bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human activity, not environmental factors, drivesScedosporiumandLomentosporadistribution in Taiwan
Authors: Wu Hsin-Mao , Fan Yu-Hsuan , Phang Guan-Jie , Zeng Wen-Ting , El-Sayid Abdrabo Khaled Abdrabo , Wu Yu-Ting , Sun Pei-Lun , Lin Ying-Hong , Huang Yin-Tse 
Published: November 2024

AbstractScedosporiumandLomentosporaspecies are emerging fungal pathogens capable of causing severe infections in both immunocompetent and immunocompromised individuals. Previous environmental surveys have suggested potential associations between these fungi and various soil chemical parameters, though the relative influence of human activity versus environmental factors has not been systematically evaluated. Here, we conducted a comprehensive survey of 406 soil samples from 132 locations across Taiwan, analyzing fungal abundance alongside soil physicochemical parameters and the Human Footprint Index (HFI). We recovered 236 fungal isolates comprising 10 species, withS. boydii(32.2%),S. apiospermum(30.9%), andS. dehoogii(14.4%) being the most prevalent. The highest fungal burdens were observed in urban environments (up to 1293 CFU/g), particularly in public spaces and healthcare facilities. Statistical analysis revealed a significant positive correlation between fungal abundance and HFI (r = 0.125, p = 0.013), while soil chemical parameters including nitrogen, carbon, pH, electrical conductivity, and various base cations showed no significant associations despite their wide ranges. These findings indicate that anthropogenic disturbance of environments, rather than soil chemistry, is the primary driver ofScedosporiumandLomentosporadistribution in Taiwan. This understanding holds important implications for predicting infection risks and developing targeted public health strategies, particularly in rapidly urbanizing regions. Future studies incorporating more specific indicators of human impact may further elucidate the mechanisms underlying these distribution patterns.Lay AbstractWe found that human activities, rather than soil properties, determine whereScedosporium/Lomentosporafungi distribute in Taiwan. These fungi are more abundant in urban areas than less-human-disturbed environments, suggesting increased infection risks in densely populated regions.
Dopamine D2receptor agonists abrogate neuroendocrine tumour angiogenesis to inhibit chemotherapy-refractory small cell lung cancer progression
Authors: Alam Sk. Kayum , Pandit Anuradha , Wang Li , Thiele Britteny A. , Manoj Parvathy , Aubry Marie Christine , Rudin Charles M. , Lo Ying-Chun , Hoeppner Luke H. 
Published: November 2024

AbstractSmall cell lung cancer (SCLC) is difficult to treat due to its aggressiveness, early metastasis, and rapid development of resistance to chemotherapeutic agents. Here, we show that treatment with a dopamine D2receptor (D2R) agonist reduces tumour angiogenesis in multiplein vivoxenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved D2R agonist, cabergoline, also sensitized chemoresistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice.Ex vivo, D2R agonist treatment decreased tumour angiogenesis through increased apoptosis of tumour-associated endothelial cells, creating a less favourable tumour microenvironment that limited cancer cell proliferation. In paired SCLC patient-derived specimens, D2R was expressed by tumour-associated endothelial cells obtained before treatment, but D2R was downregulated in SCLC tumours that had acquired chemoresistance. D2R agonist treatment of chemotherapy-resistant specimens restored expression of D2R. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.
In silicoIdentification of Novel Common Drug Targets Against Four InfectiousAcinetobacterSpecies
Authors: Rahman Soaibur , Hasnat Soharth , Mahbub M Murshida , Farzana Zinat , Sabila Sal 
Published: November 2024

AbstractThe global emergence of multidrug-resistantAcinetobacterspecies has become a major concern in the management of hospital-acquired infections. Moreover, misdiagnosis of one species ofAcinetobacterwith another has been reported, making it difficult to choose appropriate treatment. World Health Organization emphasizes the urgent need to develop new antibiotics to combatAcinetobacterinfections. This study aimed to discover novel common drug targets that will be effective againstAcinetobacter nosocomialis, Acinetobacter baumannii, Acinetobacter pittii,andAcinetobacter haemolyticus. We utilized a cluster-based subtractive genomics approach to identify potential drug targets. The main focus was to find drug targets that are absent in humans and essential for pathogens. We also performed metabolic pathway and subcellular localization analyses. Furthermore, protein structure-based studies and druggability analyses were conducted to identify viable therapeutic options. Out of 1245 protein clusters (minimum 4 proteins/cluster), 204 clusters were human non-homologous and essential for bacteria. Among them, 39 clusters were cytoplasmic and involved in unique metabolic pathways which are specific to the pathogens. After analyzing the drug target sequences of DrugBank database, 12 clusters were found to be novel drug targets. Eventually, proteins of one cluster were identified as advantageous drug targets having drug-binding pockets at very similar regions with high druggability scores. These proteins can be inhibited to disrupt the Lysine/DAP biosynthetic pathway ofAcinetobacter.Our research might open up a new possibility for drug discovery against these pathogens.
Ligand-independent c-Met activation by HHLA2 drives hepatocellular carcinoma and predicts c-MET inhibitor efficacy
Authors: Huang Xubo , Fang Runya , Pang Yuqian , Zhang Zhe , Huang Jieru , Li Yingchang , Yuan Tao , Zeng Yuyi , Yao Ziying , Vega-Rubín-de-Celis Silvia , Thinwa Josephine , Shen Hao , Wang Jiahong , Shen Feng , Wei Yongjie 
Published: November 2024

AbstractThe HGF/c-Met signaling pathway facilitates the initiation, progression, and metastasis of hepatocellular carcinoma (HCC). c-Met activation, however, is complex and not solely dependent on HGF, hindering targeted therapy development. This study identifies a critical oncogenic role for HHLA2, a B7 family member, in HCC and highlights its potential as a therapeutic target. We demonstrate that HHLA2 directly interacts with and activates c-Met through N-glycosylation, triggering sustained signaling and promoting aggressive HCC features. Mechanistically, we identified the pro-tumorigenic role of HHLA2 required downstream upregulation of MMP9 and VEGFA, both implicated in tumor progression. In multiple mouse models, HHLA2 overexpression accelerated tumor progression, metastasis, and reduced liver NK cell infiltration, all of which were reversed by c-Met inhibition. In a cohort of 176 HCC patients, HHLA2 expression strongly correlated with c-Met phosphorylation, advanced tumor stage, and poor prognosis. Importantly, HHLA2 expression predicted sensitivity to c-Met inhibitors in cell lines and patient-derived organoids and could be detected in patient serum, suggesting its potential as a prognostic biomarker. Collectively, our findings reveal an HHLA2-mediated mechanism of c-Met activation and provide a strong rationale for targeting the HHLA2-c-Met axis as a novel therapeutic strategy, with HHLA2 serving as a potential prognostic biomarker.Abstract Figure
A negative feedback loop between small GTPase Rap1 and mammalian tumor suppressor homolog KrsB regulates cell-substrate adhesion inDictyostelium
Authors: Artemenko Yulia , Niu Gengle , Arnold Megan E. , Roberts Kelsey E. , Fernandez Bianca N. , Flores Tiffany , McClave Harper D. , Paestella Michael , Borleis Jane , Devreotes Peter N. 
Published: November 2024

AbstractCell adhesion to the substrate influences a variety of cell behaviors and its proper regulation is essential for migration, although details of the molecular pathways regulating cell adhesion during migration are lacking. Rap1 is a small GTPase that regulates adhesion in mammalian cells, as well as inDictyostelium discoideumsocial amoeba, which is an established model for studying directed cell migration. InDictyostelium, Rap1 controls adhesion via its effects on adhesion mediator talin and Ser/Thr kinase Phg2, which inhibits myosin II function. Kinase responsive to stress B (KrsB), a homolog of mammalian tumor suppressor MST1/2 andDrosophilaHippo, also regulates cell adhesion and migration, although the molecular mechanism of KrsB action is not understood. Since KrsB has been shown to interact with active Rap1 by mass spectroscopy, we investigated the genetic interaction between Rap1 and KrsB. Cells lacking KrsB have increased adhesion to the substrate, which leads to reduced movement. Expression of constitutively active Rap1 G12V increased cell spreading and adhesion even in the absence of KrsB, suggesting that Rap1 does not require KrsB to mediate cell adhesion. In contrast, dominant negative Rap1 S17N completely reversed the over-adhesive phenotype of KrsB-null cells and impaired KrsB phosphorylation, suggesting that KrsB activation and function in adhesion requires Rap1. Even though Rap1 did not require KrsB for its function in adhesion, KrsB negatively regulates Rap1 function as seen by increased cortical localization of Rap1 in KrsB-null cells. Consistent with this, chemoattractant-induced activation of downstream effectors of Rap1, TalB and Phg2, was increased in the absence of KrsB. Taken together, these findings suggest that Rap1 leads to activation of KrsB, which inhibits Rap1 and its downstream targets, shutting off adhesion. The existence of a negative feedback loop between Rap1 and KrsB may contribute to the dynamic regulation of cell adhesion that is necessary for rapid amoeboid-type migration.
The single-cell spatial landscape of stage III colorectal cancers
Authors: Su Andrew , Lee HoJoon , Tran Minh , Cruz Richard D. , Sathe Anuja , Bai Xiangqi , Wichmann Ignacio , Pflieger Lance , Moulton Bryce , Barker Tyler , Haslem Derrick , Jones David , Nadauld Lincoln , Nguyen Quan , Ji Hanlee P. , Rhodes Terence 
Published: November 2024

ABSTRACTWe conducted a spatial analysis using imaging mass cytometry applied to stage III colorectal adenocarcinomas. This study used multiplexed markers to distinguish individual cells and their spatial organization from 52 colorectal cancers. We determined the landscape features of cellular spatial features in the CRC tumor microenvironment. This spatial single-cell analysis identified 10 unique cell phenotypes in the tumor microenvironment that included stromal and immune cells with a subset which had a proliferative phenotype. These special features included spatial neighborhood interactions between single cells as well as different tissue niches, especially the tumor infiltrating lymphocyte regions. We applied a robust statistical analysis to identify significant correlations of cell features with phenotypes such as microsatellite instability or recurrence. We determined that microsatellite stable (MSS) colorectal cancers had an increased risk of recurrence if they had the following features: 1) a low level of stromal tumor-infiltrating lymphocytes, and 2) low interactions between CD4+ T cells and stromal cells. Our results point to the utility of spatial single-cell interaction analysis in defining novel features of the tumor immune microenvironments and providing useful clinical cell-related spatial biomarkers.
External validation of a treatment decision algorithm for tuberculosis in children living with HIV - a diagnostic cohort study
Authors: Khosa Celso , Nguyet Minh Huyen Ton Nu , Mwanga-Amumpaire Juliet , Chabala Chishala , Moh Raoul , Roucher Clementine , Nansera Denis , Nduna Bwendo , Macassa Eugenia , Folquet Madeleine Amorrissany , Rego Dalila , Mundundu Gae , Natukunda Naome , Shankalala Perfect , Cumbe Saniata , Komena Eric , Steenhoff Andrew P. , Hesseling Anneke C. , Seddon James A , Wobudeya Eric , Bonnet Maryline , Marcy Olivier 
Published: November 2024

ABSTRACTIntroductionTuberculosis (TB) is the leading cause of death in children living with HIV (CLHIV) and is challenging to confirm the diagnosis. The PAANTHER treatment decision algorithm (TDA) was developed to improve the diagnosis of TB in CLHIV. We aimed to externally validate the PAANTHER TDA in CLHIV with presumptive TB.MethodsWe conducted a prospective diagnostic cohort study in seven tertiary hospitals across Côte d’Ivoire, Mozambique, Uganda, and Zambia, implementing the PAANTHER TDA in CLHIV aged between 1 month and 14 years with presumptive TB. TDA assessments included Xpert MTB/RIF Ultra (Ultra) on respiratory and stool samples, history of contact, symptoms (fever >2 weeks, unremitting cough, haemoptysis and/or weight loss in previous 4 weeks, tachycardia), chest radiography and abdominal ultrasound. A positive score (>100) prompted TB treatment initiation. Children were followed-up for 6 months, and retrospectively classified as having confirmed, unconfirmed or unlikely TB. The primary outcome was the proportion of missed TB cases (false negative) among children with negative scores; secondary outcomes included TDA diagnostic accuracy, feasibility, and time to treatment initiation. The TDA was considered validated if the negative predictive value (NPV, 1 - rate of false negative) was superior to a 75% pre-established confidence interval lower limit.FindingsFrom 2 October 2019 to 31 December 2021, we enrolled 277 CLHIV, including 175 (63·2%) who were on antiretroviral therapy at inclusion. 272 (98·2%) children had a complete TDA evaluation; 215 (75.8%) scored >100, including 24 (8·7%) with positive Ultra. 182 (86·7%) children who scored ≥100, and 12 children who scored negative, initiated TB treatment at a median of 1 (IQR: 0-3) and 27 [8·2; 64] days after inclusion, respectively. 62/215 children (28·8%) who scored ≥100 were classified as having unlikely TB and 4/12 (33·3%) who scored negative were initiated on treatment and were classified as having unconfirmed TB. The proportion of children with TB (confirmed and unconfirmed) was 155/273 (56·8%; 95% CI: 50·9; 62·5). The NPV was 55/67 (93·3%; 95% CI: 84·1; 97·4), reaching protocol-defined validation. The TDA sensitivity was 97·4% (95% CI: 93·6; 90·0) with specificity of 47·5 (95% CI: 38·7; 56·4).InterpretationThe PAANTHER TDA was validated in CLHIV. Its high sensitivity, excellent feasibility, and short turnaround time to treatment initiation, should allow rapid treatment decision-making and could reduce morbidity and mortality in CLHIV.FundingUNITAID
Single-cell transcriptional landscapes ofAedes aegyptimidgut and fat body after a bloodmeal
Authors: Vial Thomas , Lopez-Maestre Hélène , Couderc Elodie , Pinaud Silvain , Howick Virginia , Akorli Jewelna , Lawniczak Mara , Marti Guillaume , Merkling Sarah Hélène 
Published: November 2024

SUMMARYAedes aegyptimosquitoes are vectors for numerous arboviruses that have an increasingly substantial global health burden. Following a bloodmeal, mosquitoes experience significant physiological changes, primarily orchestrated by the midgut and fat body tissues. These changes begin with digestion and culminate in egg production. However, our understanding of those key processes at the cellular and molecular level remains limited. We have created a comprehensive cell atlas of the mosquito midgut and fat body by employing single-cell RNA sequencing and metabolomics techniques. This atlas unveils the dynamic cellular composition and metabolic adaptations that occur following a bloodmeal. Our analyses reveal highly diverse cell populations, specialized in digestion, metabolism, immunity, and reproduction. While the midgut primarily comprises enterocytes, enteroendocrine and intestinal stem cells, the fat body consists not only of trophocytes and oenocytes, but also harbors a substantial hemocyte population and a newly found fat body-yolk cell population. The fat body exhibits a complex cellular and metabolomic profile and exerts a central role in coordinating immune and metabolic processes. Additionally, an insect-specific virus, PCLV (Phasi Charoen-Like Virus) was detected in single cells, mainly in the midgut a week after the bloodmeal. These findings highlight the complexity of the mosquito’s abdominal tissues, and pave the way towards the development of exquisitely refined vector control strategies consisting of genetically targeting specific cell populations and metabolic pathways necessary for egg development after a bloodmeal.
NOODAI: A webserver for network-oriented multi-omics data analysis and integration pipeline
Authors: Totu Tiberiu , Tomasoni Mattia , Bolck Hella Anna , Buljan Marija 
Published: November 2024

SummaryOmics profiling has proven of great use for unbiased and comprehensive identification of key features that define biological phenotypes and underlie medical conditions. While each omics profile assists characterization of specific molecular components relevant for the studied phenotype, their joint evaluation can offer deeper insights into the overall mechanistic functioning of biological systems. Here, we introduce an approach where starting from representative traits (e.g., differentially expressed elements) obtained for each omics profile, we construct and analyze joint interaction networks. The resulting networks rely on the existing knowledge of confident interactions among biological entities. We use these maps to identify and describe central elements, which connect multiple entities characteristic for the studied phenotypes and we leverage MONET network decomposition tool in order to highlight functionally connected network modules. In order to enable broad usage of this approach, we developed the NOODAI software platform, which enables integrative omics analysis through a user-friendly interface. The analysis outcomes are presented both as raw output tables as well as high-quality summary plots and written reports. Since the MONET tool enables the use of algorithms with strong performance in identifying disease-relevant modules, the NOODAI software platform can be of a high value for the analysis of clinical multi-omics datasets.Availability and ImplementationThe platform is available as a web application freely accessible athttps://omics-oracle.com. The source code is freely available from GitHub under the GPL3 license at:https://github.com/TotuTiberiu/NOODAI.
Long lived liver-resident memory T cells of biased specificities for abundant sporozoite antigens drive malaria protection by radiation-attenuated sporozoite vaccination
Authors: de Menezes Maria N. , Ge Zhengyu , Cozijnsen Anton , Gras Stephanie , Bertolino Patrick , Caminschi Irina , Lahoud Mireille H. , Yui Katsuyuki , McFadden Geoffrey I. , Beattie Lynette , Heath William R. , Fernandez-Ruiz Daniel 
Published: November 2024

AbstractVaccination with radiation-attenuated sporozoites (RAS) can provide highly effective protection against malaria in both humans and mice. To extend understanding of malaria immunity and inform the development of future vaccines, we studied the protective response elicited by this vaccine in C57BL/6 mice. We reveal that successive doses ofPlasmodium bergheiRAS favour the generation of liver CD8+tissue-resident memory T cells (TRMcells) over circulating memory cells, and markedly enhance their longevity. Importantly, RAS immunisation strongly skews the composition of the liver CD8+TRMcompartment towards cells specific for abundant sporozoite antigens, such as thrombospondin-related adhesive protein (TRAP) and circumsporozoite protein (CSP), which become major mediators of protection. The increased prevalence of sporozoite specificities is associated with limited intrahepatic parasite development and inhibition of naïve T cell responses to all parasite antigens in previously vaccinated mice. This leads to the exclusive expansion of effector T cells formed upon initial immunisation, ultimately reducing the diversity of the liver TRMpool later established. These findings provide novel insights into the mechanisms governing malaria immunity induced by attenuated sporozoite vaccination and highlight the susceptibility of this vaccine to limitations imposed by strain-specific immunity associated with the abundant, yet highly variable sporozoite antigens CSP and TRAP.Author SummaryMalaria remains a significant global health challenge. An efficient vaccine could significantly enhance malaria control. Vaccination with radiation-attenuated sporozoites (RAS) can induce highly efficient protection against malaria, and our study brings critical insights into the protective mechanisms elicited by this vaccine. We show that RAS stimulates the formation of parasite-specific cytotoxic memory T cells that permanently reside in the liver (liver TRMcells). These cells are critical mediators of protection. Interestingly, multiple doses of RAS extend the lifespan of these memory cells, potentially improving long term immunity. However, we found that the induced memory T cell response is strongly skewed towards abundant, but highly variable, sporozoite proteins. Thus, this phenomenon exposes a potential limitation of the RAS vaccine against the great parasite diversity in the field, as it focuses the T cell response away from less abundant, but more conserved, parasite antigens.
RNA-Protein Interaction Classification via Sequence Embeddings
Authors: Matus Dominika , Runge Frederic , Franke Jörg K.H. , Gerne Lars , Uhl Michael , Hutter Frank , Backofen Rolf 
Published: November 2024

AbstractRNA-protein interactions (RPI) are ubiquitous in cellular organisms and essential for gene regulation. In particular, protein interactions with non-coding RNAs (ncRNAs) play a critical role in these processes. Experimental analysis of RPIs is time-consuming and expensive, and existing computational methods rely on small and limited datasets. This work introducesRNAInterAct, a comprehensive RPI dataset, alongsideRPIembeddor, a novel transformer-based model designed for classifying ncRNA-protein interactions. By leveraging two foundation models for sequence embedding, we incorporate essential structural and functional insights into our task. We demonstrate RPIembeddor’s strong performance and generalization capability compared to state-of-the-art methods across different datasets and analyze the impact of the proposed embedding strategy on the performance in an ablation study.
Transcriptomic analysis of benznidazole-resistantTrypanosoma cruziclone reveals nitroreductase I-independent resistance mechanisms
Authors: Mejía-Jaramillo Ana María , Ospina-Zapata Hader , Fernandez Geysson Javier , Triana-Chávez Omar 
Published: November 2024

AbstractThe enzyme nitroreductase I (NTRI) has been implicated as the primary gene responsible for resistance to benznidazole (Bz) and nifurtimox inTrypanosoma cruzi. However, Bz-resistantT. cruzifield isolates carrying the wild-type NTR-I enzyme suggest that additional mechanisms independent of this enzyme may contribute to the resistance phenotype. To investigate these alternative mechanisms, in this paper, we pressured aTrypanosoma cruziclone with a high Bz concentration over several generations to select Bz-resistant clones. Surprisingly, we found a highly drug-resistant clone carrying a wild-type NTRI. However, the knockout of this gene using CRISPR-Cas9 in the sensitive clone showed that NTRI indeed induces resistance to Bz and supports the idea that the resistant one exhibits mechanisms other than NTRI. To explore these new mechanisms, we performed an RNA-seq analysis, which revealed genes involved in metabolic pathways related to oxidative stress, energy metabolism, membrane transporters, DNA repair, and protein synthesis. Our results support the idea that resistance to benznidazole is a multigenic trait. A Deeper understanding of these genes is essential for developing new drugs to treat Chagas disease.