driven predominantly by secretory (s) phospholipase A2(sPLA2) dependent eicosanoid production occurs in patients with sepsis of viral and bacterial origin and relates to disease severity in COVID-19. Elevations in the cyclooxygenase (COX) products of arachidonic acid (AA), PGD2and PGI2, and the AA lipoxygenase (LOX) product, 12-HETE, and a reduction in the high abundance lipids, ChoE 18:3, LPC-O-16:0 and PC-O-30:0 exhibit relative specificity for COVID-19 amongst such patients, correlate with the inflammatory response and link to disease severity. Linoleic acid (LA) binds directly to SARS-CoV-2 and both LA and its di-HOME products reflect disease severity in COVID-19. AA and LA metabolites and LPC-O-16:0 linked variably to the immune response. These studies yield prognostic biomarkers and therapeutic targets for patients with sepsis, including COVID-19. An interactive purpose built interactive network analysis tool was developed, allowing the community to interrogate connections across these multiomic data and generate novel hypotheses.
A marine cryptochrome with an inverse photo-oligomerization mechanism
Authors: Vu Hong Ha , Behrmann Heide , Hanić Maja , Jeyasankar Gayathri , Krishnan Shruthi , Dannecker Dennis , Hammer Constantin , Gunkel Monika , Solov’yov Ilia A. , Wolf Eva , Behrmann Elmar 
Published: June 2023

AbstractCryptochromes (CRYs) are a structurally conserved but functionally diverse family of proteins that can confer unique sensory properties to organisms. In the marine bristle wormPlatynereis dumerilii, its light receptive cryptochrome L-CRY (PdLCry) allows the animal to discriminate between sunlight and moonlight, an important requirement for synchronizing its lunar cycle-dependent mass spawning. Using cryo-electron microscopy, we show that in the dark,PdLCry adopts a dimer arrangement observed neither in plant nor insect CRYs. Intense illumination disassembles the dimer into monomers. Structural and functional data suggest a mechanistic coupling between the light-sensing flavin adenine dinucleotide chromophore, the dimer interface, and the C-terminal tail helix, with a likely involvement of the phosphate binding loop. Taken together, our work establishesPdLCry as a CRY protein with inverse photo-oligomerization with respect to plant CRYs, and provides molecular insights into how this protein might help discriminating the different light intensities associated with sunlight and moonlight.
Social dynamics of vervet monkeys are dependent upon group identity
Authors: Kerjean Elena , van de Waal Erica , Canteloup Charlotte 
Published: June 2023

AbstractTraditions are widespread across the animal realm. Here, we investigated inter-group variability of social dynamics in wild vervet monkeys (Chlorocebus pygerythrus). We analysed 84 704 social behavioural interactions involving 247 individuals collected over nine years in three neighbouring groups of wild vervet monkeys. We found that, in one group - Ankhase - individuals had a higher propensity to be affiliative (i.e., sociality) and grooming interactions were more reciprocal. Despite yearly fluctuations in sociality, differences between groups remained stable over time. Moreover, our statistical model predictions confirmed that these findings were maintained for similar sex ratios, age distributions and group sizes. Strikingly, our results suggested that dispersing males adapted their sociality to the sociality of the group they integrated with. As a whole, our study sheds light on the existence of stable social dynamics dependent upon group identity in wild vervet monkeys and suggests that at least part of this variability is socially mediated.Graphical AbstractHighlightsThe sociality of vervet monkeys groups differs consistently across a nine years study despite similar genetic and ecological environments.Dispersing males adapt their sociality according to the group they integrate with.In the most social group, grooming interactions were more reciprocal.
Morphomechanic tuning of ERK by actin-TFII-IΔ regulates cell identity
Authors: Wu Qiao , Zhang Jian , Long Bing , Hu Xiao , de Faria Bruna Mafra , Scalf Stephen Maxwell , Karatepe Kutay , Cao Wenxiang , Tsopoulidis Nikolaos , Binkercosen Andres , Yagi Masaki , Weiner Aaron , Kaileh Mary , De La Cruz Enrique M. , Roy Ananda L , Hochedlinger Konrad , Guo Shangqin 
Published: June 2023

AbstractCell morphology is faithfully coupled to its identity but the coupling mechanism remains elusive. Using somatic cell reprogramming into pluripotency as a model system, we show that activity of the extracellular signal-regulated kinase (ERK) is tuned by cellular morphomechanic state to direct cell fate. Pluripotent cells and somatic cells reprogramming into pluripotency allocate large amounts of actin into their nucleus, which morphs cells to become taller than 10 μm, a minimal height required for the pluripotent identity. Accumulated nuclear actin binds to TFII-IΔ, an atypical transcription factor that translocates into the nucleus upon signaling. TFII-IΔ also binds to and activates ERK. The binding of TFII-IΔ by nuclear actin reduces ERK activity, in coordination with changes in cell/colony height. The tight coupling between cell height and nuclear actin accumulation necessitates the degree of ERK tuning to be mild. Mild ERK inhibition by chemicals recapitulates the tuning by actin-TFII-IΔ and turns most cells in reprogramming cultures into pluripotency. Thus, we uncover a novel mechanism for how cell morphology couples to its identity via the actin-TFII-IΔ-ERK axis, identifying points of intervention in cell fate manipulation.
Single-component multilayered self-assembling protein nanoparticles displaying extracellular domains of matrix protein 2 as a pan-influenza A vaccine
Authors: Gomes Keegan Braz , Zhang Yi-Nan , Lee Yi-Zong , Eldad Mor , Lim Alexander , Ward Garrett , Auclair Sarah , He Linling , Zhu Jiang 
Published: June 2023

ABSTRACTThe development of a cross-protective pan-influenza A vaccine remains a significant challenge. In this study, we designed and evaluated single-component self-assembling protein nanoparticles (SApNPs) presenting the conserved extracellular domain of matrix protein 2 (M2e) as vaccine candidates against influenza A viruses. The SApNP-based vaccine strategy was first validated for human M2e (hM2e) and then applied to tandem repeats of M2e from human, avian and swine hosts (M2ex3). Vaccination with M2ex3 displayed on SApNPs demonstrated higher survival rates and lower weight loss compared to the soluble M2ex3 antigen against lethal challenges of H1N1 and H3N2 in mice. M2ex3 I3-01v9a SApNPs formulated with a squalene-based adjuvant were retained in the lymph node follicles over eight weeks and induced long-lived germinal center reactions. Notably, a single low dose of M2ex3 I3-01v9a SApNP formulated with a potent adjuvant, either a Toll-like receptor 9 (TLR9) agonist or a stimulator of interferon genes (STING) agonist, conferred 90% protection against a lethal H1N1 challenge in mice. With the ability to induce robust and durable M2e-specific functional antibody and T cell responses, the M2ex3-presenting I3-01v9a SApNP provides a promising pan-influenza A vaccine candidate.ONE-SENTENCE SUMMARYSingle-component self-assembling protein nanoparticles (SApNPs) displaying tandem M2e elicit robust and durable immunity that may protect against influenza A viruses of diverse origins.
The basis of antigenic operon fragmentation inBacteroidotaand commensalism
Authors: Bank Nicholas C. , Singh Vaidhvi , Grubb Brandon , McCourt Blake , Burberry Aaron , Roberts Kyle D. , Rodriguez-Palacios Alex 
Published: June 2023

AbstractThe causes for variability of pro-inflammatory surface antigens that affect gut commensal/opportunistic dualism within the phylumBacteroidotaremain unclear (1, 2). Using the classical lipopolysaccharide/O-antigen ‘rfboperon’ inEnterobacteriaceaeas a surface antigen model (5-gene-clusterrfbABCDX), and a recentrfbA-typing strategy for strain classification (3), we characterized the architecture/conservancy of the entirerfboperon inBacteroidota. Analyzing complete genomes, we discovered that mostBacteroidotahave therfboperon fragmented into non-random gene-singlets and/or doublets/triplets, termed ‘minioperons’. To reflect global operon integrity, duplication, and fragmentation principles, we propose a five-category (infra/supernumerary) cataloguing system and a Global Operon Profiling System for bacteria. Mechanistically, genomic sequence analyses revealed that operon fragmentation is driven by intra-operon insertions of predominantlyBacteroides-DNA (thetaiotaomicron/fragilis) and likely natural selection in specific micro-niches.Bacteroides-insertions, also detected in other antigenic operons (fimbriae), but not in operons deemed essential (ribosomal), could explain whyBacteroidotahave fewer KEGG-pathways despite large genomes (4). DNA insertions overrepresenting DNA-exchange-avid species, impact functional metagenomics by inflating gene-based pathway inference and overestimating ‘extra-species’ abundance. Using bacteria from inflammatory gut-wall cavernous micro-tracts (CavFT) in Crohn’s Disease (5), we illustrate that bacteria with supernumerary-fragmented operons cannot produce O-antigen, and that commensal/CavFTBacteroidotastimulate macrophages with lower potency thanEnterobacteriaceae, and do not induce peritonitis in mice. The impact of ‘foreign-DNA’ insertions on pro-inflammatory operons, metagenomics, and commensalism offers potential for novel diagnostics and therapeutics.
Resolving conformational changes that mediate a two-step catalytic mechanism in a model enzyme
Authors: Greisman Jack B. , Dalton Kevin M. , Brookner Dennis E. , Klureza Margaret A. , Sheehan Candice J. , Kim In-Sik , Henning Robert W. , Russi Silvia , Hekstra Doeke R. 
Published: June 2023

AbstractEnzymes catalyze biochemical reactions through precise positioning of substrates, cofactors, and amino acids to modulate the transition-state free energy. However, the role of conformational dynamics remains poorly understood due to lack of experimental access. This shortcoming is evident withE. colidihydro-folate reductase (DHFR), a model system for the role of protein dynamics in catalysis, for which it is unknown how the enzyme regulates the different active site environments required to facilitate proton and hydride transfer. Here, we present ligand-, temperature-, and electric-field-based perturbations during X-ray diffraction experiments that enable identification of coupled conformational changes in DHFR. We identify a global hinge motion and local networks of structural rearrangements that are engaged by substrate protonation to regulate solvent access and promote efficient catalysis. The resulting mechanism shows that DHFR’s two-step catalytic mechanism is guided by a dynamic free energy landscape responsive to the state of the substrate.
Multi-tiered actions ofLegionellaeffectors to modulate host Rab10 dynamics
Authors: Kubori Tomoko , Arasaki Kohei , Oide Hiromu , Kitao Tomoe , Nagai Hiroki 
Published: June 2023

AbstractRab GTPases are representative targets of manipulation by intracellular bacterial pathogens for hijacking membrane trafficking.Legionella pneumophilarecruits many Rab GTPases to its vacuole and exploits their activities. Here, we found that infection-associated regulation of Rab10 dynamics involves ubiquitin signaling cascades mediated by the SidE and SidC families ofLegionellaubiquitin ligases. Phosphoribosyl-ubiquitination of Rab10 catalyzed by the SidE ligases is crucial for its recruitment to the bacterial vacuole. SdcB, the previously uncharacterized SidC family effector, resides on the vacuole and contributes to retention of Rab10 at the late stages of infection. We further identified MavC as a negative regulator of SdcB. By the transglutaminase activity, MavC crosslinks ubiquitin to SdcB and suppresses its function, resulting in elimination of Rab10 from the vacuole. These results demonstrate that the orchestrated actions of manyL. pneumophilaeffectors fine-tune the dynamics of Rab10 during infection.
The sustainability awareness of banking institutions in Indonesia, its implication on profitability by the mediating role of operational efficiency
Authors: Anis Idrianita , Gani Lindawati , Fauzi Hasan , Hermawan Ancella Anitawati , Adhariani Desi 
Published: June 2023

PurposeThis study aims to propose a solution to accelerate financing support low carbon (circular economy) transition. The authors developed a sustainability governance (SGOV) model and a sustainability governance (SGOV) index as a proxy for the diffusion of sustainability innovation. This study investigates the effect of SGOV practices on profitability with the mediating role of operational efficiency.Design/methodology/approachThe SGOV index consists of 32 and 122 sub-items, constructed using content analysis of annual and sustainability reports published by banks listed on the Indonesia Stock Exchange (IDX) from 2010 to 2020 (404 bank-year observations).FindingsBanks are at a moderate level of sustainability innovation. They are prioritizing the balance aspects of financial, social and environmental. SGOV practice negatively affects profitability. However, operational efficiency plays a positive mediating role that is robust.Research limitations/implicationsThe measurement of the SGOV index uses criteria that have not been tested in previous studies. There is the potential subjectivity in interpreting qualitative data, although this has been minimized by cross-checking the analysis of five raters.Practical implicationsThis study gives feedback for the Indonesia sustainable finance (SF) journey phase I to proceed into SF journey phase II.Social implicationsThe SGOV model can be applied in other industry sectors to know the readiness for entering low carbon (circular economy) transition.Originality/valueThe uniqueness of the scoring technique assuming a step-by-step innovation model to sustainable finance.
Institutionalization of corporate bribery: a measurement proposal with evidence from a Latin American sample
Authors: Yepes-López Gustavo Adolfo , Camarena José Luis , Cruz-Pulido Julián Mauricio , Quintero-Campos Luz Jeannette , Lasio Virginia , Rodriguez Jorge , Zambrano-Vera Jack , García de la Torre Consuelo Adelaida , Schwalb-Helguero María Matilde , Prialé María Ángela , Solís-Sierra José , Rossi-Undurraga Maruzella , Carvajal-Ramos Roberto , Martinez Pedro Javier , González-Gutiérrez Victoria , Sánchez-Reyna Rogelio , Lassaga Griselda , Beltramino Nicolás 
Published: June 2023

PurposeThis article aims to report on the development and validation of a bribery measurement index for the business sector, which, based on institutional theory, seeks to overcome the limitations of traditional measurements, recognizing the dynamics that originate the phenomenon and identifying process components.Design/methodology/approachTo construct the index, correlational and principal component analysis techniques were used, as well as rigorous statistical tests, validating the instrument in a sample of 2,963 companies in Latin America, including Argentina, Colombia, Chile, Ecuador, Guatemala, Mexico and Peru.FindingsThe result was an instrument composed of two dimensions: (1) anti-bribery game rules, composed of regulations knowledge and anti-bribery efforts, and (2) bribery as a perceived habit, allowing an objective representation of reality due to its internal consistency, concurrent and discriminant validity.Practical implicationsThis instrument is one of the few that focuses on measuring bribery in the business sector in terms of corrupt practices, applicable for both public and private institutions to promote game rules against bribery. Additionally, the proposed theoretical model can be used to measure other phenomena with similar characteristics.Originality/valueThis article empirically highlights different variables that make bribery possible. The results can be helpful in the design of strategies to prevent this type of behavior. It also highlights the importance of designing mechanisms to record information related to bribery and the different expressions of corruption in order to explain its different nuances.