bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitreous fluid-isolated DNA for the genetic analysis of primary uveal melanoma: a proof-of-concept study
Authors: Nell R.J. , Versluis M. , Menger N.V. , Gelmi M.C. , Vu T.H.K. , Verdijk R.M. , Luyten G.P.M. , Jager M.J. , van der Velden P.A. 
Published: February 2024

AbstractBackgroundUveal melanoma is an aggressive ocular malignancy. Early molecular characterisation of primary tumours is crucial to identify those at risk of metastatic dissemination. Although tumour biopsies are being taken, liquid biopsies of ocular fluids may form a less invasive but relatively unexplored alternative. In this study, we aim to evaluate the DNA content of vitreous fluid from eyes with a uveal melanoma to obtain molecular information from the tumour.MethodsDNA was isolated from 65 vitreous fluid samples from enucleated eyes with a uveal melanoma and studied using digital PCR. Primary and additional driver mutations (inGNAQ,GNA11,PLCB4,CYSLTR2,BAP1,SF3B1andEIF1AX) were investigated using accustomed targeted and drop-off assays. The copy numbers of chromosome 3p and 8q were measured using multiplex and single-nucleotide polymorphism-based assays. Our findings were compared to the molecular profile of matched primary tumours and to the clinicopathological tumour characteristics.ResultsAlmost all (63/65) vitreous fluids had measurable levels of DNA, but melanoma-cell derived DNA (containing the primary driver mutation) was detected in 39/65 samples (median proportion 18%, range 0.2%-94%) and was associated with a larger tumour prominence, but not with any of the molecular tumour subtypes. Among the vitreous fluids with melanoma-cell derived DNA, not all samples harboured (analysable) other mutations or had sufficient statistical power to measure copy numbers. Still, additional mutations inBAP1,SF3B1andEIF1AXwere detected in 13/15 samples and chromosome 3p and 8q copy numbers matched the primary tumour in 19/21 and 18/20 samples, respectively. Collectively, a clinically-relevant molecular classification of the primary tumour could be inferred from 27/65 vitreous fluids.DiscussionThis proof-of-concept study shows that substantial amounts of DNA could be detected in vitreous fluids from uveal melanoma patients, including melanoma-cell derived DNA in 60% of the samples. Prognostically-relevant genetic alterations of the primary tumour could be identified in 42% of the patients. A follow-up study is needed to evaluate our approach in a prospective clinical context.
Comparative efficacy and safety of anti-cryptosporidial agents: Anin vitrostudy on Nitazoxanide, HFL, KDU731, and Paromomycin againstCryptosporidium parvum
Authors: Whitta Saffron T.G. , Lamont Bridget , Suwanarusk Rossarin , Russell Bruce M. , Muhsin-Sharafaldine Morad-Rémy 
Published: February 2024

AbstractThis study evaluates thein vitroeffectiveness of the anti-cryptosporidial agents Nitazoxanide, Halofuginone, the pyrazolopyridine analogue KDU731, and Paromomycin in combating the significant zoonotic pathogenCryptosporidium parvum. The study utilizes HCT-8 host cells to cultureC. parvumand fluorescent microscopy and qPCR for detecting parasitic growth. The efficacy of the compounds was assessed by calculating their inhibitory concentrations against the total growth ofC. parvumat 48 hours post-infection. The study further investigates the impact of these compounds on early parasitophorous vacuole formation, merozoite egress, host cell viability, and cell growth cycle. KDU731 displayed the most promising profile, with low nanomolar (102 nM ± 2.28) activity and negligible host cell toxicity. This study offers new insights into the relative efficacy and safety of various anti-cryptosporidial compounds, highlighting their stage-specific effects onC. parvumand the consequential impacts on host cells. Identifying safe and effective anti-cryptosporidial agents contributes significantly to the One Health approach, emphasizing the importance of integrated strategies in controlling zoonotic diseases.
Experimental assessment of marine microbial interactions: from predatory protists promoting bacterial survival to bacterial lysis of the protists
Authors: Axelsson-Olsson Diana , Gubonin Nikolaj , Israelsson Stina , Pinhassi Jarone 
Published: February 2024

ABSTRACTBacteria in aquatic environments are a principal food source for predatory protists. Whereas interactions between bacteria and protists are recognized to play important roles in determining the pathogenesis and epidemiology of several human pathogens, few studies have systematically characterized the interactions between specific aquatic bacteria and protists beyond the prey-predator relation. We therefore surveyed the outcome of individual co-cultures between 18 different genome-sequenced marine bacteria with known virulence gene repertoires and three model protist species widely used for assessing bacteria-protist interactions. Strikingly, ten, five, and three bacterial isolates were capable of lysing the protistsAcanthamoeba polyphaga, Tetrahymena pyriformisandEuglena gracilis, respectively. A majority of the bacteria were able to grow and/or maintain viable populations in the presence of viable protists. Some bacteria survived longer in the presence of viable protists but not heat-killed protists, and were observed in protist vacuoles. In this respect, thus, marine bacteria are similar to several protist-dependent human pathogens, includingLegionella. Analyses of growth patterns in low-nutrient media showed that co-cultivation withA polyphagaallowed one bacterial strain to overcome nutritional stress and obtain active growth. Five isolates depended on viable amoebae to grow, notwithstanding nutrient media status. The remarkable capability of surviving encounters with, and even actively killing, bacterivorous protists, indicates that diverse (and possibly novel) bacterial defense strategies and virulence mechanisms to access nutrients are widespread among marine bacteria. The diversity of interactions uncovered here has important implications for understanding ecological and evolutionary consequences of population dynamics in bacteria and protists.IMPORTANCEThe microbiome constitutes the base of food webs in marine waters. Its composition partly reflects biotic interactions, where bacteria primarily are considered as prey of predatory protists. However, studies that focus on one or a few species have shown that some bacteria have abilities to escape grazing and may even be capable of lysing their protist predators. In this study, we substantially extend these findings by systematically investigating interactions among multiple taxa of both bacteria and protists. Our results show that marine bacteria display a wider and more complex range of interactions with their predators than generally recognized - from growth dependency to protist lysis. Given that such interactions play key roles in the pathogenesis and epidemiology of several human pathogens, our findings imply that bacterial virulence traits can contribute to defining the structure and ecology of the marine microbiome.
Structural insights into CXCR4 modulation and oligomerization
Authors: Saotome Kei , McGoldrick Luke L. , Ho Jo-Hao , Ramlall Trudy F. , Shah Sweta , Moore Michael J. , Kim Jee Hae , Leidich Raymond , Olson William C. , Franklin Matthew C. 
Published: February 2024

AbstractActivation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. CXCR4 also serves as a key target for diseases such as cancer and HIV. Previously reported crystal structures of CXCR4 bound to antagonists revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood, including its activation by CXCL12, as well as its assembly into higher-order oligomers. Here, we use cryoelectron microscopy (cryoEM) to investigate various modes of CXCR4 regulation in the presence and absence of Giprotein. CXCL12 activates CXCR4 by inserting its N-terminus deep into the CXCR4 orthosteric pocket. The binding of FDA-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the 7 transmembrane helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its CDR-H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal, to our knowledge, previously undescribed modes of GPCR oligomerization. Remarkably, CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.
Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications
Authors: Cookis Trinity , Lydecker Alexandria , Sauer Paul , Kasinath Vignesh , Nogales Eva 
Published: February 2024

SummaryPolycomb repressive complex 2 (PRC2) is an epigenetic regulator essential for embryonic development and maintenance of cell identity that trimethylates histone H3 at lysine 27 (H3K27me3) leading to gene silencing. PRC2 is regulated by association with protein cofactors and crosstalk with histone posttranslational modifications. Trimethylated histone H3 K4 (H3K4me3) and K36 (H3K36me3) localize to sites of active transcription where H3K27me3 is absent and inhibit PRC2 activity through unknown mechanisms. Using cryo-electron microscopy we reveal that histone H3 tails modified with H3K36me3 engage poorly with the PRC2 active site and preclude its effective interaction with chromatin, while the H3K4me3 modification binds to the allosteric site in the EED subunit, acting as an antagonist that competes with allosteric activators required for the spreading of the H3K27me3 repressive mark. Thus, the location along the H3 tail of the H3K4me3 and H3K36me3 modifications allow them to target two essential requirements for efficient trimethylation of histone H3K27. We further show that the JARID2 cofactor modulates PRC2 activity in the presence of these histone modifications.
Comparative genomics illuminates adaptive evolution of DVNP with lifestyle and with loss of histone H1 in dinoflagellates
Authors: Wang Jingtian , Li Hongfei , Li Ling , Wang Yujie , Lin Senjie 
Published: February 2024

ABSTRACTAbout ten years ago dinoflagellate/viral nucleoprotein (DVNP) was discovered in dinoflagellates, an ecologically important and evolutionarily enigmatic group of aquatic protists. Apparently acquired from a viral origin, the appearance of DVNP coincided with the loss of nucleosome, a rare event in eukaryote evolution. Despite the potential importance of DVNP as the substitute of histones, its evolutionary trajectory and adaptive significance remain elusive. Here, we conducted comparative analyses using existing dinoflagellate genomes and transcriptomes from 26 species ranging from ancestral to later-diverging lineages to investigate the pattern of sequence and structural divergence. Results showed that the functional domestication of DVNP in ancestral dinoflagellates coincided with the loss of histone H1, while subsequent DVNP differentiation was accompanied by the yet another genomic innovation: acquisition of bacterial-originated histone-like protein. Furthermore, our data split DVNP into two major groups: the core DVNP that resembles histone H1 and shows consistently high levels of expression and the non-core DVNP with higher sequence variability and showing lower yet variable levels of expression. In addition, we observed a trend in DVNP evolution tracing that in lifestyle differentiation. This work offers insights into the adaptive evolution of DVNP, laying the foundation for further inquiries of evolutionary drivers and functional innovation of DVNP to enhance our understanding of dinoflagellate evolution and ecological success.
Preferred left-handed conformations of glycyls with pathogenic variants protect against aggregation
Authors: Mishra Purva , Potlia Rajesh , Sandhu Kuljeet Singh 
Published: February 2024

AbstractDue to the lack of Cβatom, the glycyl residues can exhibit left-handed Ramachandran conformations that are mostly disallowed for L-amino acids. The structural and functional significance of distinct glycyl conformations remains under-appreciated. Through systematic analyses of various datasets, we show that: i) the left-handed glycyl residues are over-represented at disease-associated sites and are evolutionarily conserved. ii) The mutations of L-disallowed Gly tend to destabilize the native folding as assessed through the change in free energies. An independent analysis of folding nuclei further corroborates the findings. iii) L-disallowed Gly are enriched at the aggregation gatekeepers, more significantly so in thermophiles, and the mutations thereof reduce the protein solubility. (iv) The positiveΦdihedral angle of L-disallowed Gly disorients its Cαatom out of the phase of alternating pleats ofβ-strand, conforming a crescent that is incompatible to further pair with otherβ-strands, and thus discourages the inter-molecular aggregation of β-strands during protein folding. v) L-disallowed conformation of Gly holds predictive power to identify sites having pathogenic variants. Altogether, our observations highlight that the L-disallowed conformations of glycyls are evolutionarily selected to endow protein stability and protection against aggregation. Apart from enhancing the existing knowledge, the findings have implications in prioritizing the genetic lesions implicated in diseases, and in designing proteins with greater stability and solubility.
Androgens at the skin surface regulateS. aureuspathogenesis through the activation ofagrquorum sensing
Authors: John Maria Sindhura , Chinnappan Mahendran , Artami Methinee , Bhattacharya Mohini , Keogh Rebecca A. , Kavanaugh Jeffrey , Sharma Tripti , Horswill Alexander R. , Harris-Tryon Tamia A. 
Published: February 2024

AbstractStaphylococcus aureus,the most frequent cause of skin infections, is more common in men than women and selectively colonizes the skin during inflammation. Yet, the specific cues that drive infection in these settings remain unclear. Here we show that the host androgens testosterone and dihydrotestosterone promoteS. aureuspathogenesis and skin infection. Without the secretion of these hormones, skin infectionin vivois limited. Testosterone activatesS. aureusvirulence in a concentration dependent manner through stimulation of theagrquorum sensing system, with the capacity to circumvent other inhibitory signals in the environment. Taken together, our work defines a previously uncharacterized inter-kingdom signal between the skin and the opportunistic pathogenS. aureusand identifies the mechanism of sex-dependent differences inS. aureusskin infection.One-Sentence SummaryTestosterone promotesS. aureuspathogenesis through activation of theagrquorum sensing system.
Do light eaters live shorter lives? The case of ultralightCaenorhabditis elegans
Authors: Zhang Xuepei , Gharibi Hassan , Beusch Christian M. , Meng Zhaowei , Saei Amir A. , Gaetani Massimiliano , Zubarev Roman A. 
Published: February 2024

AbstractThe idea that ingesting heavy stable isotopes can increase longevity emerged shortly after the discovery of deuterium in the early 1930s and has been extensively tested since then on animals. Here we present the first experimental evidence for the opposite. GrowingC. eleganson bacteriaE. colithat are in turn fed on a diet depleted of heavy isotopes of C, H, N and O produced ultralight worms that grow and mature faster but have a shorter lifespan. Based on the differences in expression and solubility of proteins, we established an aging pseudo-time scale. Notably, the newly born ultralight worms appear to be significantly “younger” than their normal counterparts, while at day 10 they are significantly “older”. Pathway analysis revealed involvement of mitochondria; analysis of reactive oxygen species (ROS) confirmed significant ROS overproduction in ultralight worms that increases further with age. These findings provide a new modality of affecting the lifespan in this important animal model of human diseases and aging.
Coexistence of asynchronous and clustered dynamics in noisy inhibitory neural networks
Authors: Feld Yannick , Hartmann Alexander K. , Torcini Alessandro 
Published: February 2024

AbstractA regime of coexistence of asynchronous and clustered dynamics is analyzed for globally coupled homogeneous and heterogeneous inhibitory networks of quadratic integrate-and-fire (QIF) neurons subject to Gaussian noise. The analysis is based on accurate extensive simulations and complemented by a mean-field description in terms of low-dimensionalnext generationneural mass models for heterogeneously distributed synaptic couplings. The asynchronous regime is observable at low noise and becomes unstable via a sub-critical Hopf bifurcation at sufficiently large noise. This gives rise to a coexistence region between the asynchronous and the clustered regime. The clustered phase is characterized by population bursts in theγ-range (30-120 Hz), where neurons are split in two equally populated clusters firing in alternation. This clustering behaviour is quite peculiar: despite the global activity being essentially periodic, single neurons display switching between the two clusters due to heterogeneity and/or noise.
Characterization of relativistic electron bunch duration and traveling wave structure phase velocity based on momentum spectra measurements
Authors: Vinatier T. , Assmann R. W. , Burkart F. , Dinter H. , Jaster-Merz S. M. , Kellermeier M. , Kuropka W. , Mayet F. , Stacey B. , Bruni C. 
Published: February 2024

The Accelerator Research Experiment at Sinbad (ARES) linac at DESY aims to generate and characterize ultrashort electron bunches (fs to sub-fs duration) with high momentum and arrival time stability for the purpose of applications related to accelerator research and development, e.g., development of advanced and compact diagnostics and accelerating structures, test of new accelerator components, medical applications studies, machine learning, etc. During its commissioning phase, the bunch duration characterization of the electron bunches generated at ARES has been performed with an rf-phasing technique relying on momentum spectra measurements, using only common accelerator elements (rf accelerating structures and magnetic spectrometers). The sensitivity of the method allowed highlighting different response times for Mo and Cs2Te cathodes. The measured electron bunch duration in a wide range of machine parameters shows excellent agreement overall with the simulation predictions, thus demonstrating a very good understanding of the ARES operation on the bunch duration aspect. The importance of a precise experimental determination of the phase velocity of the first traveling wave accelerating structure after the electron source, for which we propose a simple new beam-based method precise down to a variation of one part per ten thousand respective to the speed of light in vacuum, is emphasized for this purpose. A minimum bunch duration of 20 fs rms, resolution-limited by the space charge forces, is reported. This is, to the best of our knowledge, around 4 times shorter than what has been previously experimentally demonstrated based on rf-phasing techniques with a single rf structure. The present study constitutes a strong basis for future time characterization down to the sub-fs level at ARES, using dedicated X-band transverse deflecting structures.

Published by the American Physical Society
2024
A failure of accountancy professionalisation: corporate financial reporting and accounting knowledge
Authors: Lee Thomas A. 
Published: February 2024

PurposeThe purpose of this study is to analyse historical events to argue the improbable prospect of radical accounting reform in corporate financial reporting (CFR) due to the absence of abstract accounting knowledge as part of accountancy professionalisation (AP).Design/methodology/approachA historical database of CFR and AP events in the UK is categorised and analysed to observe the evolution of accounting in CFR from the perspective of the sociology of professions relating to abstract knowledge in professionalisation.FindingsCFR has always been a statutory function in the UK dependent on arbitrary accounting rules rather than expert measurements based on abstract accounting knowledge. Accounting rules have evolved as part of AP and currently form part of the statutory regulation of CFR. The accountancy profession has eschewed abstract accounting knowledge in a mutually beneficial and uncompetitive relationship with the law profession in CFR.Research limitations/implicationsThe study is limited to the history of CFR and AP in the UK and its findings are contrary to the sociology of professions regarding abstract knowledge, consistent with the accountancy profession’s 19th-century experience of court-related services, and indicative of normative accounting research’s redundancy.Practical implicationsRegarding CFR and AP in the UK, the accountancy profession is an expert subordinate branch of the law profession and has no incentive to alter the status quo of statutory accounting rule compliance prevailing over abstract accounting knowledge-based expertise in CFR.Originality/valueThe study questions the optimism of prior research of accounting in CFR that suggests the possibility of radical reform using abstract knowledge.
Effect of organisational culture on employer branding and resultant employee brand equity in the private banking sector
Authors: Kaur Rajwinder , Pingle Sameer , Jaiswal Anand Kumar 
Published: February 2024

PurposeThis research aims to investigate the relationship between employer branding and its antecedent organisational culture within the context of the private banking sector. The study also investigates the relationship between employer branding and employee brand equity as a consequential construct. Additionally, the mediating role of trust and the moderating role of gender in the relationship between employer branding and employee brand equity has been examined.Design/methodology/approachThe present study’s findings result from data analysis collected from a sample of 454 employees working in private banks in India. The data analysis was conducted utilising the structural equation modelling technique with the assistance of analysis of moment structures (AMOS) software.FindingsThe study’s findings indicate that supportive and bureaucratic (formal) culture in private banks exhibit a significant relationship with employer branding. However, the relationship between innovative culture and employer branding was found to be insignificant. The research also reveals a significant positive association between employer branding and employee brand equity variables: brand consistent behaviour, brand endorsement and brand allegiance. Further, the study highlights the mediating role of employee trust in management in the relationship between employer branding and employee brand equity. Examining demographic variables suggests that gender moderates the relationship between employer branding and employee brand equity.Originality/valueThe originality of this study lies in its exploration of the critical role of organisational culture variables in shaping employer branding within the context of private banks. The findings highlight that cultivating supportive and bureaucratic cultures can effectively enhance the employer branding of private banks. The study emphasises the outcomes of employer branding initiatives, signifying that they contribute to developing brand equity among employees. This leads to long-term employee commitment and advocacy towards the organisation, as employees become brand advocates for the bank with which they are affiliated. The study contributes to a better understanding of the relationship between organisational culture, employer branding and employee brand equity, providing valuable implications for the private banking sector aiming to reinforce their employer brand and increase employee engagement.