bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone Mineralization Regulation: Using Zebrafish as a Model to Study ANKH-associated Mineralization Disorders
Authors: Wathuliyadde Nuwanthika , Willmore Katherine E. , Kelly Gregory M. 
Published: March 2024

AbstractCraniometaphyseal Dysplasia (CMD) is a rare skeletal disorder that can result from mutations in theANKHgene. This gene encodes progressive ankylosis (ANK), which is responsible for transporting inorganic pyrophosphate (PPi) and ATP from the intracellular to the extracellular environment, where PPi inhibits bone mineralization. When ANK is dysfunctional, as in patients with CMD, the passage of PPi to the extracellular environment is reduced, leading to excess mineralization, particularly in bones of the skull. Zebrafish may serve as a promising model to study the mechanistic basis of CMD. Here we provide a detailed analysis of the zebrafish ankh paralogs, ankha and ankhb, in terms of their phylogenic relationship with ANKH in other vertebrates as well as their spatiotemporal expression patterns during zebrafish development. We found a closer evolutionary relationship exists between the zebrafish ankhb protein and its human and other “higher” vertebrate counterparts. Furthermore, we noted distinct temporal expression patterns withankhamore prominently expressed in early development stages, andankhbexpression at larval growth stages. Whole mountin situhybridization was used to compare spatial expression patterns of each paralog during bone development. Both paralogs showed strong expression in the craniofacial region as well as the notochord and somites, with only subtle patterning differences. Given the substantial overlap in spatiotemporal expression ofankhaandankhb, the exact roles of these genes remain speculative. However, this study lays the groundwork for functional analyses of each ankh paralog and the potential of using zebrafish to find possible targeted therapies for CMD.
ComPRePS: An Automated Cloud-based Image Analysis tool to democratize AI in Digital Pathology
Authors: Mimar Sayat , Paul Anindya S. , Lucarelli Nicholas , Border Samuel , Santo Briana A. , Naglah Ahmed , Barisoni Laura , Hodgin Jeffrey , Rosenberg Avi Z , Clapp William , Sarder Pinaki ,   the Kidney Precision Medicine Project
Published: March 2024

ABSTRACTArtificial intelligence (AI) has extensive applications in a wide range of disciplines including healthcare and clinical practice. Advances in high-resolution whole-slide brightfield microscopy allow for the digitization of histologically stained tissue sections, producing gigapixel-scale whole-slide images (WSI). The significant improvement in computing and revolution of deep neural network (DNN)-based AI technologies over the last decade allow us to integrate massively parallelized computational power, cutting-edge AI algorithms, and big data storage, management, and processing. Applied to WSIs, AI has created opportunities for improved disease diagnostics and prognostics with the ultimate goal of enhancing precision medicine and resulting patient care.The National Institutes of Health (NIH) has recognized the importance of developing standardized principles for data management and discovery for the advancement of science and proposed the Findable, Accessible, Interoperable, Reusable, (FAIR) Data Principles1with the goal of building a modernized biomedical data resource ecosystem to establish collaborative research communities. In line with this mission and to democratize AI-based image analysis in digital pathology, we propose ComPRePS: an end-to-end automatedComputationalRenalPathologySuite which combines massive scalability, on-demand cloud computing, and an easy-to-use web-based user interface for data upload, storage, management, slide-level visualization, and domain expert interaction. Moreover, our platform is equipped with both in-house and collaborator developed sophisticated AI algorithms in the back-end server for image analysis to identify clinically relevant micro-anatomic functional tissue units (FTU) and to extract image features.
LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients
Authors: Frenger Quentin , Lucas Julie , Petitdemange Arthur , Path Luisa , Wadier Nadège , Depauw Sabine , Giorgiutti Stéphane , Gong Yazhuo , Merlin Hélène , Meyer Aurore , Herber Mathilde , Jaquel Léa , Mertz Philippe , Felten Renaud , Chatelus Emmanuel , Dieudonne Yannick , Guffroy Aurélien , Arnaud Laurent , Poindron Vincent , Gottenberg Jacques-Eric , Sibilia Jean , Korganow Anne-Sophie , Martin Thierry , Gros Frédéric 
Published: March 2024

AbstractAutophagy is a fundamental catabolic process performed by a network of autophagy related (ATG) proteins. Some ATG proteins coordinate parallel roles in so-called “noncanonical” autophagy such as LC3-associated phagocytosis (LAP). Both autophagy and LAP share key functions in immunity and inflammation and have been linked to autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by excessive fibrosis in skin and multiple internal organs linked with an aberrant immune activation. Several polymorphisms of genes coding for ATG proteins, particularly inATG5, are more frequent in SSc patients. We hypothesized that autophagy and/or LAP could be dysregulated in immune cells from SSc patients. No defect of canonical autophagy was found in lymphocytes and monocytes isolated from peripheral blood mononuclear cells of SSc patients. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess LAP activity. While M0 macrophage polarization appears similar than in healthy donors, we showed that LAP is downregulated in SSc patients. We now need to understand the molecular mechanisms underlying LAP dysregulations. Future investigations leading to the discovery of LAP modulating drugs could then open new therapeutic options for SSc treatment.Key messagesPolymorphisms of autophagy-related genes are associated with several autoimmune and autoinflammatory diseases, including SSc and SLEWhile autophagy has been shown to be dysregulated in circulating cells from SLE patients, no information is available for SScWe show here that autophagy is comparable between PBMCs from patients and matched controlsWe find a strong impartment of LAP, another ATG-dependent mechanism, in monocyte-derived macrophages from SSc patientsAs LAP is involved in efferocytosis and the regulation of inflammation, we propose that restoring LAP activity could be a therapeutic option to limit fibrosis and inflammation
Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes
Authors: Pino Diego Chillón , Badonyi Mihaly , Semple Colin A. , Marsh Joseph A. 
Published: March 2024

AbstractAdvances in structure determination and computational modelling are enabling us to study the protein structural context of human genetic variants at an unprecedented scale. Here, we investigate millions of human cancer-associated missense mutations in terms of their structural locations and predicted perturbative effects. We find that, while cancer-driving mutations have properties similar to other known disease-causing mutations, this is obscured by the abundance of passenger mutations in cancer sequencing datasets. Nevertheless, by considering the collective properties of mutations at the level of individual proteins, we identify distinct mutational signatures associated with tumour suppressors and oncogenes. Tumour suppressors are enriched in structurally damaging mutations, consistent with loss-of-function mechanisms. In contrast, oncogene mutations tend to be structurally mild, reflecting selection for gain-of-function driver mutations and against loss-of-function mutations. Although oncogenes are difficult to distinguish from genes with no role in cancer using only structural damage, we find that an alternate metric based on the clustering of mutations in three-dimensional space is highly predictive of oncogenes, particularly when mutation recurrence is considered. These observations allow us to identify novel candidate driver genes and speculate about their molecular roles, which we expect to have general utility in the analysis of cancer sequencing data.
CrossModal Correspondence based MultisensoryIntegration: A pilot study showing how HAV cues can modulate the reaction time
Authors: Banerjee Swati , Shumkova Daria 
Published: March 2024

AbstractWe live in a multisensory world, where all our senses work together for giving us a fulfilling experience of the environment that we are in or during our use of immersive technologies.For gaining more insight into the temporal scale understanding of the integration phenomenon EEG based BCI can give us the understanding of the transient changes in the brain.In this study, we investigated the potential of incorporating haptics into crossmodal correspondence based research to induce MSI effect through either the active touch users’ feedback or crossmodal correspondences with visual and auditory modalities, such as Kiki Bouba effect.We designed two experiments:Visual stimuli were presented on a standard computer monitor, and auditory stimuli were delivered through computer dynamics. Participants responded using left or right hand by pressing either CapsLock or Enter buttons respectively. Visual cue consisted of a red circle displayed randomly either on the left or on the right side of the screen. Auditory cue was a brief high tone presented through left or right headphones for 500 ms. Text stimuli that appeared on the screen instructed participants to respond with their left or right hand. Before each trial there was a fixation central cross displayed for 500 ms.This experiment was inspired by previous studies on Kiki-Bouba correspondence. Visual stimuli consisted of 4 shapes - circle, triangle, polygon with 6 vertices, and star - presented on a computer screen. Locations of the visual stimuli were randomized. Auditory stimuli were generated using the Online Tone Generator website (https://onlinetonegenerator.com/). 2 sets of sounds were used: the first set included sine, triangle, square, and sawtooth waveforms, each at a frequency of 500 Hz; the second set included sawtooth waveforms at frequencies of 50 Hz, 300 Hz, 600 Hz, and 2000 Hz (summarised in Table 2).Results suggested that it is indeed possible to achieve this type of integration without relying on complex haptic devices. Introducing haptics into BCI technologies through feedback touch or crossmodal correspondances holds potential to improve the user experience and information transfer rate (ITR).Participants, as expected, showed the lowest reaction times in congruent sequential test and the highest – in incongruent HAV cues based test. This indicates the importance preference for sequential cue presentation over simultaneous one. The time was significantly higher in case of Incongruent Haptic cues.
Computational Exploration of Protein Structure Dynamics and RNA structural Consequences ofPKD1Missense Variants: Implications in ADPKD Pathogenesis
Authors: Devi Chandra , Ranjan Prashant , Raj Sonam , Das Parimal 
Published: March 2024

AbstractAutosomal dominant polycystic kidney disease (ADPKD), a genetic disorder characterized by the formation of fluid-filled cysts within the kidneys, leading to progressive renal dysfunction, is primarily caused by mutations inPKD1, a gene encoding for the protein polycystin-1 (PC1). Understanding the structural consequences ofPKD1variants is crucial for elucidating disease mechanisms and developing targeted therapies. In this study, we analyzed the effects of nine missensePKD1variants, including c.6928G>A p.G2310R, c.8809G>A p.E2937K, c.2899T>C p.W967R, c.6284A>G p.D2095G, c.6644G>A p.R2215Q, c.7810G>A p.D2604N, c.11249G>C p.R3750P, c.1001C>T p.T334M, and c.3101A>G p.N1034S on RNA structures, their interactions utilizing computational tools. We also explain the effects of these variants on PC1 protein dynamics, stability, and interactions using molecular dynamics (MD) simulation. These variants are located at crucial domains such as the REJ domain, PKD domains, and cation channel domain, potentially compromising PC1’s function and contributing to ADPKD pathogenesis. Findings reveal substantial deviations in RNA structures and their interactions with other proteins or RNAs and also protein structure and dynamics for variants such as c.8809G>A (p.E2937K), c.11249G>C (p.R3750P), c.3101A>G (p.N1034S), c.6928G>A (p.G2310R), c.6644G>A (p.R2215Q) suggesting their potential implications in disease etiology. The study also suggests that although certain variants may have minimal effects on RNA conformations, their observed alterations in MD simulations indicate potential impact on protein structure dynamics highlighting the importance of evaluating the functional consequences of genetic variants by considering both RNA and protein levels. This study offers valuable perspectives of the utility of studying the structure dynamics through computational tools in prioritizing the variants for their functional implications and understanding the molecular mechanisms underlying ADPKD pathogenesis and developing therapeutic interventions.GRAPHICAL ABSTRACT
Low-Cost Robotic Manipulation of Live Microtissues for Cancer Drug Testing
Authors: Stepanov Ivan , Gottshall Noah R. , Ahmadianyazdi Alireza , Sinha Daksh , Lockhart Ethan J. , Nguyen Tran N.H. , Hassan Sarmad , Horowitz Lisa F. , Yeung Raymond S. , Gujral Taranjit S. , Folch Albert 
Published: March 2024

AbstractThe scarcity of human biopsies available for drug testing is a paramount challenge for developing new therapeutics, disease models, and personalized treatments. Microtechnologies that combine the microscale manipulation of tissues and fluids offer the exciting possibility of miniaturizing both disease models and drug testing workflows on scarce human biopsies. Unfortunately, these technologies presently require microfluidic devices or robotic dispensers that are not widely accessible. We have rapidly-prototyped an inexpensive platform based on an off-the-shelf robot that can microfluidically manipulate live microtissues into/out of culture plates without using complicated accessories such as microscopes or pneumatic controllers. The robot integrates complex functions with a simple, cost-effective and compact construction, allowing placement inside a tissue culture hood for sterile workflows. We demonstrated a proof-of-concept cancer drug evaluation workflow of potential clinical utility using patient tumor biopsies with multiple drugs on 384-well plates. Our user-friendly, low-cost platform promises to make drug testing of microtissues broadly accessible to pharmaceutical, clinical, and biological laboratories.TeaserA low-cost robot for handling microtissues and catalyzing their use in cancer drug evaluation and personalized oncology.
The smoking cessation drug cytisine requires systemically circulating estrogen for sex-specific neuroprotection in female parkinsonian mice
Authors: Zarate Sara M. , Garcia Roger C. , Pandey Gauri , Srinivasan Rahul 
Published: March 2024

AbstractThe smoking cessation drug cytisine exerts neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of female but not male 6-hydroxydopamine (6-OHDA) lesioned parkinsonian mice. To address the important question of whether circulating estrogen mediates this effect, we employ two mouse models aimed at depleting systemically circulating estrogen: (i) bilateral ovariectomy (OVX), and (ii) aromatase inhibition with systemically administered letrozole. In both models, depleting systemically circulating estrogen in female 6-OHDA lesioned parkinsonian mice results in the loss of cytisine-mediated neuroprotection as measured using apomorphine-induced contralateral rotations and SNc DA neurodegeneration. Our experiments also reveal that OVX alone exerts neuroprotection in SNc DA neurons due to compensatory changes not observed in the letrozole model, which underscores the importance of using independent models of estrogen depletion to study neuroprotection. Taken together, our findings suggest that the smoking cessation drug cytisine is a viable neuroprotective drug for pre-menopausal women with Parkinson’s disease.
Single cell resolution analysis of multi-tissue derived human iNKT cells reveals novel transcriptional paradigms
Authors: Jayasinghe Reyka G. , Hollingsworth Derek , Boonchalermvichian Chaiyaporn , Gupta Biki , Yan Hao , Baker Jeanette , Dejene Beruh , Weinberg Kenneth I , Negrin Robert S. , Mavers Melissa 
Published: March 2024

ABSTRACTInvariant natural killer T (iNKT) cells are evolutionarily conserved innate lymphocytes important for host defense against pathogens. Further, they are increasingly recognized to play a role in tumor immune surveillance and in protection against graft versus host disease, and they are of particular importance as a universal donor for cellular therapies. Therefore, a thorough understanding of the biology of iNKT cells is critical. Murine studies have revealed the existence of transcriptionally and functionally distinct subsets, similar to T helper cell subsets. However, a comprehensive study of human iNKT cell heterogeneity is lacking. Herein, we define the transcriptomic heterogeneity of human iNKT cells derived from multiple immunologically relevant tissues, including peripheral blood, cord blood, bone marrow, and thymus, using single cell RNA-sequencing. We describe human iNKT cells with a naïve/precursor transcriptional pattern, a Th2-like signature, and Th1/17/NK-like gene expression. This combined Th1/17 pattern of gene expression differs from previously described murine iNKT subsets in which Th1- and Th17- like iNKT cells are distinct populations. We also describe transcription factors regulating human iNKT cells with distinct gene expression patterns not previously described in mice. Further, we demonstrate a novel T effector memory RA+(TEMRA)-like pattern of expression in some human iNKT cells. Additionally, we provide an in-depth transcriptional analysis of human CD8+iNKT cells, revealing cells with two distinct expression patterns—one consistent with naïve/precursor cells and one consistent with Th1/17/NK-like cells. Collectively, our data provide critical insights into the transcriptional heterogeneity of human iNKT cells, providing a platform to facilitate future functional studies and to inform the development of iNKT-based cellular therapies.
Gene regulatory network co-option is sufficient to induce a morphological novelty inDrosophila
Authors: Rice Gavin , Gaitan-Escudero Tatiana , Charles-Obi Kenechukwu , Zeitlinger Julia , Rebeiz Mark 
Published: March 2024

AbstractIdentifying the molecular origins by which new morphological structures evolve is one of the long standing problems in evolutionary biology. To date, vanishingly few examples provide a compelling account of how new morphologies were initially formed, thereby limiting our understanding of how diverse forms of life derived their complex features. Here, we provide evidence that the large projections on theDrosophila eugracilisphallus that are implicated in sexual conflict have evolved through co-option of the trichome genetic network. These unicellular apical projections on the phallus postgonal sheath are reminiscent of trichomes that cover theDrosophilabody but are up to 20-fold larger in size. During their development, they express the transcription factor Shavenbaby, the master regulator of the trichome network. Consistent with the co-option of the Shavenbaby network during the evolution of theD. eugracilisprojections, somatic mosaic CRISPR/Cas9 mutagenesis shows thatshavenbabyis necessary for their proper length. Moreover, mis-expression of Shavenbaby in the sheath ofD. melanogaster, a naïve species that lacks these extensions, is sufficient to induce small trichomes. These induced extensions rely on a genetic network that is shared to a large extent with theD. eugracilisprojections, indicating its co-option but also some genetic rewiring. Thus, by leveraging a genetically tractable evolutionarily novelty, our work shows that the trichome-forming network is flexible enough that it can be co-opted in a new context, and subsequently refined to produce unique apical projections that are barely recognizable compared to their simpler ancestral beginnings.
Novel non-immunogenic trained immunity inducing small molecule with improved anti-tumor properties
Authors: Ajit Jainu , Knight Hannah Riley , Chen Qing , Solanki Ani , Shen Jingjing , Kahn Aaron P. Esser 
Published: March 2024

AbstractTrained immunity refers to the non-specific innate immune memory response triggered by the epigenetic and metabolic rewiring of innate immune cells. A strengthened innate immune system significantly improves disease resistance. However, very few trained immunity-inducing molecules have been identified. Almost all molecules for training are primarily immunogenic and then subsequently induce training. Non-immunogenic molecules that induce training could be employed in therapies without the concern of adverse inflammatory reactions. We identified a small molecule, A1155463, that modulates cellular metabolism to induce trained immunity in macrophagesin-vitro. We show that nanomolar concentrations of these compounds uniquely alter only cellular metabolism without leading to apoptosis. We further observed that these compounds could induce training in anin-vivomodel in mice. A1155463 training improved anti-tumor resistance to B16.F10 melanoma cells. The effect was enhanced upon combination with checkpoint therapy. In summary, we report the discovery of a novel trained immunity-inducing small molecule with enhanced anti-tumor properties.