bluuebunny/crossref_metadata_2025_split huggingface dataset:
ESRP2-microRNA-122 axis directs the postnatal onset of liver polyploidization and maturation
Authors: Bangru Sushant , Chen Jackie , Baker Nicholas , Das Diptatanu , Chembazhi Ullas V. , Derham Jessica M. , Chorghade Sandip , Arif Waqar , Alencastro Frances , Duncan Andrew W. , Carstens Russ P. , Kalsotra Auinash 
Published: July 2024

SUMMARYHepatocyte polyploidy and maturity are critical to acquiring specialized liver functions. Multiple intra- and extracellular factors influence ploidy, but how they cooperate temporally to steer liver polyploidization and maturation or how post-transcriptional mechanisms integrate into these paradigms is unknown. Here, we identified an important regulatory hierarchy in which postnatal activation of Epithelial-Splicing-Regulatory-Protein-2 (ESRP2) stimulates biogenesis of liver-specific microRNA (miR-122), thereby facilitating polyploidization, maturation, and functional competence of hepatocytes. By determining transcriptome-wide protein-RNA interactionsin vivoand integrating them with single-cell and bulk hepatocyte RNA-seq datasets, we delineate an ESRP2-driven RNA processing program that drives sequential replacement of fetal-to-adult transcript isoforms. Specifically, ESRP2 binds the primary miR-122 host gene transcript to promote its processing/biogenesis. Combining constitutive and inducible ESRP2 gain- and loss-of-function mice models with miR-122 rescue experiments, we demonstrate that timed activation of ESRP2 augments miR-122-driven program of cytokinesis failure, ensuring proper onset and extent of hepatocyte polyploidization.
A Systematic Review of the Neuroprotective Role and Biomarker Potential of GDF15 in Neurodegeneration
Authors: Isik Finula I. , Thomson Shannon , Cueto John F. , Spathos Jessica , Breit Samuel N. , Tsai Vicky W.W. , Brown David A. , Finney Caitlin A. 
Published: July 2024

AbstractNeurodegeneration is characteristically multifaceted, with limited therapeutic options. One of the chief pathophysiological mechanisms driving these conditions is neuroinflammation, prompting increasing clinical interest in immunomodulatory agents. Growth differentiation factor 15 (GDF15; previously also called macrophage inhibitory cytokine-1 or MIC-1), an anti-inflammatory cytokine with established neurotrophic properties, has emerged as a promising therapeutic agent in recent decades. However, methodological challenges and the delayed identification of its specific receptor GFRAL have hindered research progress. This review systematically examines literature about GDF15 in neurodegenerative diseases and neurotrauma. The evidence collated in this review indicates that GDF15 expression is upregulated in response to neurodegenerative pathophysiology and increasing its levels in preclinical models typically improves outcomes. Key knowledge gaps are addressed for future investigations to foster a more comprehensive understanding of the neuroprotective effects elicited by GDF15.
Improving Mannanase Production inBacillus subtilisfor Fibre Hydrolysis during Solid-State Fermentation of Palm Kernel Meal
Authors: Ong Wei Li , Li Zhi , Ng Kian-Hong , Zhou Kang 
Published: July 2024

AbstractThe primary challenge in utilizing palm kernel meal (PKM, an agricultural by-product) as non- ruminant livestock feed is its high fibre content, predominantly in the form of mannan. Microbial fermentation offers an economically favourable alternative to enzyme supplementation for breaking down fibre in lignocellulosic biomass. In a recent study, we have isolated and characterized an undomesticated strain (Bacillus subtilisF6) that is able to secrete mannanase. In this work, the mannanase production was substantially improved by optimizing multiple regulatory elements controlling the mannanase expression. Mannanase GmuG, sourced fromB. subtilisF6 and verified for its hydrolytic activity on PKM fibre, was expressed using a replicative plasmid (pBE-S). The recombinant strain ofB. subtilisF6 exhibited 1.9-fold increase in the mannanase activity during solid-state fermentation. Optimization of signal peptide and ribosome binding site further enhanced mannanase activity by 3.1-fold. Subsequently, promoter screening based on highly transcribed genes inB. subtilisF6 resulted in a significant 5.4-fold improvement in mannanase activity under thenprEpromoter. ThenprEpromoter was further refined by eliminating specific transcription factor binding sites, enhancing the mannanase activity further by 1.8-fold. Notably, a substantial 35-40% reduction in PKM fibre content was observed after 30 h of fermentation using the recombinant strains. Lastly, the highest mannanase-producing strain was examined for scaled-up fermentation. The impacts of fermentation on fibre and protein contents, as well as the surface morphology of PKM, were analysed. The outcomes of this study offer an efficient method for robust mannanase expression inB. subtilisand its potential application in the biotransformation of PKM and other mannan-rich bioresources for improved feed utilization.Graphical abstract
MJF-14 proximity ligation assay detects early non-inclusion alpha-synuclein pathology with enhanced specificity and sensitivity
Authors: Jensen Nanna Møller , Fu YuHong , Betzer Cristine , Li Hongyun , Elfarrash Sara , Shaib Ali H. , Krah Donatus , Vitic Zagorka , Reimer Lasse , Gram Hjalte , Buchman Vladimir , Denham Mark , Rizzoli Silvio O. , Halliday Glenda M. , Jensen Poul Henning 
Published: July 2024

AbstractLewy pathology, consisting of Lewy bodies and Lewy neurites, is the pathological hallmark of synucle-inopathies such as Parkinson’s disease and dementia with Lewy bodies, but it is generally thought to represent late-stage pathological changes. In contrast, α-synuclein oligomers are regarded as early-stage pathology, likely involved in disease progression and cellular toxicity. Oligomers, however, are not de-tected by standard immunohistochemistry but require specific detection techniques such as the proxim-ity ligation assay (PLA). Here, we describe the MJF-14 PLA, a new PLA towards aggregated α-synuclein with unprecedented specificity, attained by the utilization of aggregate conformation-specific α-synu-clein antibody MJFR-14-6-4-2 (hereafter MJF-14). Signal in the assay directly correlates with α-synuclein aggregation in SH-SY5Y cells, as treatment with aggregation inhibitor ASI1D significantly lowers PLA sig-nal. In human cortical neurons, MJF-14 PLA detects pre-formed fibril-induced aggregation, especially prominent when using stealth PFFs invisible to the MJF-14 antibody. Co-labelling of MJF-14 PLA and pS129-α-synuclein immunofluorescence in post-mortem dementia with Lewy bodies cases showed that while the MJF-14 PLA reveals extensive non-inclusion pathology, it is not sensitive towards Lewy bodies. In Parkinson’s disease brain, direct comparison of PLA and IHC with the MJF-14 antibody, combined with machine learning-based quantification, showed striking α-synuclein pathology preceding the formation of conventional Lewy pathology. The majority of the PLA-revealed non-inclusion pathology was found in the neuropil, including some clearly located in the presynaptic terminals. With this work, we introduce an improved α-synuclein aggregate PLA to uncover abundant non-inclusion pathology, which deserves future validation with multiple brain bank resources and in different synucleinopathies.
Early 2022 breakthrough infection sera from India target the conserved cryptic class 5 epitope to counteract immune escape by SARS-CoV-2 variants
Authors: Das Jana Indrani , Kanjo Kawkab , Roy Subhanita , Bhasin Munmun , Bhattacharya Shatarupa , Banerjee Indranath , Jana Subhasis , Chatterjee Arjun , Chakraborty Alok , Chakraborty Suman , Mukherjee Budhaditya , Varadarajan Raghavan , Mondal Arindam 
Published: July 2024

AbstractDuring the COVID-19 pandemic, the vast majority of epitope mapping studies have focused on sera from mRNA-vaccinated populations from high-income countries. In contrast, here we report an analysis of 164 serum samples isolated from breakthrough infection patients in India during early 2022 who received two doses of the ChAdOx viral vector vaccine. Sera were screened for neutralization breadth against wildtype, Kappa, Delta, and Omicron BA.1 viruses. Three sera with the highest neutralization breadth and potency were selected for epitope mapping using charged scanning mutagenesis coupled to yeast surface display and Next Generation Sequencing. All of these sera primarily targeted the recently identified class 5 cryptic epitope along with the class 1 and class 4 epitopes, targeted to a lesser extent. The class 5 epitope is completely conserved across all SARS-CoV-2 variants and for the majority of the Sarbecoviruses. In line with these observations, a major fraction of the serum samples, including the selected three, show broad neutralizing activity against recent Omicron subvariants including XBB.1.5. This is in contrast with the results obtained with the sera from individuals receiving multiple doses of original and updated mRNA vaccines, where impaired neutralization of XBB and later variant of concerns was observed. Our study demonstrates that two doses of the ChAdOx vaccine in a highly exposed population was sufficient to drive substantial neutralization breadth against emerging and upcoming variants of concern, thus paves the path towards the development of future vaccine candidates.ImportanceWorldwide implementation of COVID19 vaccine and parallel emergence of newer SARS-CoV-2 variants has shaped the humoral immune response in a population specific manner. While characterization of this immune response is important for monitoring the disease progression at population level, it is also imperative for the development of effective countermeasures in the form of novel vaccines and therapeutics. India has implemented the world’s second largest COVID19 vaccination drive and also encountered large number of post vaccination “breakthrough” infections. From a cohort of breakthrough infection patients, we identified individuals whose sera showed broadly cross-reactive immunity against different SARS-CoV-2 variants. Interestingly, these sera primarily target a novel cryptic epitope which was not identified in previous population level studies conducted in western countries. This rare cryptic epitope remains conserved across all SARS-CoV-2 variants including the recently emerged ones and also for the SARS-like coronaviruses that may cause future outbreaks, thus representing a potential target for future vaccines.
RNA splicing variants of the novel long non-coding RNA, CyKILR, possess divergent biological functions in non-small cell lung cancer
Authors: Xie Xiujie , Macknight H. Patrick , Lu Amy L. , Chalfant Charles E. 
Published: July 2024

ABSTRACTThe CDKN2A gene, responsible for encoding the tumor suppressors p16(INK4A) and p14(ARF), is frequently inactivated in non-small cell lung cancer (NSCLC). Herein, an uncharacterized long non-coding RNA (lncRNA) (ENSG00000267053) on chromosome 19p13.12 was found to be overexpressed in NSCLC cells with an active, wild-type CDKN2A gene. This lncRNA, namedCyclin-DependentKinaseInhibitor 2A-regulatedlncRNA (CyKILR), also correlated with an active WT STK11 gene, which encodes the tumor suppressor, Liver kinase B1. CyKILR displayed two splice variants, CyKILRa (exon 3 included) and CyKILRb (exon 3 excluded), which are cooperatively regulated by CDKN2A and STK11 as knockdown of both tumor suppressor genes was required to induce a significant loss of exon 3 inclusion in mature CyKILR RNA. CyKILRa localized to the nucleus, and its downregulation using antisense RNA oligonucleotides enhanced cellular proliferation, migration, clonogenic survival, and tumor incidence. In contrast, CyKILRb localized to the cytoplasm, and its downregulation using siRNA reduced cell proliferation, migration, clonogenic survival, and tumor incidence. Transcriptomics analyses revealed enhancement of apoptotic pathways with concomitant suppression of key cell cycle pathways by CyKILRa demonstrating its tumor-suppressive role. CyKILRb inhibited tumor suppressor microRNAs indicating an oncogenic nature. These findings elucidate the intricate roles of lncRNAs in cell signaling and tumorigenesis.
Long-read RNA sequencing reveals allele-specific N6-methyladenosine modifications
Authors: Park Dayea , Cenik Can 
Published: July 2024

ABSTRACTLong-read sequencing technology enables highly accurate detection of allele-specific RNA expression, providing insights into the effects of genetic variation on splicing and RNA abundance. Furthermore, the ability to directly sequence RNA promises the detection of RNA modifications in tandem with ascertaining the allelic origin of each molecule. Here, we leverage these advantages to determine allele-biased patterns of N6-methyladenosine (m6A) modifications in native mRNA. We utilized human and mouse cells with known genetic variants to assign allelic origin of each mRNA molecule combined with a supervised machine learning model to detect read-level m6A modification ratios. Our analyses revealed the importance of sequences adjacent to the DRACH- motif in determining m6A deposition, in addition to allelic differences that directly alter the motif. Moreover, we discovered allele-specific m6A modification (ASM) events with no genetic variants in close proximity to the differentially modified nucleotide, demonstrating the unique advantage of using long reads and surpassing the capabilities of antibody-based short-read approaches. This technological advancement promises to advance our understanding of the role of genetics in determining mRNA modifications.
SARS-CoV-2 neutralization and protection of hamsters via nasal administration of a humanized neutralizing antibody
Authors: Lebedin Mikhail , Petrovsky Nikolai , Tabynov Kairat , Tabynov Kaissar , Lebedin Yuri 
Published: July 2024

ABSTRACTMonoclonal antibodies are widely used for the treatment of infectious human diseases, including COVID-19. Since the start of the pandemic, eight monoclonal antibodies against SARS-CoV-2 were granted emergency use authorization. High mutation rate of the SARS-CoV-2 virus has led to the emergence of highly transmissible variants efficiently evading vaccine-induced immunity. This highlights the importance of identifying broadly neutralizing antibodies with therapeutic potential. In this study, we used a panel of murine monoclonal antibodies (mAb) to identify a subset that bound and neutralized a broad spectrum of SARS-CoV-2 variants. Intranasal delivery of XR10, the most promising murine mAb, protected hamsters against infection by Alpha and Delta variants. We next humanized XR10 mAb using a combination of CDR-grafting and Vernier zones preservation approaches (CRVZ) to create a panel of humanized antibody variants. We ranked the variants based on their spike binding ability and virus neutralization. Of these, XR10v48 demonstrated the best ability to neutralize SARS-CoV-2 variants. XR10v48 was protective in hamsters when given as a single 50 µg/kg intranasal dose at the time of viral challenge. XR10v48 features 34 key amino acid residues retained from the murine progenitor. Our work introduces a potent humanized antibody that demonstrates neutralizing activityin vivoat a low dose.
Hadronic spectrum in the chiral large
Nc
extension of quantum chromodynamics
Authors: Kristensen Axel Halgaard , Ryttov Thomas A. 
Published: July 2024

We study quantum chromodynamics in the chiral large Nc limit which contains a left-handed Weyl fermion in the fundamental representation, a left-handed Weyl fermion in the two index antisymmetric representation and (Nc−3) left-handed Weyl fermions in the antifundamental representation of the SU(Nc) gauge group. We construct gauge singlet composite operators and study their masses and correlation functions at large Nc. It is shown that all hadron masses scale as ∼Nc0nq where nq is the number of constituent quarks in the hadron. In addition by simple gluon exchange considerations it is seen that scattering amplitudes between hadrons have the same Nc scaling as the mass of the lightest hadron involved. This is the case provided the hadrons in the scattering amplitude share a sufficiently large number of constituent quarks. The chiral large Nc extension also allows for other nontrivial processes. For instance we consider two different baryonium states that are unique to this extension and that decay via emissions of two- and three-quark hadrons. Also other nontrivial scattering processes are considered. Finally, we study composites made of a mix of left- and right-handed fields. We categorize multiple groups of hadrons within the full spectrum according to their flavor structure. Within these groups all n-point functions scale the same.

Published by the American Physical Society
2024
Continuum-extrapolated high-order baryon fluctuations
Authors: Borsányi Szabolcs , Fodor Zoltán , Guenther Jana N. , Katz Sándor D. , Parotto Paolo , Pásztor Attila , Pesznyák Dávid , Szabó Kálmán K. , Wong Chik Him 
Published: July 2024

Fluctuations play a key role in the study of QCD phases. Lattice QCD is a valuable tool to calculate them, but going to high orders is challenging. Up to the fourth order, continuum results have been available since 2015. We present the first continuum results for sixth-order baryon fluctuations for temperatures between T=130 and 200 MeV and eighth order at T=145  MeV in a fixed volume. Comparison with earlier studies with imaginary chemical potential suggests that the volume effect is under control for T<145  MeV. Our results are in sharp contrast with well-known results in the literature obtained at finite lattice spacing.

Published by the American Physical Society
2024
The scale effects of agricultural credits, institutional governance and microfinance sustainability in Sub-Saharan African countries
Authors: Mba Fokwa Arsène 
Published: July 2024

PurposeThe study examines the synthesized influences of institutional governance and the scale effects of agricultural credits on the sustainability of microfinance institutions (MFIs) in Sub-Saharan Africa.Design/methodology/approachUsing a sample of 840 MFIs (300 independent and 540 networked), the study applied Generalized Method of Moments (GMM) and Lewbel’s estimator.FindingsResults indicate positive effects of financial structure, efficiency and agricultural credit scale on sustainability, with a non-linear U-shaped relationship between agricultural credit size and microfinance sustainability. Depending on institutional governance quality, a threshold is identified where agricultural credit scale significantly enhances the quality of Portfolio at Risk (lnPAR) in independent MFIs and Returns on Assets (lnROA) in networked MFIs.Research limitations/implicationsStudy suggests strengthening governance for transparency and operating within optimal size for enduring sustainable performance. While focused on Sub-Saharan Africa, future research could expand to various economies or introduce additional variables for a comprehensive analysis.Practical implicationsMFIs can achieve sustainability by implementing management guided by better institutional norms, innovative financial transformations better suited to financing agricultural activities and techniques and an organizational structure more aligned with their performance targets.Social implicationsBroader and more reliable access to financial services, particularly in the agricultural sector, can stimulate production and alleviate poverty.Originality/valueThe study’s originality lies in its contribution to the literature by examining the role of institutional governance in microfinance institution performance and evaluating microfinance in a broader Sub-Saharan African context, proposing threshold limits where agricultural microcredit compromises performance.
Identifying new earnings management components: a machine learning approach
Authors: Almasarwah Adel , Aram Khalid Y. , Alhaj-Yaseen Yaseen S. 
Published: July 2024

Purpose
This study aims to apply machine learning (ML) to identify new financial elements managers might use for earnings management (EM), assessing their impact on the Standard Jones Model and modified Jones model for EM detection and examining managerial motives for using these components.

Design/methodology/approach
Using eXtreme gradient boosting on 23,310 the US firm-year observations from 2012 to2021, the study pinpoints nine financial variables potentially used for earnings manipulation, not covered by traditional accruals models.

Findings
Cost of goods sold and earnings before interest, taxes, depreciation and amortization are identified as the most significant for EM, with relative importances of 40.2% and 11.5%, respectively.

Research limitations/implications
The study’s scope, limited to a specific data set and timeframe, and the exclusion of some financial variables may impact the findings’ broader applicability.

Practical implications
The results are crucial for researchers, practitioners, regulators and investors, offering strategies for detecting and addressing EM.

Social implications
Insights from the study advocate for greater financial transparency and integrity in businesses.

Originality/value
By incorporating ML in EM detection and spotlighting overlooked financial variables, the research brings fresh perspectives and opens new avenues for further exploration in the field.
The role of third actors in the dyadic business relationship initiation: an empirical perspective of sommelier in the wine context
Authors: Fraboni Pier Franco Luigi , Sabatini Andrea , Marcone Maria Rosaria , Temperini Valerio 
Published: July 2024

PurposeStarred restaurants, as significant outlets for small wineries, present a unique business opportunity. In this context, the sommelier, as a third actor, assumes a pivotal role in shaping the business relationships between these entities. This study, employing a grounded theory approach, delves into the sommeliers’ roles and activities in the initiation of relationships between small wineries and starred restaurants.Design/methodology/approachA qualitative methodology was adopted. Twenty-four semi-structured interviews, direct observations, and informal conversations with starred restaurants, small wineries, and sommeliers were collected and analysed using an abductive approach.FindingsThe findings suggest that the sommelier acts as a contributor to the business relationship initiation between the small winery and the starred restaurant, performing several continuous, simultaneous, and bilateral roles toward both actors.Originality/valueThe study sheds light on the role of wine stewards in the B2B context and provides useful insights to close the theoretical gap between business relationship initiation and the role of third actors.