bluuebunny/crossref_metadata_2025_split huggingface dataset:
What NLR you recognizing? Predicted binding affinities- and energies may be used to identify novel NLR-effector interactions
Authors: Fick Alicia , Fick Jacobus Lukas Marthinus , Swart Velushka , van den Berg Noëlani 
Published: July 2024

AbstractNucleotide binding Leucine-rich repeat (NLR) proteins play a crucial role in effector recognition and activation of Effector triggered immunity in plants following pathogen infection. Advances in genome sequencing have led to the identification of a myriadNLRsin numerous agriculturally important plant species. However, deciphering which NLR proteins recognize specific pathogen effectors remains a challenge. Predicting NLR-effector interactionsin silicowould provide a more targeted approach for experimental validation, critical for elucidating function, and advancing our understanding of NLR-triggered immunity. In this study, NLR-effector protein complex structures were predicted using AlphaFold2-Multimer for all experimentally validated NLR-effector interactions. Binding affinities– and energies were predicted using 97 machine learning models from Area-affinity. We show that predicted structures with an AlphaFold confidence score > 0.42 have acceptable accuracy, and can be used to investigate NLR-effector interactionsin silico. Binding affinities for 58 NLR-effector complexes ranged between –8.5 and –10.6 log(K), and binding energies between –11.8 and –14.4 kcal/mol, depending on the Area-Affinity model used. For 2427 “forced” NLR-effector complexes, these estimates showed larger variability, enabling the identification of novel NLR-effector complexes with 99% accuracy using an Ensemble machine learning model. The narrow range of binding energies– and affinities for true interactions suggest a specific change in Gibbs free energy, and thus conformational change, is required for NLR activation. This is the first study to provide a method for predicting NLR-effector interactions, applicable to all plant-pathogen interactions. Finally, the NLR-Effector Interaction Classification (NEIC) resource can streamline research efforts by identifying NLRs important for providing resistance against plant pathogens, advancing our understanding of plant immunity.
Concatemer Assisted Stoichiometry Analysis (CASA): targeted mass spectrometry for protein quantification
Authors: Cai Jiaxi , Quan Yun , Zhang Cindy Yuxuan , Wang Ziyi , Hinshaw Stephen M. , Zhou Huilin , Suhandynata Raymond T. 
Published: July 2024

AbstractLarge multi-protein machines are central to multiple biological processes. However, stoichiometric determination of protein complex subunits in their native states presents a significant challenge. This study addresses the limitations of current tools in accuracy and precision by introducing concatemer-assisted stoichiometry analysis (CASA). CASA leverages stable isotope-labeled concatemers and liquid chromatography parallel reaction monitoring mass spectrometry (LC-PRM-MS) to achieve robust quantification of proteins with sub-femtomole sensitivity. As a proof-of-concept, CASA was applied to study budding yeast kinetochores. Stoichiometries were determined forex vivoreconstituted kinetochore components, including the canonical H3 nucleosomes, centromeric (Cse4CENP-A) nucleosomes, centromere proximal factors (Cbf1 and CBF3 complex), inner kinetochore proteins (Mif2CENP-C, Ctf19CCANcomplex), and outer kinetochore proteins (KMN network). Absolute quantification by CASA revealed Cse4CENP-Aas a cell-cycle controlled limiting factor for kinetochore assembly. These findings demonstrate that CASA is applicable for stoichiometry analysis of multi-protein assemblies.SummaryThis study presents Concatemer-Assisted Stoichiometry Analysis (CASA) to address a common challenge in cell biological research: quantifying the number of each protein subunit in a native protein complex.
A fluorescent biosensor for the visualization of agmatine
Authors: Kröger Pascal , Stiel Andre C. , Stüven Birthe , Shanmugaratnam Sooruban , Schoch Susanne , Wachten Dagmar , Höcker Birte 
Published: July 2024

AbstractAgmatine is known to regulate various neurotransmitter systems, yet the underlying molecular mechanisms remain elusive. To visualize agmatine dynamics in cellular networks and thereby unravel its physiological functions, we developed a genetically encoded fluorescent agmatine biosensor (AGMsen) based on the periplasmic putrescine binding protein PotF. We first analyzed the agmatine binding properties of the PotF receptor module based on its crystal structure and introduced mutations into the binding pocket to favor agmatine binding over other biogenic amines. Validation of AGMsen functionality across different cell types, including primary neuronal cultures, demonstrates its ability of real-time agmatine visualization. Thus, the sensor can serve as a valuable tool to advance our understanding of agmatine distribution and dynamics, and shed light on their effect on neuronal functionsin vivo.
Sex Dimorphism in Expression of Immune Response Genes in Drosophila
Authors: Khan MD Mursalin , Graze Rita M. 
Published: July 2024

AbstractSex dimorphism in immunity is commonly observed in a wide variety of taxa and is thought to arise from fundamental life history differences between females and males. InDrosophila melanogaster, infection with different pathogens typically results in different modes of immune sex dimorphism, with male-or female-bias, likely due to specific disease-causing mechanisms of pathogens and host-pathogen interactions. Studies showed that some pathways, such as IMD and Toll, can explain these sex-dimorphic immune responses in Drosophila. However, it is unclear if sex differences in the immune response observed inD. melanogasterare conserved, even in closely related species. One window into identifying conserved and evolving sex differences in the immune response is to examine the sex-differential expression of immunity-related genes. Here, we aim to understand whether two closely related species,D. melanogasterandD. simulans, show conserved sex dimorphism in innate immunity, focusing on associated changes in gene expression in response to infection with a gram-negative bacterium,Providencia rettgeri. Survival, bacterial load, and bacterial load upon death (BLUD) were investigated to assess overall sex differences.D. melanogasterfemales and males differed significantly in survival, whereasD. simulansdid not. Enrichment analyses revealed that both sexes and species upregulate genes involved in similar immune-related biological processes, but downregulated groups differed. We identified conserved sex differential gene expression of genes in the bacterial infection response pathways IMD, Toll, Jak/STAT, their regulators, and other immune-related gene classes (e.g., BOMs), as well as sex and species differences. InD. melanogaster,the effector antimicrobial peptides (AMPs) regulated by IMD were more highly upregulated relative toD. simulansin both sexes. Moreover,D. melanogasterfemales uniquely initiated high levels of gene expression that were involved in negative feedback mechanisms that controlled the overstimulation of IMD. Genes in the Toll pathway were also sex-differentially expressed with a higher level of upregulation inD. melanogaster. Remarkably, comparing expression across species, we find thatD. simulanslikely employs both the conventional peptidoglycan recognition-driven PRR-SPE-Spz pathway and the microbial protease recognition-based Psh-dependent activation of Toll; in contrast,D. melanogasterappears to solely rely on the PRR-SPE-Spz pathway in this context. In summary, our findings indicate that sex differences are conserved in both species for the majority of upregulated genes, while downregulation patterns and specific gene subsets show notable differences between sexes or species.
Prognostic significance of somatic mutations in myeloid cells of men with chronic heart failure – interaction between loss of Y chromosome and clonal hematopoiesis
Authors: Cremer Sebastian , von Scheidt Moritz , Kirschbaum Klara , Tombor Lukas , Mas-Peiro Silvia , Abplanalp Wesley , Rasper Tina , Krefting Johannes , Ware Akshay , Leistner David , Schunkert Heribert , Speer Thimoteus , Dimmeler Stefanie , Zeiher Andreas Michael 
Published: July 2024

AbstractAge-associated clonal hematopoiesis of indeterminate potential (CHIP) has been associated with increased incidence and worse prognosis of chronic heart failure. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPC). Mosaic loss of the Y chromosome (LOY), the most common somatic mutation in blood cells of men, also correlates with clonal expansion of myeloid cells, increases with age and was experimentally shown to lead to diffuse cardiac fibrosis and subsequent heart failure in mice. However, the prognostic significance of LOY as well as its potential interaction with CHIP in patients with chronic heart failure is unknown. We investigated the prevalence and prognostic significance of the extent of LOY and the two most common CHIP-driver mutations DNMT3A and TET2 in 705 male patients with established chronic heart failure across the entire spectrum of left ventricular ejection fraction. Both, LOY and DNMT3A/TET2 mutations, increased with age, and LOY co-occurred with DNMT3A/TET2 mutations in 27.1% of men at age > 70 years. LOY was an independent predictor of death during 3-years of follow-up across the entire spectrum of left ventricular ejection fraction. The co-occurrence of harboring LOY and DNMT3A/TET2 mutations significantly contributed to the observed increased mortality observed in carriers of DNMT3A/TET2 mutations. The detrimental effect of LOY on prognosis was confirmed in a validation cohort of patients with ischemic heart disease. scRNA sequencing of peripheral blood cells in patients with chronic ischemic heart failure showed increased profibrotic signaling in LOY monocytes with elevated markers of monocyte mediated inflammation and profibrotic cardiac remodeling (S100A8, TLR2, CLEC4D) and reduced expression of TGF-β inhibiting genes (SMAD7, TGIF2). The proinflammatory phenotype of LOY monocytes was further amplified in LOY monocytes of patients simultaneously harboring DNMT3A mutations, who displayed heightened expression of alarmins (S100A8, HMGB2) and interferon signaling related genes (IFNGR1, TRIM56, CD84) compared to patients without CHIP mutations. Thus, the age-associated acquisition of somatic mutations in blood cells of men with chronic heart failure is associated with increased mortality, with loss of Y chromosome emerging as an independent predictor of all-cause death across the entire spectrum of left ventricular function.
A phase I clinical trial of intrahepatic artery delivery of TG6002 in combination with oral 5-fluorocytosine in patients with liver-dominant metastatic colorectal cancer
Authors: West Emma J. , Sadoun Alain , Bendjama Kaidre , Erbs Philippe , Smolenschi Cristina , Cassier Philippe A. , de Baere Thierry , Sainte-Croix Sophie , Brandely Maud , Melcher Alan A. , Ismail Fay , Scott Karen J. , Bennett Angela , Banks Emma , Gasior Ewa , Kent Sarah , Kurzawa Marta , Hammond Christopher , Patel Jai V. , Collinson Fiona J. , Twelves Chris , Anthoney D. Alan , Swinson Dan , Samson Adel 
Published: July 2024

ABSTRACTBackgroundEffective treatment for patients with metastatic cancer is limited, particularly for colorectal cancer patients with metastatic liver lesions (mCRC), where accessibility to numerous tumours is essential for favourable clinical outcomes. Oncolytic viruses (OVs) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous (i.v.) or intratumoural (i.t.) administration routes.MethodsWe conducted a multi-centre, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral pro-drug 5-fluorocytosine (5-FC) to fifteen mCRC patients.ResultsSuccessful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by virus within tumour biopsies. Functional transcription of theFCU1transgene indicates viral replication within the tumour, with higher plasma concentrations of 5-fluorouracil (5-FU) associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death. Gene Ontology analyses of differentially-expressed genes reveal a significant immune response at the transcriptional level in response to treatment. Moreover, an increase in the number and frequency of T cell receptor clones against both cancer- and neo-antigens, with elevated functional activity, may be associated with improved anti-cancer activity. Despite these findings, no clinical efficacy was observed.ConclusionsIn summary, these data demonstrate delivery of OV to tumour via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data supports the need for future studies using IHA administration of OVs.SUMMARYA phase Ia study of TG6002 oncolytic vaccinia virus administration via the hepatic artery in patients with colorectal cancer liver metastases. Virus was delivered to tumour with functional activity of the virus-encodedFCU1transgene, eliciting innate and adaptive anti-cancer immunity.
RESP2: An uncertainty aware multi-target multi-property optimization AI pipeline for antibody discovery
Authors: Parkinson Jonathan , Hard Ryan , Ko Young Su , Wang Wei 
Published: July 2024

ABSTRACTDiscovery of therapeutic antibodies against infectious disease pathogens presents distinct challenges. Ideal candidates must possess not only the properties required for any therapeutic antibody (e.g. specificity, low immunogenicity) but also high affinity to many mutants of the target antigen. Here we present RESP2, an enhanced version of our RESP pipeline, designed for the discovery of antibodies against diverse antigens with simultaneously optimized developability properties. RESP2 provides a suite of methods to estimate the uncertainty of predictions including a new model combining neural network and Gaussian process with great flexibility to model protein engineering data, which accelerates in silico directed evolution to identify tight binders even those not present in the original screening library. An interpretable model is then exploited to assess antibody humanness to minimize immunogenicity risk of the selected candidates. To demonstrate the power of this pipeline, we use the receptor binding domain (RBD) of the COVID-19 spike protein as a case study, and discover a highly human antibody with broad (mid to high-affinity) binding to at least 8 different variants of the RBD. These results illustrate the advantages of this pipeline for antibody discovery against a challenging target. The code needed to reproduce the experiments in this paper is available athttps://github.com/Wang-lab-UCSD/RESP2.
Understanding the development of neural abnormalities in adolescents with mental health problems: a longitudinal study
Authors: Hou Jiangyun , van de Mortel Laurens , Liu Weijian , Liu Shu , Popma Arne , Smit Dirk J.A. , van Wingen Guido 
Published: July 2024

AbstractMany mental health problems are neurodevelopmental in nature and have an onset during childhood. Mental health disorders are associated with neural abnormalities, but it is unclear when those emerge and how this relates to the development of different mental health problems. We used data from the largest longitudinal neurodevelopmental study to identify the structural and functional brain changes that co-occur with the onset of six mental health problems. The results showed premorbid brain-wide abnormalities that were comparable between internalizing and different from externalizing problems, and differential neurodevelopmental trajectories for specific brain regions in 11- to 12-year-old adolescents who developed ADHD, conduct, depressive and oppositional defiant problems. These results reveal that the onset of different mental health problems co-occur with common as well as problem-specific brain abnormalities.
Toscana Virus Infection Clinical Characterization
Authors: Ayhan Nazli , Eldin Carole , Charrel Remi 
Published: July 2024

AbstractBackgroundToscana virus (TOSV) is a sandfly-borne phlebovirus causing central nervous system (CNS) infection in Mediterranean countries, during summer season. However, clinical aspects of the disease caused by this virus are poorly known by clinicians, so that its prevalence is probably underestimated due to a lack of diagnosis.Study designWe gathered data from all available case series and retrospective studies identifying TOSV as the causative viral agent. The informations of age, sex, clinical characteristics, laboratory findings, imaging results and clinical outcomes of TOSV infection were recorded and analyzed.ResultsIn our review a total of 95 articles including TOSV infections resulting in a total of 1,381 cases were analyzed. Our findings indicate, TOSV affects individuals across various age groups, with a median age of 44.45 years. A notable disparity in infection rates between genders, with men being significantly more likely to present symptoms due to TOSV than women, with a sex ratio of 2.0 (p<0.001). The clinical presentation of TOSV infection encompasses a range of symptoms, including fever, headache, retro-orbital pain, neurological and muscular manifestations with less common reports of cutaneous and gastrointestinal symptoms. To date, six fatalities have been attributed to TOSV infections, with a median age of 76 years.Diagnostic evaluation of TOSV infections often involves the analysis of cerebrospinal fluid, where findings may include an elevated white blood cell count.ConclusionsThese findings underscore the diverse clinical manifestations of TOSV infections and highlight the importance of considering this pathogen in the differential diagnosis of patients presenting with acute febrile illness, especially in endemic regions. TOSV represents an emerging infectious threat that warrants inclusion in the diagnostic protocols for patients presenting with CNS, particularly within the Mediterranean basin or for those with recent travel history to endemic regions during warmer months when sandflies are actively circulating.
Destination image and revisit intentions: a mediation-moderation study through tourist satisfaction and place attachment
Authors: Zulfiqar Urooj , Aman-Ullah Attia , Mehmood Waqas , Singh Hacharanjit 
Published: July 2024

Purpose
The purpose of this study is to test the relationship of cognitive destination image and affective destination image with tourist satisfaction and revisit intention. This study also tested the mediation effect of tourist satisfaction between cognitive destination image and affective destination image with revisit intention. Furthermore, place attachment is aimed to test as a moderator between tourist satisfaction and revisit intention.

Design/methodology/approach
Participants in this study are international visitors who were visiting different tourist places in Pakistan. A total of 340 tourists participated in the data collection process, and subsequent data analysis was performed using SPSS and smart-PLS.

Findings
The results confirmed a significant effect of affective destination image on revisit intention, whilst’ cognitive destination image does not signify a significant influence on revisit intention for international tourists; however, tourist satisfaction confirmed the mediation effect between cognitive-affective destination image and revisit intention. Furthermore, the place attachment confirmed significant moderation with revisit intention.

Originality/value
This study provides valuable insights into the context of tourist revisit intention in Pakistan. To the best of the authors’ knowledge, the model tested in this study (affective destination image and cognitive destination image > tourists’ satisfaction > place attachment > revisit intention) is developed for the first time and is the first of its kind to test the moderation effect of place attachment with revisit intention. This study is supported by the Oliver expectancy disconfirmation theory and the Bowlby theory, which is another novelty of this study.
Homeownership through asnaf home financing in Malaysia: an empirical investigation
Authors: Amin Hanudin 
Published: July 2024

Purpose
The purpose of this study is to examine asnafs’ acceptance of home financing in Malaysia.

Design/methodology/approach
This work developed and introduced the maqasid theory of consumer behaviour (MTCB) to examine the effects of educational programmes, mortgage welfare, consumer justice and Islamic debt policy on receptiveness. Data analysis involving 733 respondents was conducted using partial least squares (PLS), where SmartPLS4.0 software comes into play.

Findings
In the core model, the effects of the MTCB’s variables helped shape the development of asnaf home financing acceptance.

Research limitations/implications
This study was based on quantitative data and geographical constraints.

Practical implications
The findings provide valuable inputs for the Joint Committee Body (JCB), combining Islamic banks and State Islamic Religious Councils to develop action plans for improving the facility offered.

Social implications
This work functioned as a social benchmark for improving Islamic home financing that includes asnafs’ homeownership.

Originality/value
A new conceptual framework for asnaf home financing drawn from MTCB is developed in the context of asnafs’ homeownership.
Workplace bullying and job burnout: the moderating role of employee voice
Authors: Ullah Atiat , Ribeiro Neuza 
Published: July 2024

PurposeThis study aims to investigate the connection between workplace bullying and job burnout while also examining how employee voice moderates this relationship.Design/methodology/approachThe study's sample comprises 303 employees employed in the automobile sector of Pakistan. Statistical analysis was conducted using tools such as SPSS, AMOS, and the PROCESS macro. Methods like CFA and regression were utilized to assess the study hypotheses.FindingsBased on Conservation of Resource (COR) Theory, this study unveiled a positive effect of workplace bullying on employees' job burnout. Moreover, it found that employee voice moderates the association between workplace bullying and job burnout.Practical implicationsThe study confirmed that workplace bullying leads to increased job burnout. Furthermore, when top management considers employee voice, it reduces the impact of workplace bullying on job burnout. Therefore, it is recommended that management in automobile organizations can promote a culture that encourages employee voice to effectively lessen the effects of workplace bullying on job burnout.Originality/valueFirstly, this research pioneers the examination of workplace bullying's impact on job burnout among employees in the automobile sector. Secondly, it enhances our understanding of how employee voice affects the indirect influence of workplace bullying on job burnout. Thirdly, within an international context, this study pioneers the examination of how employee voice influences the association between workplace bullying and job burnout. Finally, this study is motivated by the increasing concern that workplace bullying leads to negative workplace experiences, adversely affecting employee well-being, and ultimately resulting in devastating long-term effects on organizations.