bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Osseointegration of Titanium Alloy Bone Implants Coated With Carob-calcium Hydroxide Nanoparticles: A Comparative Study
Authors: AlNatheer Yaser , Alghamdi Osama G. , Devanesan Sandhanasamy , AlSalhi Mohamad S. , Alshawakir Yasser A. , Khounganian Rita M. , Alrahlah Ali , Seif Sameh A. 
Published: December 2024

Objectives:
This study aimed to evaluate the osseointegration properties of titanium bone implants coated with carob-mediated calcium hydroxide nanoparticles biomechanically, radiographically, and histologically on rabbit tibias.

Material and Methods:
Forty coated and forty uncoated titanium alloy bone implants were inserted into 20 New Zealand rabbits; each tibia received 2 implants. The rabbits were sacrificed after 4 or 8 weeks, and samples were retrieved for biomechanical evaluation through removal torque test to assess the bond between implant and bone, radiographic evaluation through microcomputed tomography analysis to compare the bone-to-implant contact percentage and bone volume of the peri-implant area, scanning electron microscopic and histologic evaluation through hematoxylin and eosin stain. Statistical analyses between pairs of means were conducted using the independent t test. Multiple comparisons between the study groups across time intervals were performed using a 2-way analysis of variance. P-values ≤0.05 were considered statistically significant.

Results:
Higher removal torque values (P<0.01) were needed to remove the coated implants when biomechanically tested. In addition, the microcomputed tomography evaluation revealed a higher bone-to-implant contact percentage (P<0.05) in favor of coated implants. In addition, the 4-week healing interval of the coated implants showed no significant difference when compared with the 8-week healing interval of the uncoated implants biomechanically and radiographically, suggesting early osseointegration.

Conclusions:
The findings of this study imply that coating titanium implants with carob-mediated calcium hydroxide nanoparticles improved and fastened osseointegration and bone ingrowth, resulting in early osteogenesis and shortening the treatment time.
Rethinking cancer drug synergy prediction: a call for standardization in machine learning applications
Authors: Wong Alexandra M. , Crawford Lorin 
Published: December 2024

AbstractDrug resistance poses a significant challenge to cancer treatment, often caused by intratumor heterogeneity. Combination therapies have been shown to be an effective strategy to prevent resistant cancer cells from escaping single-drug treatments. However, discovering new drug combinations through traditional molecular assays can be costly and time-consuming.In silicoapproaches can overcome this limitation by exploring many candidate combinations at scale. This study systematically evaluates the utility of various machine learning algorithms, input features, and drug synergy prediction tasks. Our findings indicate a pressing need for establishing a standardized framework to measure and develop algorithms capable of predicting synergy.
The Ulcerative Colitis-Associated Gene NXPE1 Catalyzes Glycan Modifications on Colonic Mucin
Authors: Humeidi Ranad , Rapley Noriko , Gu Xiebin , An Joon Soo , Ananthakrishnan Ashwin N. , Creasey Elizabeth A. , Daly Mark J. , Schreiber Stuart L. , Graham Daniel B. , Seyedsayamdost Mohammad R. , Xavier Ramnik J. 
Published: December 2024

ABSTRACTColonic mucus forms a first line of defense against bacterial invasion while providing nutrition to support coinhabiting microbes in the gut. Mucus is composed of polymeric networks of mucin proteins, which are heavily modified post-translationally. The full compendium of enzymes responsible for these modifications and their roles in health and disease remain incompletely understood. Herein we determine the biochemical function of NXPE1, a gene implicated in ulcerative colitis (UC), and demonstrate that it encodes an acetyltransferase that modifies mucin glycans. Specifically, NXPE1 utilizes acetyl-CoA to regioselectively modify the mucus sialic acid, 5-N-acetylneuraminic acid (Neu5Ac), at the 9-OH group to generate 9-O-acetylated Neu5Ac (Neu5,9Ac2). We further demonstrate that colonic organoids derived from donors harboring the missense variant NXPE1 G353R, which is protective against UC, exhibit severely impaired acetylation of Neu5Ac on mucins. Together, our findings support a model in which NXPE1 masks the alcohols of mucus sialoglycans via acetylation, which is important for modulating mucus barrier properties that limit interactions with commensal microbes.
A somatic multiple myeloma mutation unravels a mechanism of oligomerization-mediated product inhibition in GGPPS
Authors: Yehia Ruba , Portašiková Jasmína Mária , Mor Yosef Rut , Da’adoosh Benny , Kádek Alan , Man Petr , Giladi Moshe , Haitin Yoni 
Published: December 2024

AbstractProtein prenylation regulates the cellular localization of small GTPases and is pivotal for multiple myeloma (MM) pathology. Geranylgeranyl diphosphate synthase (GGPPS), synthesizing a prenylation moiety, exhibits dimeric or hexameric stoichiometry in different species. However, the functional significance of this divergence remains elusive. Focusing on the hexameric human paralog, formed by trimer-of-dimers, we uncover that GGPPSR235C, expressed in an MM cell line, localizes to the active site lid region at the inter-dimeric interface. Using crystallography and mass spectrometry (MS), we show that GGPPSR235Cretains its hexameric stoichiometry but exhibits destabilized inter-dimer interactions. Unexpectedly, this results in increased apparent substrate affinity and product release kinetics. These functional effects are further enhanced in a dimeric mutant, GGPPSY246D. Combining MS and fluorescence spectroscopy, we exposed that reduced lid dynamics and increased active site occupancy by the product are intertwined. Together, our results expose product inhibition as a regulatory mechanism in GGPPS, driven by hexamerization.
ChromBPNet: bias factorized, base-resolution deep learning models of chromatin accessibility reveal cis-regulatory sequence syntax, transcription factor footprints and regulatory variants
Authors: Pampari Anusri , Shcherbina Anna , Kvon Evgeny Z. , Kosicki Michael , Nair Surag , Kundu Soumya , Kathiria Arwa S. , Risca Viviana I. , Kuningas Kristiina , Alasoo Kaur , Greenleaf William James , Pennacchio Len A. , Kundaje Anshul 
Published: December 2024

ABSTRACTDespite extensive mapping of cis-regulatory elements (cREs) across cellular contexts with chromatin accessibility assays, the sequence syntax and genetic variants that regulate transcription factor (TF) binding and chromatin accessibility at context-specific cREs remain elusive. We introduce ChromBPNet, a deep learning DNA sequence model of base-resolution accessibility profiles that detects, learns and deconvolves assay-specific enzyme biases from regulatory sequence determinants of accessibility, enabling robust discovery of compact TF motif lexicons, cooperative motif syntax and precision footprints across assays and sequencing depths. Extensive benchmarks show that ChromBPNet, despite its lightweight design, is competitive with much larger contemporary models at predicting variant effects on chromatin accessibility, pioneer TF binding and reporter activity across assays, cell contexts and ancestry, while providing interpretation of disrupted regulatory syntax. ChromBPNet also helps prioritize and interpret regulatory variants that influence complex traits and rare diseases, thereby providing a powerful lens to decode regulatory DNA and genetic variation.
Accuratede novodesign of a voltage-gated anion channel
Authors: Zhou Chen , Li Huican , Wang Jiaxing , Chu Zhilin , Sun Shijin , Sun Ke , Zhu Aiqin , Wang Jiawei , Jin Xueqin , Yang Fan , Gamal El-Din Tamer M. , Wu Kun , Lu Peilong 
Published: December 2024

SUMMARYIon channels gated by environmental cues play key roles in fundamental biological processes. Designing ion channels with tailored gating mechanisms remains a significant challenge due to the complexities involved in designing conformational changes in proteins. Here we report the accuratede novodesign of a voltage-gated anion channel, namely VGAC. VGAC adopts a 15-helix pentameric structure featuring a constriction composed of five arginine residues within the transmembrane span. In patch-clamp experiments, VGAC showed strictly voltage-dependent currents and demonstrated selectivity for chloride anions over iodide anions. Our data suggests that the arginine constriction undergoes voltage-induced conformational changes, serving as both the voltage sensor and selectivity filter. A 2.9-Å-resolution cryo-electron microscopy structure of VGAC closely aligns with the design model. The ability to design ion channels with custom-designed conformational changes provides new insights into our understanding of the fundamental principles of membrane biophysics and unveils a wide range of potential applications.
Differentiating BOLD and non-BOLD signals in fMRI time series using cross-cortical depth delay patterns
Authors: Chen Jingyuan E. , Blazejewska Anna I. , Fan Jiawen , Fultz Nina E. , Rosen Bruce R. , Lewis Laura D. , Polimeni Jonathan R. 
Published: December 2024

AbstractOver the past two decades, rapid advancements in magnetic resonance technology have significantly enhanced the imaging resolution of functional Magnetic Resonance Imaging (fMRI), far surpassing its initial capabilities. Beyond mapping brain functional architecture at unprecedented scales, high-spatial-resolution acquisitions have also inspired and enabled several novel analytical strategies that can potentially improve the sensitivity and neuronal specificity of fMRI. With small voxels, one can sample from different levels of the vascular hierarchy within the cerebral cortex and resolve the temporal progression of hemodynamic changes from parenchymal to pial vessels. We propose that this characteristic pattern of temporal progression across cortical depths can aid in distinguishing neurogenic blood-oxygenation-level-dependent (BOLD) signals from typical nuisance factors arising from non-BOLD origins, such as head motion and pulsatility. In this study, we examine the feasibility of applying cross-cortical depth temporal delay patterns to automatically categorize BOLD and non-BOLD signal components in modern-resolution BOLD-fMRI data. We construct an independent component analysis (ICA)-based framework for fMRI de-noising, analogous to previously proposed multi-echo (ME) ICA, except that here we explore the across-depth instead of across-echo dependence to distinguish BOLD and non-BOLD components. The efficacy of this framework is demonstrated using visual task data at three graded spatiotemporal resolutions (voxel sizes = 1.1, 1.5, and 2.0 mm isotropic at temporal intervals = 1700, 1120, and 928 ms). The proposed framework leverages prior knowledge of the spatiotemporal properties of BOLD-fMRI and serves as an alternative to ME-ICA for cleaning moderate- and high-spatial-resolution fMRI data when multi-echo acquisitions are not available.
Histone H3.3 ensures cell proliferation and genomic stability during myeloid cell development
Authors: Chauhan Sakshi , Dey Anup , Macfarlan Todd , Ozato Keiko 
Published: December 2024

AbstractVariant histone H3.3 is thought to be critical for survival of many cells, since it is deposited in expressed genes, a feature different from core histones. For example, H3.3 deletion leads to embryonic lethality in mice. However, requirement of H3.3 in later stage of development has remained unclear. The aim of this work was to elucidate the role of H3.3 for development of myeloid lineage, important for innate immunity. We conditionally knocked out (cKO) the H3.3 genes in myeloid progenitor cells differentiating into bone marrow derived macrophages (BMDMs). Progenitor cells lacking H3.3 were defective in replication, suffered from extensive DNA damage, and underwent apoptosis. SurvivingH3.3cKO cells expressed many interferon stimulated genes (ISGs) throughout differentiation. Further,H3.3cKO BMDMs possessed chromatin accessible sites, and histone posttranslational modifications consistent with the gene expression profiles, Accordingly,H3.3cKO BMDMs retained general nucleosomal structure genome wide. In summary, H3.3 is required for proliferation of myeloid progenitor cells, but is in large part dispensable for differentiation of BMDMs.
PrecisionTrack: Reliable Tracking of Large Groups of Animals Interacting in Complex Environments Over Extended Periods
Authors: Coulombe Vincent , Roussel David-Alexandre , Monfared Mohamad Sadegh , Leboulleux Quentin , Peralta Modesto R. , Aghel Khadijeh , Gosselin Benoit , Labonté Benoit 
Published: December 2024

AbstractMice living in complex social groups within ethological environments exhibit a wide range of adaptive behaviors, including individual and group dynamics, often undetected in standard behavioral studies. To better understand the coping and adaptive strategies employed by each member of a social colony, it is necessary to develop tools that enable accurate, long-term monitoring of large groups of animals in a fully automated and unbiased manner. In this work, we introduce PrecisionTrack, a practical solution to the multi-animal pose tracking problem. This solution enables an accurate and reliable tracking of large groups of animal socially interacting within complex environments, even over prolonged periods. Our algorithm builds on a Transformer-CNN hybrid neural network for cross-species classification, detection, and pose estimation, leveraging pose-based matching AI-driven ArUco identification for fast and accurate re-identification. PrecisionTrack demonstrates superior performance in tracking accuracy and latency compared to current gold standards, while sustaining these capabilities over extended periods when tracking large groups of animals in complex environments. Furthermore, we trained PrecisionTrack to identify and monitor over 30 animal species. Overall, PrecisionTrack represents a reliable, accessible step toward adopting more ethological methodologies in behavioral research.
A General Strategy to Endow Dyes with Genic Fluorescence for Wash-Free Imaging of Proteins in Living Cells
Authors: Zhou Xuelian , Miao Lu , Xu Ning , Chen Yonghui , Shi Jinjing , Zhou Jinhua , Wang Guangying , Qiao Qinglong , Xu Zhaochao 
Published: December 2024

AbstractFluorescent dyes are the main fluorophore for protein labeling and fluorescent imaging in living cells. However, due to the inevitable nonspecific binding of the dye to non-targets within the cell, background signals are generated, which severely affect the imaging quality. Here, we endow the dye with genic fluorescence by introducing a fluorescent proteins FRET pair, such that only the dye bound to the target protein emits fluorescence (λex= FPs, λem= Dyes), while nonspecifically bound dye remains non-fluorescent. This significantly improves the signal-to-noise ratio (SNR) in wash-free imaging. This strategy is achieved by fusing the Halo-tag to fluorescent proteins (sfGFP, mCherry) that can generate FRET with Halo dyesO-RhoandSi-Rho. The FPs serve as the donor, and the FRET mechanism imparts genic fluorescence property toO-RhoandSi-Rho. Since the excitation wavelength of the donor (λex= FPs) cannot excite the unspecifically dye fluorescence, background fluorescence interference is reduced. We further improved the SNR by increasing the FRET efficiency between the FPs and dyes. The system was used for four-color super-resolution imaging of target proteins and dynamic SIM tracking of mitochondria. In addition, the genic FRET fluorophore constructed with the ultra-stable mStayGold showed significant photobleaching resistance and can be used for long-term dynamic super-resolution imaging. Theoretically, by selecting appropriate FRET pairs, this method can improve the SNR of any fluorophore, providing a new labeling strategy for live-cell wash-free imaging.
TLS_Finder: An algorithm for Identifying Tertiary Lymphoid Structures Using Immune Cell Spatial Coordinates
Authors: Koksoy Ayse A , Salvatierra Maria Esther ,   MOSAIC Team, Solis Soto Luisa Maren , Haymaker Cara 
Published: December 2024

AbstractTertiary lymphoid structures (TLS) are lymphoid formations that develop in non-lymphoid tissues during chronic inflammation, autoimmune diseases, and cancer. Accurate identification and quantification of TLS in tissue can provide crucial insights into the immune response of several disease processes including antitumor immune response. TLS are defined as aggregates of T cells, B cells and dendritic cells. In histological tissue sections stained with Hematoxylin and Eosin they are identified as aggregates of 50 or more lymphoid cells, however immunohistochemical analysis are required to confirm presence of distinct immune cell patterns. Assessment of lymphoid aggregates can be done in H&E slides or in slides stained with single or multiplex immunohistochemistry or other tissue based high-plex approaches with key biomarkers such as CD3 (T cells) and CD20 (B cells), however manual assessment of them is time consuming thus limiting its full evaluation. To our knowledge, published algorithms that identify TLS within a tissue are based on histological assessment of H&E slides or through use of ML algorithms trained on images that show the TLS presence in tissues; and quantification and spatial analysis of TLS still remains a challenge. This study aims to develop a robust algorithm to recognize TLS using the spatial coordinates of immune cells in any given tissue. The algorithm uses X and Y coordinates of T and B cells in tissues identified by a pathologist-supervised digital image analysis of multiplex chromogenic immunohistochemistry of tissues stained with CD3 and CD20. The algorithm is flexible to be used for detailed analysis of TLS stages; including other cell types within the definition of TLS; such as dendritic cells (DC) and high endothelial venules (HEV); to assess different stages of TLS formation.
Fibroblast mechanoperception instructs pulmonary developmental and pattern specification gene expression programs
Authors: Miller Andrew E. , Hu Ping , Bhogaraju Rishi , Hannan Riley T. , Abebayehu Daniel , Civelek Mete , Barker Thomas H. 
Published: December 2024

AbstractDysregulation of the cellular mechanisms that coordinate the interpretation and transduction of microenvironmental biophysical signals are a unifying feature of tissue remodeling pathologies such as fibrosis and cancer. While genomic regulation downstream of normal mechanotransduction (i.e. cases where cells sense soft and stiff appropriately) is well studied, significantly less is known about the consequences of abnormal mechanoperception and subsequent misinterpretation of the mechanical environment. Leveraging Thy-1 (a.k.a. CD90) loss as a model of impaired mechanoperception, we employed ATAC- and RNA-sequencing in parallel to characterize the changes in lung fibroblast genomic activity in response to a combination of substrate stiffness and culture time. Notably, we find perturbed mechanoperception elicits a near-complete shutdown ofHOXA5, a transcription factor responsible for pattern specification and development in the nascent lung.In vitroinvestigation of HOXA5 expression reveals a potential mechanism connecting increased αvintegrin signaling, cytoskeletal tension, and SRC kinase activity to HOXA5 silencing. These results establish novel links between integrin signaling and the expression dynamics of genes necessary for tissue formation and regeneration in the injured and/or developing lung, particularlyHOXA5.
Enolase-1 is essential for neutrophil recruitment during acute inflammation
Authors: Lu Hseuh-Yen , Huang Ping-Hsiang , Lee Ting-Wei , Chang Hui-Wen , Chen Nai-Yu , Zhuang Yu-Jing , Yuan Ta-Tung , Chen Chun-Jen 
Published: December 2024

SummaryEnolase-1 (ENO1) is a ‘moonlighting protein’ with multiple functions. When expressed on the cell surface, ENO1 binds plasminogen (PLG) and facilitates cell migration via plasmin (PLM)-mediated lysis of extracellular matrix proteins. Here, we observed that ENO1 expression on the neutrophil surface was markedly increased upon inflammatory stimulation both in vitro and in vivo. An anti-ENO1 monoclonal antibody (mAb), 7E5, which blocks ENO1-PLG interaction, effectively suppressed the fibrinolytic activity of inflammatory neutrophils. In mouse models of acute inflammation, including lipopolysaccharide (LPS)-induced lung injury and necrotic cell challenge, the 7E5 mAb significantly reduced neutrophil recruitment and the formation of neutrophil extracellular traps (NETs). Furthermore, 7E5 neutralized the immunostimulatory activity of soluble ENO1 protein, which was substantially elevated in the circulation of animals during acute inflammation. These findings suggest that ENO1 plays a crucial role in triggering inflammation and mediating neutrophil infiltration. Targeting ENO1 using antibodies could represent a promising strategy to mitigate tissue damage caused by excessive neutrophilic inflammation.
An Independent Coding Scheme for Distance versus Position in the Hippocampus
Authors: Nordlund Mathilde , Levernier Nicolas , Trippa Massimiliano , Bourboulou Romain , Marti Geoffrey , Monasson Rémi , Rouault Hervé , Epsztein Jérôme , Koenig-Gambini Julie 
Published: December 2024

ABSTRACTAnimals navigate using cognitive maps of their environment, integrating external landmarks and distances between them. Hippocampal place cells are the neuronal substrate of these cognitive maps. However, while hippocampal allocentric position coding in reference to external landmarks is well characterized, the determinants of idiothetic hippocampal distance coding remain poorly understood. Using virtual reality, electrophysiological recordings in mice, and local cue manipulations we could dissociate distance from position coding. In the cue-poor condition, we found pervasive distance coding with high distance indices in all bidirectional place cells including both superficial and deep CA1 pyramidal cells. In this condition, the mapping of distance onto a low-dimensional manifold and rigid distance relationships between place fields suggested strong attractor dynamics similar to those observed for grid cells. Inactivation of the medial septum (MS), which disrupts grid cells, significantly reduced both distance coding and rigid distance dynamics, suggesting an alteration (but not complete abolition) of the underlying attractor. In contrast, allocentric position coding could be observed in cue-rich environments, predominantly engaged deep CA1 pyramidal cells, and persisted during MS inactivation. These results are consistent with a selective contribution of grid cells and associated rigid attractor dynamics to hippocampal idiothetic distance coding but not allocentric position coding.