bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative Spatial Analysis of H&E and IHC Images Identifies Prognostic Immune Subtypes Correlated with Progression-Free Survival in Human Papillomavirus (HPV)-Related Oropharyngeal Squamous Cell Carcinoma
Authors: Nakkireddy Sumanth Reddy , Jang Inyeop , Kim Minji , Yin Linda X. , Rivera Michael , Garcia Joaquin J. , Bartemes Kathleen R. , Routman David M. , Moore Eric. J. , Abdel-Halim Chadi N. , Ma Daniel J. , Van Abel Kathryn M. , Hwang Tae Hyun 
Published: September 2023

AbstractPurposeDeep learning techniques excel at identifying tumor-infiltrating lymphocytes (TILs) and immune phenotypes in hematoxylin and eosin (H&E)-stained slides. However, their ability to elucidate detailed functional characteristics of diverse cellular phenotypes within tumor immune microenvironment (TME) is limited. We aimed to enhance our understanding of cellular composition and functional characteristics across TME regions and improve patient stratification by integrating H&E with adjacent immunohistochemistry (IHC) images.MethodsA retrospective study was conducted on patients with HPV(+) oropharyngeal squamous cell carcinoma (OPSCC). Using paired H&E and IHC slides for 11 proteins, a DL pipeline was used to quantify tumor, stroma, and TILs in the TME. Patients were classified into immune inflamed (IN), immune excluded (IE), or immune desert (ID) phenotypes. By registering the IHC and H&E slides, we integrated IHC data to capture protein expression in the corresponding tumor regions. We further stratified patients into specific immune subtypes, such as IN, with increased or reduced CD8+ cells, based on the abundance of these proteins. This characterization provided functional insight into the H&E-based subtypes.ResultsAnalysis of 88 primary tumors and 70 involved lymph node tissue images revealed an improved prognosis in patients classified as IN in primary tumors with high CD8 and low CD163 expression (p = 0.007). Multivariate Cox regression analysis confirmed a significantly better prognosis for these subtypes.ConclusionsIntegrating H&E and IHC data enhances the functional characterization of immune phenotypes of the TME with biological interpretability, and improves patient stratification in HPV(+) OPSCC.
MocFormer: A Two-Stage Pre-training-Driven Transformer for Drug-Target Interactions Prediction
Authors: Zhang Yilun , Wang Wentao , Guan Jiahui , Jain Deepak Kumar , Wang Tianyang , Roy Swalpa Kumar 
Published: September 2023

AbstractDrug-target interactions (DTIs) is essential for advancing pharmaceuticals. Traditional drug-target interaction studies rely on labor-intensive laboratory techniques. Still, recent advancements in computing power have elevated the importance of deep learning methods, offering faster, more precise, and cost-effective screening and prediction. Nonetheless, general deep learning methods often yield low-confidence results due to the complex nature of drugs and proteins, bias, limited labeled data, and feature extraction challenges. To address these challenges, a novel two-stage pre-trained framework is proposed for DTIs prediction. In the first stage, pre-trained molecule and protein models develop a comprehensive feature representation, enhancing the framework’s ability to handle drug and protein diversity. This also reduces bias, improving prediction accuracy. In the second stage, a transformer with bilinear pooling and a fully connected layer (FCN) enables predictions based on feature vectors. Comprehensive experiments were conducted using DrugBank dataset and Epigenetic-regulators dataset to evaluate the framework’s effectiveness. The results demonstrate that the proposed framework outperforms the state-of-the-art methods regarding accuracy, area under the ROC curve (AUC), recall, and the area under the precision-recall curve (AUPRC). The code will be available after being accepted:https://github.com/rickwang28574/MocFormer
The Discovery and Characterization of 1,4-Dihydroxy-2-naphthoic Acid Prenyltransferase Involved in the Biosynthesis of Anthraquinones inRubia cordifolia
Authors: Liu Changzheng , Wang Ruishan , Wang Sheng , Chen Tong , Lyu Chaogeng , Kang Chuanzhi , Wan Xiufu , Guo Juan , Huang Luqi , Guo Lanping 
Published: September 2023

AbstractAnthraquinones constitute the largest group of natural quinones, which are used as safe natural dyes and have many pharmaceutical applications. In plants, anthraquinones are biosynthesized through two main routes: the polyketide pathway and the shikimate pathway. The shikimate pathway primarily forms alizarin-type anthraquinones, and the prenylation of 1,4-dihydroxy-2-naphthoic acid is the first pathway-specific step. However, the prenyltransferase responsible for this key step remains uncharacterized. In this study, the cell suspension culture ofRubia cordifolia, a plant rich in alizarin-type anthraquinones, was used in target prenyltransferase mining. The microsomal protein prepared from the cell suspension culture prenylated 1,4-dihydroxy-2-naphthoic acid to form 2-carboxyl-3-prenyl-1,4-naphthoquinone and 3-prenyl-1,4-naphthoquinone. Then a candidate gene belonging to UbiA superfamily,RcDT1, was discovered to account for the prenylation activity. Substrate specificity studies revealed that the recombinant RcDT1 recognized naphthoic acids primarily, followed by 4-hydroxyl benzoic acids. The prenylation activities ofR. cordifoliamicrosomes and the recombinant RcDT1 were both strongly inhibited by 1,2- and 1,4-dihydroxynaphthalene. The plastid localization and root-specific expression further confirmed the participation ofRcDT1in anthraquinone biosynthesis. The phylogenetic analyses ofRcDT1and its rubiaceous homologs indicated that DHNA-prenylation activity evolved convergently in Rubiaceae via recruitment from the ubiquinone biosynthetic pathway. The discovery and evolutionary studies ofRcDT1provide useful guidance for identifying additional and evolutionarily varied prenyltransferases which enable entry into quinones derived from shikimate pathway. Moreover, these findings will have profound implications for understanding the biosynthetic process of the anthraquinone/naphthoquinone ring derived from shikimate pathway.
Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer
Authors: Tummala Tej , Uruchurtu Ashley Sanchez Sevilla , De La Cruz Arielle , Huntington Kelsey E. , George Andrew , Liguori Nicholas R. , Zhang Leiqing , Zhou Lanlan , Abbas Abbas E. , Azzoli Christopher G. , El-Deiry Wafik S. 
Published: September 2023

AbstractPancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin stalls and degrades RNA Polymerase II and introduces breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin’s highly efficient killing of human-derived pancreatic tumor cell lines PANC-1, BxPC-3, and HPAF-II as a single agent. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of γH2AX, a DNA damage marker, and the Chk1/ATR pathway, involved in replicative stress and DNA damage response. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-fluorouracil (5-FU) results in highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer.
Picomolar-Level Sensing of Cannabidiol by Metal Nanoparticles Functionalized with Chemically Induced Dimerization Binders
Authors: Ikbal MD Ashif , Kang Shoukai , Chen Xiahui , Gu Liangcai , Wang Chao 
Published: September 2023

AbstractSimple and fast detection of small molecules is critical to health and environmental monitoring. Methods for chemical detection often use mass spectrometers or enzymes; the former relies on expensive equipment and the latter is limited to those that can act as enzyme substrates. Affinity reagents like antibodies can target a variety of small-molecule analytes, but the detection requires successful design of chemically conjugated targets or analogs for competitive binding assays. Here, we developed a generalizable method for highly sensitive and specific in-solution detection of small molecules, using cannabidiol (CBD) as an example. Our sensing platform uses gold nanoparticles (AuNPs) functionalized with a pair of chemically induced dimerization (CID) nanobody binders (nano-binders), where CID triggers AuNPs aggregation and sedimentation in the presence of CBD. Despite moderate binding affinities of the two nano-binders to CBD (KDs of ∼6 and ∼56 µM), a scheme consisting of CBD-AuNP pre-analytical incubation, centrifugation, and electronic detection (ICED) was devised to demonstrate a high sensitivity (limit of detection of ∼100 picomolar) in urine and saliva, a relatively short assay time (∼2 hours), a large dynamic range (5 logs), and a sufficiently high specificity to differentiate CBD from its analog, tetrahydrocannabinol. The high sensing performance was achieved with the multivalency of AuNP sensing, the ICED scheme that increases analyte concentrations in a small assay volume, and a portable electronic detector. This sensing system is readily coupled to other binders for wide molecular diagnostic applications.
Automatic vocalisation detection delivers reliable, multi-faceted, and global avian biodiversity monitoring
Authors: Sethi Sarab S. , Bick Avery , Chen Ming-Yuan , Crouzeilles Renato , Hillier Ben V. , Lawson Jenna , Lee Chia-Yun , Liu Shih-Hao , Freitas Parruco Celso Henrique de , Rosten Carolyn , Somveille Marius , Tuanmu Mao-Ning , Banks-Leite Cristina 
Published: September 2023

AbstractTracking biodiversity and its dynamics at scale is essential if we are to solve global environmental challenges. Detecting animal vocalisations in passively recorded audio data offers a highly automatable, inexpensive, and taxonomically broad way to monitor biodiversity. However, uptake is slow due to the expertise and labour required to label new data and fine-tune algorithms for each deployment. In this study, we applied an off-the-shelf bird vocalisation detection model, BirdNET, to 152,376 hours of audio comprising of datasets from Norway, Taiwan, Costa Rica, and Brazil. We manually listened to a subset of detections for each species in each dataset and found precisions of over 80% for 89 of the 139 species (100% for 57 species). Whilst some species were reliably detected across multiple datasets, the performance of others was dataset specific. By filtering out unreliable detections, we could extract species and community level insight on diel (Brazil) and seasonal (Taiwan) temporal scales, as well as landscape (Costa Rica) and national (Norway) spatial scales. Our findings demonstrate that, with a relatively fast validation step, a single vocalisation detection model can deliver multi-faceted community and species level insight across highly diverse datasets; unlocking the scale at which acoustic monitoring can deliver immediate applied impact.
A latent cardiomyocyte regeneration potential in human heart disease
Authors: Derks Wouter , Rode Julian , Collin Sofia , Rost Fabian , Heinke Paula , Hariharan Anjana , Pickel Lauren , Simonova Irina , Lázár Enikő , Graham Evan , Jashari Ramadan , Andrä Michaela , Jeppsson Anders , Salehpour Mehran , Alkass Kanar , Druid Henrik , Kyriakopoulos Christos P. , Taleb Iosif , Shankar Thirupura S. , Selzman Craig H. , Sadek Hesham , Jovinge Stefan , Brusch Lutz , Frisén Jonas , Drakos Stavros , Bergmann Olaf 
Published: September 2023

AbstractCardiomyocytes in the adult human heart show a regenerative capacity, with an annual renewal rate around 0.5%. Whether this regenerative capacity of human cardiomyocytes is employed in heart failure has been controversial. Using retrospective14C birth dating we analyzed cardiomyocyte renewal in patients with end-stage heart failure. We show that cardiomyocyte generation is minimal in end-stage heart failure patients at rates 18-50 times lower compared to the healthy heart. However, patients receiving left ventricle support device therapy, who showed significant functional and structural cardiac improvement, had a >6-fold increase in cardiomyocyte renewal relative to the healthy heart. Our findings reveal a substantial cardiomyocyte regeneration potential in human heart disease, which could be exploited therapeutically.
Blimp-1 and c-Maf regulate common and unique gene networks to protect against distinct pathways of pathobiont-induced colitis
Authors: Alvarez-Martinez Marisol , Cox Luke S. , Pearson Claire F. , Branchett William J. , Chakravarty Probir , Wu Xuemei , Slawinski Hubert , Al-Dibouni Alaa , Samelis Vasileios A. , Gabryšová Leona , Priestnall Simon L. , Suárez-Bonnet Alejandro , Mikolajczak Anna , Briscoe James , Powrie Fiona , O’Garra Anne 
Published: September 2023

ABSTRACTIntestinal immune responses to commensals and pathogens are controlled by IL-10 to avoid intestinal immune pathology. We show that the transcription factors Blimp-1(Prdm-1)and c-Maf are co-dominant regulators ofIl10in Foxp3+regulatory T cells, but also negatively regulate proinflammatory cytokines in effector T cells. Mice with T cell-specific deletion ofPrdm-1, Mafor the combination of both transcription factors did not develop inflammatory intestinal pathologies at the steady state. Double deficientPrdm1fl/flMaffl/flCd4Cremice infected withHelicobacter hepaticusdeveloped severe colitis with a major increase in TH1/NK/ILC1 effector genes in lamina propria leucocytes (LPLs), whilePrdm1fl/flCd4CreandMaffl/flCd4Cremice showed mild/moderate pathology and a less-marked Type I effector response. LPLs from infectedMaffl/flCd4Cremice showed increasedIl17aexpression and an accompanying increase in granulocytes and myeloid cells, which was less marked inPrdm1fl/flMaffl/flCd4Cremice, with increased T cell-myeloid-neutrophil interactions inferred from scRNA-seq analysis and confirmed by immunofluorescent analysis of colon sections. Genes over-expressed in human IBD showed differential expression in the LPL from infected mice in the absence ofPrdm1orMaf,revealing potential pathobiologic mechanisms of human disease.
Keras/TensorFlow in Drug Design for Immunity Disorders
Authors: Dragan Paulina , Joshi Kavita , Atzei Alessandro , Latek Dorota 
Published: September 2023

AbstractHomeostasis of the host immune system is regulated by white blood cells with a variety of cell surface receptors for cytokines. Chemotactic cytokines (chemokines) activate their receptors to evoke the chemotaxis of immune cells in homeostatic migrations or inflammatory conditions towards inflamed tissue or pathogens. Dysregulation of the immune system leading to disorders such as allergies, autoimmune diseases, or cancer requires efficient, fast-acting drugs to minimize the long-term effects of chronic inflammation. Here, we performed structure-based virtual screening (SBVS) assisted by the Keras/TensorFlow neural network (NN) to find novel compound scaffolds acting on three chemokine receptors: CCR2, CCR3 and one CXC receptor CXCR3. Keras/TensorFlow NN was used here not as a typically used binary classifier, but as an efficient multi-class classifier that can discard not only inactive compounds but also low or medium-activity compounds. Several compounds proposed by SBVS and NN were tested in 100 ns all-atom molecular dynamics simulations to confirm their binding affinity. To improve the basic binding affinity of the compounds, new chemical modifications were proposed. The modified compounds were compared with known antagonists of these three chemokine receptors. Known CXCR3 were among the top predicted compounds and thus benefits of using Keras/TensorFlow in drug discovery have been shown in addition to structure-based approaches. Furthermore, we showed that Keras/TensorFlow NN can accurately predict the receptor subtype selectivity of compounds, for which SBVS often fails. We cross-tested chemokine receptor datasets retrieved from ChEMBL and curated datasets for cannabinoid receptors available at:http://db-gpcr-chem.uw.edu.pl. The NN model trained on the cannabinoid receptor datasets retrieved from ChEMBL was the most accurate in the receptor subtype selectivity prediction. Among NN models trained on the chemokine receptor datasets, the CXCR3 model showed the highest accuracy in differentiating the receptor subtype for a given compound dataset.
Effects of age and noise on tympanal displacement in the Desert Locust
Authors: Austin Thomas T , Woodrow Charlie , Montealegre-Z Fernando , Warren Ben 
Published: September 2023

AbstractInsect cuticle is an evolutionary-malleable exoskeleton that has specialised for various functions. Insects that detect the pressure component of sound bear specialised sound-capturing tympani evolved from cuticular thinning. Whilst the outer layer of insect cuticle is composed of non-living chitin, its mechanical properties change during development and aging. Here, we measured the displacements of the tympanum of the desert Locust,Schistocerca gregaria, to understand biomechanical changes as a function of age and noise-exposure. We found that the stiffness of the tympanum decreases within 12 hours of noise-exposure and increases as a function of age, independent of noise-exposure. Noise-induced changes were dynamic with an increased tympanum displacement to sound within 12 hours post noise-exposure. Within 24 hours, however, the tone-evoked displacement of the tympanum decreased below that of control Locusts. After 48 hours, the tone-evoked displacement of the tympanum was not significantly different to Locusts not exposed to noise. Tympanal displacements reduced predictably with age and repeatably noise-exposed Locusts (every three days) did not differ from their non-noise-exposed counterparts. Changes in the biomechanics of the tympanum may explain an age-dependent decrease in auditory detection in tympanal insects.
Global analysis of Poales diversification – parallel evolution in space and time into open and closed habitats
Authors: Elliott Tammy L , Spalink Daniel , Larridon Isabel , Zuntini Alexandre Rizzo , Escudero Marcial , Hackel Jan , Barrett Russell L , Martín-Bravo Santiago , Márquez-Corro José Ignacio , Mendoza Carolina Granados , Mashau Aluoneswi C. , Romero-Soler Katya J , Zhigila Daniel A. , Gehrke Berit , Andrino Caroline Oliveira , Crayn Darren M , Vorontsova Maria S , Forest Félix , Baker William J , Wilson Karen L , Simpson David A , Muasya A Muthama 
Published: September 2023

SummaryPoales are one of the most species-rich, ecologically and economically important orders of plants and often characterise open habitats, enabled by unique suites of traits. We test the hypotheses that Poales species are assembled into distinct phyloregions, with centres of high phylogenetic diversity and endemism clustered in tropical regions, and that cosmopolitan families show parallel transitions into open and closed habitats at different times.We sampled 42% of Poales species and obtained taxonomic and biogeographic data from the World Checklist of Vascular Plants database, which was combined with open/closed habitat data scored by taxonomic experts. A dated supertree of Poales was constructed. We integrated spatial phylogenetics with regionalization analyses, historical biogeography, ancestral state estimations, and models of contingent evolution.Diversification in Poales and assembly of open and closed habitats result from dynamic evolutionary processes that vary across lineages, time, space, and traits, most prominently in tropical and southern latitudes. Our results reveal parallel and recurrent patterns of habitat and trait transitions in the species-rich families Poaceae and Cyperaceae, yet other smaller families display unique evolutionary trajectories.The Poales have achieved global dominance via parallel evolution in open habitats, with notable, spatially and phylogenetically restricted divergences into strictly closed habitats.
Reversions mask the contribution of adaptive evolution in microbiomes
Authors: Torrillo Paul A. , Lieberman Tami D. 
Published: September 2023

AbstractWhen examining bacterial genomes for evidence of past selection, the results obtained depend heavily on the mutational distance between chosen genomes. Even within a bacterial species, genomes separated by larger mutational distances exhibit stronger evidence of purifying selection as assessed by dN/dS, the normalized ratio of nonsynonymous to synonymous mutations. Here, we show that the classical interpretation of this scale-dependence, weak purifying selection, leads to problematic mutation accumulation when applied to available gut microbiome data. We propose an alternative, adaptive reversion model with exactly opposite implications for dynamical intuition and applications of dN/dS. Reversions that occur and sweep within-host populations are nearly guaranteed in microbiomes due to large population sizes, short generation times, and variable environments. Using analytical and simulation approaches, we show that adaptive reversion can explain the dN/dSdecay given only dozens of locally-fluctuating selective pressures, which is realistic in the context ofBacteroidesgenomes. The success of the adaptive reversion model argues for interpreting low values of dN/dSobtained from long-time scales with caution, as they may emerge even when adaptive sweeps are frequent. Our work thus inverts the interpretation of an old observation in bacterial evolution, illustrates the potential of mutational reversions to shape genomic landscapes over time, and highlights the importance of studying bacterial genomic evolution on short time scales.
Unique territorial and compartmental organization of chromosomes in the holocentric silkmoth
Authors: Gil J. , Navarrete E. , Rosin L.F. , Chowdhury N. , Abraham S. , Cornilleau G. , Lei E.P. , Mozziconacci J. , Mirny L.A. , Muller H. , Drinnenberg I.A. 
Published: September 2023

AbstractThe hallmarks of chromosome organization in multicellular eukaryotes are chromosome territories (CT), chromatin compartments, and insulated domains, including topologically associated domains (TADs). Yet, most of these elements of chromosome organization are derived from analyses of a limited set of model organisms, while large eukaryotic groups, including insects, remain mostly unexplored. Here we combine Hi-C, biophysical modeling, and microscopy to characterize the 3D genome architecture of the silkworm,Bombyx mori. In contrast to other eukaryotes,B. morichromosomes form highly separated territories. Similar to other eukaryotes,B. morichromosomes segregate into active A and inactive B compartments, yet unlike in vertebrate systems, contacts between euchromatic A regions appear to be a strong driver of compartmentalization. Remarkably, we also identify a third compartment, called secluded “S,” with a unique contact pattern. Each S region shows prominent short-range self-contacts and is remarkably devoid of contacts with the rest of the chromosome, including other S regions. Compartment S hosts a unique combination of genetic and epigenetic features, localizes towards the periphery of CTs, and shows developmental plasticity. Biophysical modeling reveals that the formation of such secluded domains requires highly localized loop extrusion within them, along with a low level of extrusion in A and B. Our Hi-C data supports predicted genome-wide and localized extrusion. Such a broad, non-uniform distribution of extruders has not been seen in other organisms. Overall, our analyses support loop extrusion in insects and highlight the evolutionary plasticity of 3D genome organization, driven by a new combination of known processes.