bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting glioblastoma tumor hyaluronan to enhance therapeutic interventions that regulate metabolic cell properties
Authors: Neves Edward R , Anand Achal , Mueller Joseph , Remy Roddel A , Xu Hui , Selting Kim A , Sarkaria Jann N. , Harley Brendan AC , Pedron-Haba Sara 
Published: January 2024

AbstractDespite extensive advances in cancer research, glioblastoma (GBM) still remains a very locally invasive and thus challenging tumor to treat, with a poor median survival. Tumor cells remodel their microenvironment and utilize extracellular matrix to promote invasion and therapeutic resistance. We aim here to determine how GBM cells exploit hyaluronan (HA) to maintain proliferation using ligand-receptor dependent and ligand-receptor independent signaling. We use tissue engineering approaches to recreate the three-dimensional tumor microenvironment in vitro, then analyze shifts in metabolism, hyaluronan secretion, HA molecular weight distribution, as well as hyaluronan synthetic enzymes (HAS) and hyaluronidases (HYAL) activity in an array of patient derived xenograft GBM cells. We reveal that endogenous HA plays a role in mitochondrial respiration and cell proliferation in a tumor subtype dependent manner. We propose a tumor specific combination treatment of HYAL and HAS inhibitors to disrupt the HA stabilizing role in GBM cells. Taken together, these data shed light on the dual metabolic and ligand - dependent signaling roles of hyaluronan in glioblastoma.SignificanceThe control of aberrant hyaluronan metabolism in the tumor microenvironment can improve the efficacy of current treatments. Bioengineered preclinical models demonstrate potential to predict, stratify and accelerate the development of cancer treatments.
Spatial Morphoproteomic Features Predict Uniqueness of Immune Microarchitectures and Responses in Lymphoid Follicles
Authors: Hu Thomas , Allam Mayar , Kaushik Vikram , Goudy Steven L. , Xu Qin , Mudd Pamela , Manthiram Kalpana , Coskun Ahmet F. 
Published: January 2024

AbstractMultiplex imaging technologies allow the characterization of single cells in their cellular environments. Understanding the organization of single cells within their microenvironment and quantifying disease-status related biomarkers is essential for multiplex datasets. Here we proposed SNOWFLAKE, a graph neural network framework pipeline for the prediction of disease-status from combined multiplex cell expression and morphology in human B-cell follicles. We applied SNOWFLAKE to a multiplex dataset related to COVID-19 infection in humans and showed better predictive power of the SNOWFLAKE pipeline compared to other machine learning and deep learning methods. Moreover, we combined morphological features inside graph edge features to utilize attribution methods for extracting disease-relevant motifs from single-cell spatial graphs. The underlying subgraphs were further analyzed and associated with disease status across the dataset. We showed that SNOWFLAKE successfully extracted significant low dimensional embedding from subgraphs with a clear separation between disease status and helped characterize unique cellular interactions in the subgraphs. SNOWFLAKE is a generalizable pipeline for the analysis of multiplex imaging data modality by extracting disease-relevant subgraphs guided by graph-level prediction.
Neural interference between real and imagined visual stimuli
Authors: Sulfaro Alexander A , Robinson Amanda K , Carlson Thomas A 
Published: January 2024

AbstractEvidence suggests that mental imagery and veridical perception recruit similar components of the human visual system. If so, neural representations of imagined and real stimuli should interact with one another, combining constructively or competing antagonistically. To determine if and how real and imagined visual stimuli interact in the brain, we asked participants to mentally visualise white bars at specific orientations after a rhythmic countdown while their brain activity was recorded using electroencephalography. Stimuli were imagined in isolation, or while another stimulus at a highly or poorly congruent orientation appeared on-screen. Multivariate pattern analysis was used to assess whether overlap between imagined and real stimulus features enhanced or diminished stimulus-specific sensory information in the brain. Findings showed that imagined and real orientation could be decoded from brain activity, with real orientation decoding mildly amplified by highly congruent, but not poorly congruent, imagined orientations. Although interactions between real and imagined stimuli were observed, no evidence was detected to suggest that imagined and real stimuli use the same neural activity patterns to encode sensory information. Instead, congruent imagery seemed only to amplify activity which had already been induced by real percepts, targeting late- but not early-stage perceptual representations. Ultimately, this study suggests that imagined and real stimuli interact in a mildly constructive manner, with imagination mostly acting in a modulatory capacity.
System-level analysis of genes mutated in muscular dystrophies reveals a functional pattern associated with muscle weakness distribution
Authors: Ozisik Ozan , Gorokhova Svetlana , Cerino Mathieu , Bartoli Marc , Baudot Anaïs 
Published: January 2024

ABSTRACTMuscular dystrophies (MDs) are inherited genetic diseases causing weakness and degeneration of muscles. The distribution of muscle weakness differs between MDs, involving distal muscles or proximal muscles. While the mutations in most of the MD-associated genes lead to either distal or proximal onset, there are also genes whose mutations can cause both types of onsets.We hypothesized that the genes associated with different MD onsets code proteins with distinct cellular functions. To investigate this, we collected the MD-associated genes and assigned them to three onset groups: genes mutated only in distal onset dystrophies, genes mutated only in proximal onset dystrophies, and genes mutated in both types of onsets. We then systematically evaluated the cellular functions of these gene sets with computational strategies based on functional enrichment analysis and biological network analysis.Our analyses demonstrate that genes mutated in either distal or proximal onset MDs code proteins linked with two distinct sets of cellular processes. Interestingly, these two sets of cellular processes are relevant for the genes that are associated with both onsets. Moreover, the genes associated with both onsets display high centrality and connectivity in the network of muscular dystrophy genes. Our findings support the hypothesis that the proteins associated with distal or proximal onsets have distinct functional characteristics, whereas the proteins associated with both onsets are multifunctional.
Mycobacterium tuberculosisexploits SIRT2 for iron acquisition to facilitate its intracellular survival
Authors: Talukdar Sharmila , Modanwal Radheshyam , Chaubey Gaurav Kumar , Dhiman Asmita , Dilawari Rahul , Raje Chaaya Iyengar , Raje Manoj 
Published: January 2024

AbstractIron availability is a critical factor for both bacteria and humans, and its availability significantly influences host-pathogen dynamics. AsMtbhas coevolved with the human race,Mtbrelentlessly tries to exploit iron from the tightly regulated iron machinery of host. Sirtuins are evolutionary conserved NAD+-dependent deacetylases involved in various cellular processes including infection. Notably, the cytosolic protein, Sirtuin 2 regulates cellular iron homeostasis in hepatocytes and afterMtbinfection, SIRT2 translocates to the nucleus leading to decreased protective immune response. However, the underlying mechanism as to howMtbexploits SIRT2 for iron acquisition remains unknown. In the current study, we observe that the decreased bacillary load in SIRT2 inhibited or knock down cells is due to low availability of iron to the bacilli. Inhibition or knockdown of SIRT2 inMtbinfected cells displays differential modulation of iron import and export proteins suggesting ongoing tussle by host to limit the bioavailability of iron to pathogen. More specifically, by flow cytometry analysis, we show significant upregulation of cell surface Apo Tf and GAPDH in infected SIRT2 inhibited macrophages. Thus, in SIRT2 depleted state, we delineate a different mechanism of iron export occurring through Apo Tf and GAPDH during infection in contrast to the classical iron exporter Fpn1. Collectively, our findings showed the importance of SIRT2-mediated iron regulation inMtbpathogenesis and can encourage designing of novel host-targeted therapeutics.
CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells and its pulmonary levels correlate with viral clearance in critical COVID-19 patients
Authors: Barbosa Bomfim Caio César , Genin Hugo , Cottoignies-Callamarte Andréa , Gallois-Montbrun Sarah , Murigneux Emilie , Sams Anette , Rosenberg Arielle R , Belouzard Sandrine , Dubuisson Jean , Kosminder Olivier , Pène Frédéric , Terrier Benjamin , Bomsel Morgane , Ganor Yonatan 
Published: January 2024

AbstractUpon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with critical coronavirus disease 2019 (COVID-19) present with life-threatening respiratory distress, pulmonary damage and cytokine storm. One unexplored hub in COVID-19 is the neuropeptide calcitonin gene-related peptide (CGRP), which is highly abundant in the airways and could converge in multiple aspects of COVID-19-related pulmonary pathophysiology. Whether CGRP affects SARS-CoV-2 infection directly remains elusive. We show that in critical COVID-19 patients, CGRP is increased in both plasma and lungs. Importantly, CGRP pulmonary levels are elevated in early SARS-CoV-2-positive patients, and restore to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analogue SAX directly inhibit infection of bronchial Calu-3 epithelial cells with SARS-CoV-2 Omicron and Alpha variants in a dose-dependent manner. Both pre- and post-infection treatment with GRRP and/or SAX is enough to block SARS-CoV-2 productive infection of Calu3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of SARS-CoV-2 entry receptors at the surface of Calu-3 cells. Together, we propose that increased pulmonary CGRP mediates beneficial viral clearance in critical COVID-19 patients, by directly inhibiting SARS-CoV-2 infection. Hence, CGRP-based interventions could be harnessed for management of COVID-19.Brief summaryPulmonary levels of the neuropeptide CGRP are increased in critical COVID-19 patients, and could clear virus by directly inhibiting SRAS-CoV-2 infection of bronchial epithelia cells.
Mean Shift Clustering as a Loss Function for Accurate and Segmentation-aware Localization of Macromolecules in Cryo-electron Tomography
Authors: Lamm Lorenz , Righetto Ricardo D. , Peng Tingying 
Published: January 2024

ABSTRACTCryo-electron tomography allows us to visualize and analyze the native cellular environment on a molecular level in 3D. To reliably study structures and interactions of proteins, they need to be accurately localized. Recent detection methods train a segmentation network and use post-processing to determine protein locations, often leading to inaccurate and inconsistent locations.We present an end-to-end learning approach for more accurate protein center identification by introducing a differentiable, scoremap-guided Mean Shift clustering implementation. To make training computationally feasible, we sample random cluster points instead of processing the entire image.We show that our Mean Shift loss leads to more accurate cluster center positions compared to the classical Dice loss. When combining these loss functions, we can enhance 3D protein shape preservation and improve clustering with more accurate, localization-focused score maps. In addition to improved protein localization, our method provides more efficient training with sparse ground truth annotations, due to our point sampling strategy.
Deciphering the diversity and sequence of extracellular matrix and cellular spatial patterns in lung adenocarcinoma using topological data analysis
Authors: Yoon Iris H.R. , Jenkins Robert , Colliver Emma , Zhang Hanyun , Novo David , Moore David , Ramsden Zoe , Rullan Antonio , Fu Xiao , Yuan Yinyin , Harrington Heather A. , Swanton Charles , Byrne Helen M. , Sahai Erik 
Published: January 2024

AbstractExtracellular matrix (ECM) organization influences cancer development and progression. It modulates the invasion of cancer cells and can hinder the access of immune cells to cancer cells. Effective quantification of ECM architecture and its relationship to the position of different cell types is, therefore, important when investigating the role of ECM in cancer development. Using topological data analysis (TDA), particularly persistent homology and Dowker persistent homology, we develop a novel analysis pipeline for quantifying ECM architecture, spatial patterns of cell positions, and the spatial relationships between distinct constituents of the tumour microenvironment. We apply the pipeline to 44 surgical specimens of lung adenocarcinoma from the lung TRACERx study stained with picrosirius red and haematoxylin. We show that persistent homology effectively encodes the architectural features of the tumour microenvironment. Inference using pseudo-time analysis and spatial mapping to centimetre scale tissues suggests a gradual and progressive route of change in ECM architecture, with two different end states. Dowker persistent homology enables the analysis of spatial relationship between any pair of constituents of the tumour microenvironment, such as ECM, cancer cells, and leukocytes. We use Dowker persistent homology to quantify the spatial segregation of cancer and immune cells over different length scales. A combined analysis of both topological and non-topological features of the tumour microenvironment indicates that progressive changes in the ECM are linked to increased immune exclusion and reduced oxidative metabolism.
Swinging lever mechanism of myosin directly demonstrated by time-resolved cryoEM
Authors: Klebl David P. , McMillan Sean N. , Risi Cristina , Forgacs Eva , Virok Betty , Atherton Jennifer L. , Stofella Michele , Winkelmann Donald A. , Sobott Frank , Galkin Vitold E. , Knight Peter J. , Muench Stephen P. , Scarff Charlotte A. , White Howard D. 
Published: January 2024

AbstractMyosins are essential for producing force and movement in cells through their interactions with F-actin. Generation of movement is proposed to occur through structural changes within the myosin motor domain, fuelled by ATP hydrolysis, that are amplified by a lever swing1, transitioning myosin from a primed (pre-powerstroke) state to a post-powerstroke state. However, the initial, primed actomyosin state, proposed to form prior to lever swing, has never been observed. Nor has the mechanism by which actin catalyses myosin ATPase activity been resolved. To address this, we performed time-resolved cryoEM of a myosin-5 mutant having slow hydrolysis product release. Primed actomyosin was captured 10 ms after mixing primed myosin with F-actin, whereas post-powerstroke actomyosin predominated at 120 ms, with no abundant intermediate structures. The structures were solved to 4.4Å and 4.2Å global resolution respectively. The primed motor binds to actin through its lower 50 kDa subdomain, with the actin-binding cleft open and Pi release prohibited. N-terminal actin interactions with myosin promote rotation of the upper 50 kDa subdomain, which closes the actin-binding cleft, and enables Pi release. Formation of upper 50 kDa subdomain interactions with actin creates the strong-binding interface required for effective force production. The myosin-5 lever swings through an angle of 93°, predominantly along the actin axis, with little twisting, to produce the post-powerstroke state. The magnitude of the lever swing matches the typical step length of myosin-5 walking along actin. These time-resolved structures directly demonstrate the swinging lever mechanism, ending decades of conjecture on how myosin produces force and movement.
Lettuce seedlings rapidly assemble their microbiome from the environment through deterministic processes
Authors: Mohamed Nesma Zakaria , Schena Leonardo , Malacrinò Antonino 
Published: January 2024

AbstractPlant-associated microorganisms have significant impacts on plant biology, ecology, and evolution. Although several studies have examined the factors driving variations in plant microbiomes, the mechanisms underlying the assembly of the plant microbiome are still poorly understood. In this study, we used gnotobiotic plants to test (i) whether seedlings create a selective environment and drive the assembly of root and leaf microbiomes through deterministic or stochastic processes, and (ii) whether seedlings structure the microbiome that is transferred through seeds using deterministic processes and whether this pattern changes when seedlings are exposed to the environmental microbiome. Our results show that the microbiome of gnotobiotic plants (i.e., inherited through seeds) is not under the selective influence of the host plant but changes quickly when plants are exposed to soil microbiomes. Within one week, plants were able to select microorganisms from the inocula, assemble the root microbiome, and assemble the shoot microbiome. This study supports the hypothesis that plants at early developmental stages might exert strong selective activity on their microbiomes and contribute to clarifying the mechanisms of plant microbiome assembly.
Stable Individual Differences from Dynamic Patterns of Function: Brain Network Flexibility Predicts Openness/Intellect and Intelligence
Authors: Sassenberg Tyler A. , Safron Adam , DeYoung Colin G. 
Published: January 2024

AbstractGrowing understanding of the nature of brain function has led to increased interest in interpreting the properties of large-scale brain networks. Methodological advances in network neuroscience provide means to decompose these networks into smaller functional communities and measure how they reconfigure over time as an index of their dynamic and flexible properties. Recent evidence has identified associations between flexibility and a variety of traits pertaining to complex cognition including creativity and working memory. The present study used measures of dynamic resting-state functional connectivity in data from the Human Connectome Project (N= 994) to test associations with Openness/Intellect and general intelligence, two traits that involve flexible cognition. Using a machine-learning cross-validation approach, we identified reliable associations of intelligence with cohesive flexibility of parcels in large communities across the cortex, and of Openness/Intellect with overall flexibility among parcels in smaller communities. These findings are reasonably consistent with previous theories of the neural correlates of intelligence and Openness/Intellect, and help to expand on previous associations of behavior and dynamic functional connectivity within the context of broader personality dimensions.
Contaminant Spot Check and Removal Assay (ContamSPOT) for Mass Spectrometry Analysis
Authors: Smeriglio Noah , Li Haorong , binti Mazli Wan Nur Atiqah , Bendel Katharine , Hao Ling 
Published: January 2024

ABSTRACTMass spectrometry (MS) analysis is often challenged by contaminations from detergents, salts, and polymers that compromise the data quality and can damage the chromatography and mass spectrometry instruments. However, researchers may not discover contamination issues until after data acquisition. There is no existing contaminant assay that is sensitive enough to detect trace amounts of contaminants from a few microliters of samples prior to MS analysis. To address this crucial need in the field, we developed a sensitive, rapid, and low-cost contaminant spot check and removal assay (ContamSPOT) to detect and quantify trace amounts of contaminants, such as detergents, salts, and other chemicals commonly used in MS sample preparation workflow. Only one microliter of sample was used prior to MS injection to quantify contaminants by ContamSPOT colorimetric or fluorometric assay on a thin layer chromatography (TLC) plate. We also optimized contaminant removal methods to salvage samples with minimal loss when ContamSPOT showed a positive result. ContamSPOT was then successfully applied to evaluate commonly used bottom- up proteomic methods, regarding the effectiveness of removing detergents, peptide recovery, and reproducibility. We expect ContamSPOT to be widely adopted by MS laboratories as a last-step quality checkpoint prior to MS injection. ContamSPOT can also provide a unique readout of sample cleanness for developing and evaluating MS-based sample preparation methods. We provided a practical decision tree and a step-by-step protocol with a troubleshooting guide to facilitate the use of ContamSPOT by other researchers.Table of Contents (TOC) graphic(All images used in the TOC graphic are original, in compliance with copyright guidelines.)
Invariant crossmodal equivalence evokes visual imagery from sounds in rhesus monkeys
Authors: Cabrera-Ruiz Elizabeth , Alva Marlen , Mata Miguel , Treviño Mario , Vergara José , Figueroa Tonatiuh , Perez-Orive Javier , Lemus Luis 
Published: January 2024

AbstractAfter hearing the words Little Red Riding Hood, many humans instantly visualize a girl wearing a red hood in the woods. However, whether nonhuman primates also evoke such visual imagery from sounds remains an open question. We explored this from direct behavioral measurements from two rhesus macaques trained in a delayed crossmodal equivalence task. In each trial, they listened to a sound, such as a monkey vocalization or a word, and three seconds later, selected a visual equivalent out of a pool of 2 to 4 pictures appearing on a touchscreen. We show that monkeys can be trained to discriminate perceptual objects of numerous properties and furthermore that they perceive as invariant different versions of the learned sounds. We propose two potential mechanisms for the brain to solve this task: acoustic memory or visual imagery. After analyzing the monkeys’ choice accuracies and reaction times in the task, we find that they experience visual imagery when listening to sounds. Therefore, the ability of rhesus monkeys to perceive crossmodal equivalences between learned categories poses rhesus monkeys as an ideal model organism for studying high-order cognitive processes like semantics and conceptual thinking at the single-neuron level.