bluuebunny/crossref_metadata_2025_split huggingface dataset:
HEXIM1 is correlated with Alzheimer’s disease pathology and regulates immediate early gene dynamics in neurons
Authors: Htet Myo , Estay-Olmos Camila , Hu Lan , Wu Yiyang , Powers Brian E. , Campbell Clorissa D. , Ahmed M. Rafiuddin , Hohman Timothy J. , Schneider Julie A. , Bennett David A. , Menon Vilas , De Jager Philip L. , Kaas Garrett A. , Colbran Roger J. , Greer Celeste B. 
Published: September 2024

ABSTRACTImpaired memory formation and recall is a distinguishing feature of Alzheimer’s disease, and memory requires de novo gene transcription in neurons. Rapid and robust transcription of many genes is facilitated by the formation of a poised basal state, in which RNA polymerase II (RNAP2) has initiated transcription, but is paused just downstream of the gene promoter. Neuronal depolarization releases the paused RNAP2 to complete the synthesis of messenger RNA (mRNA) transcripts. Paused RNAP2 release is controlled by positive transcription elongation factor b (P-TEFb), which is sequestered into a larger inactive complex containing Hexamethylene bisacetamide inducible protein 1 (HEXIM1) under basal conditions. In this work, we find that neuronal expression ofHEXIM1mRNA is highly correlated with human Alzheimer’s disease pathologies. Furthermore, P-TEFb regulation by HEXIM1 has a significant impact on the rapid induction of neuronal gene transcription, particularly in response to repeated depolarization. These data indicate that HEXIM1/P-TEFb has an important role in inducible gene transcription in neurons, and for setting and resetting the poised state that allows for the robust activation of genes necessary for synaptic plasticity.GRAPHICAL ABSTRACT
Investigating Cell Viability under Shear Stress in Complex Microstreaming Flows Generated by Ultrasound-Driven Actuated Microbubbles
Authors: Bakhtiari Amirabas , Schumm Benedikt , Schönfelder Martin , Kähler Christian J. 
Published: September 2024

AbstractThe analysis of rare or specialized cells is often a time-consuming process due to their low concentrations. In this study, we applied, for the first time, a method previously used on polymer particles to manipulate human cells. This technique enables the automatic direction and collection of target cells passing through a microchannel, significantly increasing their concentration for further analysis. The movement of the cells is controlled by an acoustically induced vortex flow generated by a microbubble. By modulating the activation of this microstreaming, the cells are shifted either to the upper or lower regions of the channel and directed into a side channel for collection downstream. The localized stress distribution, along with long-term testing that showed no cell damage, confirmed the biocompatibility of this method, making it a promising tool for lab-on-a-chip systems and biomedical diagnostics.Impact StatementThis study presents an innovative use of ultrasound-driven microbubble streaming for the precise manipulation and sorting of human cells in microfluidic environments, all while maintaining cell viability. The research shows that the localized shear stress near the microbubble is significantly below the damage threshold for cells, confirming the biocompatibility of this method. The potential impact of this work is considerable for lab-on-a-chip systems and biomedical diagnostics. It offers a reliable, non-invasive solution for the manipulation, sorting, and removal of compromised cells, thus streamlining research and diagnostic procedures. By ensuring the safe and efficient handling of rare or specialized cells, this technique can accelerate various biomedical applications. Additionally, the study’s evidence of sustained cell viability under microstreaming conditions suggests broader applicability in biomedical devices, particularly in automated dead cell removal and selective cell positioning.
Charting cortical-layer specific area boundaries using Gibbs’ ringing attenuated T1w/T2w-FLAIR myelin MRI
Authors: Autio Joonas A. , Uematsu Akiko , Ikeda Takuro , Ose Takayuki , Hou Yujie , Magrou Loïc , Kimura Ikko , Ohno Masahiro , Murata Katsutoshi , Coalson Tim , Kennedy Henry , Glasser Matthew F. , Van Essen David C. , Hayashi Takuya 
Published: September 2024

AbstractCortical areas have traditionally been defined by their distinctive layer cyto- and/or myelo- architecture using postmortem histology. Recent studies have delineated many areas by measuring overall cortical myelin content and its spatial gradients using the T1w/T2w ratio MRI in living primates, including humans. While T1w/T2w studies of areal transitions might benefit from using the layer profile of this myelin-related contrast, a significant confound is Gibbs’ ringing artefact, which produces signal fluctuations resembling cortical layers. Here, we address these issues with a novel approach using cortical layer thickness-adjusted T1w/T2w-FLAIR imaging, which effectively cancels out Gibbs’ ringing artefacts while enhancing intra-cortical myelin contrast. Whole-brain MRI measures were mapped onto twelve equivolumetric layers, and layer-specific sharp myeloarchitectonic transitions were identified using spatial gradients resulting in a putative 182 area/subarea partition of the macaque cerebral cortex. The myelin maps exhibit notably high homology with those in humans, suggesting cortical myelin shares a similar developmental program across species. Comparison with histological Gallyas myelin stains explains over 80% of the variance in the laminar T1w/T2w-FLAIR profiles, substantiating the validity of the method. Altogether, our approach provides a novel, noninvasive means for precision mapping layer myeloarchitecture in the primate cerebral cortex, advancing the pioneering work of classical neuroanatomists.
Pexidartinib plus FLT3-directed CAR-Macrophage for the treatment of FLT3-ITD-mutated acute myeloid leukemia in preclinical model
Authors: Chen Fan , Lv Min-Hong , Li Chun-Wei , Zhang Yi-Qiong , Wei Ze-Xiao , Yuan Zhi , Cao Jian-Yong , Yang Xinming , Xu Jing-Bo , Wang Li , He Bai-Liang 
Published: September 2024

AbstractAcute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations occur in about 25%-30% of AML cases and are associated with adverse prognosis. Recent advances indicate that M2-like leukemia-associated macrophages (M2-LAM) are highly infiltrated in the bone marrow of FLT3-ITD+ AML patients; however, the underlying mechanisms and therapeutic implications are still elusive. Herein, we reveal that conditioned medium from FLT3-ITD+ MOLM-13 AML cells polarized M2-LAM and impaired their phagocytic activities. Unexpectedly, co-culture of M2-LAM protected MOLM-13 cells from the treatment of FLT3 inhibitor quizartinib by activating their FLT3 signaling pathway. Pharmaceutically, FLT3/CSF1R dual inhibitor pexidartinb effectively suppressed M2-LAM, reduced leukemic burden, and prolonged the survival of MOLM-13-xenografted mice. To enhance the phagocytic activities of macrophages, FLT3-directed chimeric antigen receptor-engineered macrophages (FLT3L-CAR-Macrophage) were generated using FLT3 ligand (FLT3L) as the recognizing domain of CAR. Transfection of THP-1 monocytic cells-or umbilical cord blood mononuclear cells-derived macrophages with FLT3L-CAR-encoding mRNA enhanced their phagocytic activities to MOLM-13 cells in vitro. Consistently, FLT3L-CAR-Macrophage differentiated from FLT3L-CAR-expressing THP-1 cells effectively phagocytosed MOLM-13 cells in vitro, reduced leukemic burden and prolonged the survival of MOLM-13-xenografted mice. Importantly, treatment of pexidartinib resulted in upregulation and surface localization of FLT3-ITD protein in MOLM-13 cells, sensitized MOLM-13 cells to the treatment of FLT3L-CAR-Macrophage in vitro, and synergized with FLT3L-CAR-Macrophage to further reduce leukemic burden in MOLM-13-xenografted mice. Together, our data indicate that pexidartinib plus FLT3L-CAR-Macrophage could be a promising therapeutic strategy for the treatment of FLT3-ITD+ AML in preclinical model which warrants further investigation.Graphical AbstractPexidartinib plus FLT3L-CAR-Mφ for the treatment of FLT3-ITD+ AML in preclinical model. Pexidartinib suppressed AML growth, reduced M2-LAM, increased FLT3 surface expression and synergized with FLT3L-CAR-Mφ to target FLT3-ITD+ AML in vitro and in vivo.
Insertion of fluorescent proteins near the plug domain of MotB generates functional stator complex
Authors: Gurung Jyoti P , Ridone Pietro , Biquet-Bisquert Anaïs , Bryant Gary , Pedaci Francesco , Nord Ashley L. , Baker Matthew AB 
Published: September 2024

AbstractMany bacteria swim by the rotation of the bacterial flagellar motor (BFM). The BFM is powered by proton translocation across the inner membrane through the hetero-heptameric MotA5MotB2protein complex. Two periplasmic domains of MotB are critical in activating BFM rotation: (1) the peptidoglycan binding (PGB) domain that anchors MotB in the peptidoglycan layer and (2) the plug domain that modulates the proton flow. Existing cytoplasmic fluorescent probes have been shown to negatively affect motor rotation and switching. Here we inserted a fluorescent probe in the periplasm near the plug of MotB in an attempt to circumvent issues with cytoplasmic probes and for possible use in observing the mechanism of plug-based regulation of proton flow. We inserted green fluorescent protein (GFP) and iLOV, a fluorescent version of the light-oxygen-voltage (LOV) domain, in four periplasmic locations in MotB. Insertions near the plug retained motility but showed limited fluorescence for both fluorophores. Additional short, flexible glycine-serine (GS) linkers improved motility but did not improve brightness. Further optimization is necessary to improve the fluorescence of these periplasmic probes.
A framework for gene representation on spatial transcriptomics
Authors: Cao Shenghao , Yuan Ye 
Published: September 2024

AbstractRecent foundation models for single-cell transcriptomics data generate informative, context-aware gene representations. The spatially resolved transcriptomics data offer extra positional insights, yet corresponding gene representation methods that integrate both intracellular and spatial context are still lacking. Here, we introduce a gene representation framework tailored for spatial transcriptomics data. It incorporates ligand genes within the spatial niche into the transformer encoder of single-cell transcriptomics. We further propose a biased cross-attention method to enable the framework to do learning with single-cell resolution on low-resolution, whole-transcriptome Visium data. We implemented our framework on a hybrid Visium dataset derived from two human tissue types with distinct developmental and disease states, and tested on various downstream applications. Compared with the latest foundation model for single-cell transcriptomics, our spatially informed gene representations could identify cell groups and gene functions more accurately, and could predict the perturbation effects of cell-cell ligand-receptor interactions on downstream targets.
Plasmid conjugation drives within-patient plasmid diversity
Authors: Grayson Fan , Loman Leo , Nonnenmacher Toby , Pople Diane , Pollard Jack , Williams David , Patel Bharat , Hounsome Luke , Hopkins Katie L , Robotham Julie , Ledda Alice 
Published: September 2024

AbstractPlasmids are well known vehicles of antimicrobial resistance (AMR) genes dissemination. Through conjugation, plasmid–encoded AMR genes are spread among neighbouring bacteria, irrespective of their strain or even their species. This process is very concerning from a public health perspective, as plasmid-borne AMR gene outbreaks are often not confined to single species or strains and are therefore more difficult to be fully uncovered. At the moment, the impact of plasmid conjugation on within-patient plasmid diversity is not well understood. In this work we will tackle the role of conjugation on within-patient plasmid diversity using a dataset of carbapenemase-producingEnterobacterales(CPEs). The dataset of 256 sequences from 115 patients was sampled across England over 30 months. Each patient has more than one sequence, with at least one sequence carrying an OXA-48 gene, a well-known plasmid-borne carbapenemase-encoding gene. If more than one sequence carries the OXA-48 gene, they are carried on different bacterial hosts. Using a hybridde novo-on-reference assembly pipeline, we were able to reconstruct the full OXA-48 plasmid from short read sequencing data for 232 of the 256 sequences. Of the 115 patients, 83 (72%) of patients had an identical OXA-48 plasmid in two or more sequences. Only 2 patients carried very different (>200 SNPs) alleles of the OXA-48 plasmid, probably from separate acquisitions. Our study shows that when more than one bacterial host carrying an OXA-48 plasmid is found in a patient, it is most likely that the same plasmid has been shared via conjugation. The event of separate acquisition of different plasmids in different bacterial hosts is highly unlikely in our dataset.Data StatementWe use data provided by Hopkins et al 2022 [16]. The data can be accessed from the National Center for Biotechnology Information (NCBI) and can be found at Bioproject Accession no. PRJNA788733. None of the data used was synthetically generated.Impact StatementConjugative plasmids are well known vessels of horizontal gene transfer, with a prominent role in the spread of antimicrobial resistance genes among different bacterial species or strains. At the epidemiological level, conjugation combined with sequencing a single colony per patient, results in plasmids outbreaks carrying antimicrobial resistance genes being found in different bacterial species and strains in different patients, potentially eluding surveillance protocols based on same bacterium/same resistance scheme. In this study we analyse within-patient plasmid diversity in a dataset with more than one sequence per patient. Only two patients show clear genomic signs of separate plasmids acquisition, while 83 patients share identical plasmids in different bacterial hosts. This points out to a very strong role of plasmid conjugation in shaping within-patient plasmid diversity.
Ancient origin and high diversity of zymocin-like killer toxins in the budding yeast subphylum
Authors: Heneghan Padraic G. , Salzberg Letal I. , Cinnéide Eoin Ó , Dewald Jan A. , Weinberg Christina E. , Wolfe Kenneth H. 
Published: September 2024

AbstractZymocin is a well-characterized killer toxin secreted by some strains of the yeastKluyveromyces lactis. It acts by cleaving a specific tRNA in sensitive recipient cells. Zymocin is encoded by a killer plasmid or virus-like element (VLE), which is a linear DNA molecule located in the cytosol. We hypothesized that a tRNA-cleaving toxin similar to zymocin may have caused the three parallel changes to the nuclear genetic code that occurred during yeast evolution, in which the codon CUG became translated as Ser or Ala instead of Leu. However, zymocin-like toxins are rare – both among species, and among strains within a species – and only four toxins of this type have previously been discovered. Here, we identified 45 new zymocin-like toxin genes in Saccharomycotina, the budding yeast subphylum, using a novel bioinformatics strategy, and verified that many of them are toxic toS. cerevisiaewhen expressed. Some of the new toxin genes are located on cytosolic VLEs, whereas others are on VLE-derived DNA integrated into the nuclear genome. The toxins are extraordinarily diverse in sequence and show evidence of positive selection. Toxin genes were found in five taxonomic orders of budding yeasts, including two of the three orders that reassigned CUG codons, indicating that VLEs have been parasites of yeast species for at least 300 million years and that their existence pre-dates the genetic code changes.
Cannabis Expression Atlas: a comprehensive resource for integrative analysis ofCannabis sativaL. gene expression
Authors: Barbosa-Xavier Kevelin , Pedrosa-Silva Francisnei , Almeida-Silva Fabricio , Venancio Thiago M. 
Published: September 2024

AbstractCannabis sativaL., a plant originating from Central Asia, is a versatile crop with applications spanning textiles, construction, pharmaceuticals, and food products. This study aimed to compile and analyze publicly available Cannabis RNA-Seq data and develop an integrated database tool to help advance Cannabis research in various topics such as fiber production, cannabinoid biosynthesis, sex determination, and plant development. We identified 515 publicly available RNA-Seq samples that, after stringent quality control, resulted in a high-quality dataset of 394 samples. Utilizing the Jamaican Lion genome as reference, we constructed a comprehensive database and developed the Cannabis Expression Atlas (https://cannatlas.venanciogroup.uenf.br/), a web application for visualization of gene expression, annotation, and functional classification. Key findings include the quantification of 27,640 Cannabis genes and their classification into seven expression categories: not-expressed, low-expressed, housekeeping, tissue-specific, group-enriched, mixed, and expressed-in-all tissues. The study revealed substantial variability and coherence in gene expression across different tissues and chemotypes. We found 2,382 tissue-specific genes, including 177 transcription factors.. The Cannabis Expression Atlas constitutes a valuable tool for exploring gene expression patterns and offers insights into Cannabis biology, supporting research in plant breeding, genetic engineering, biochemistry, and functional genomics.
Terrestrial herbivory drives adaptive evolution in an aquatic community via indirect effects
Authors: Schäfer Martin , Malacrinò Antonino , Walcher Christoph , Spaak Piet , Sárazová Marie Serwaty- , Käser Silvana , Bulas Thea , Dambone-Bösch Christine , Dexter Eric , Hottinger Jürgen , Böttner Laura , Vorburger Christoph , Ebert Dieter , Xu Shuqing 
Published: September 2024

AbstractIndirect ecological effects, which occur when the impact of one species on another is mediated by a third species or the shared environment, are ubiquitous in nature. Given the complexity of natural systems, indirect ecological effects were thought to be important in driving eco-evolutionary processes across community boundaries. However, we know remarkably little about such effects. Here we show that indirect effects of terrestrial insect (aphids) herbivory on macrophytes (duckweed) drives adaptive evolution of water fleas (Daphnia) in large outdoor aquatic mesocosms. Aphid herbivory reduced macrophyte growth and increased the abundance of phytoplankton, which in turn increased the abundance ofDaphnia. Whole genome pool sequencing and phenotypic assays revealed an impact on the genetic compositions of theDaphniapopulations and transplant experiments indicated that these evolutionary changes were adaptive. Furthermore, these changes in the aquatic community altered the interactions of the aphids and the macrophytes. These results demonstrate that indirect ecological effects can shape eco-evolutionary interactions between different communities.
TMED9 coordinates the clearance of misfolded GPI-anchored proteins out of the endoplasmic reticulum and into the Golgi
Authors: Ronzier Elsa , Satpute-Krishnan Prasanna 
Published: September 2024

AbstractThe p24-family member, TMED9, has recently emerged as a player in secretory pathway protein quality control (PQC) that influences the trafficking and degradation of misfolded proteins. Here we show that TMED9 plays a central role in the PQC of GPI-anchored proteins (GPI-APs). Typically, upon release from the endoplasmic reticulum (ER)-resident chaperone calnexin, misfolded GPI-APs traffic to the Golgi by an ER-export pathway called Rapid ER stress-induced Export (RESET). From the Golgi, they access the plasma membrane where they are rapidly internalized for lysosomal degradation. We used biochemical and imaging approaches in cultured cells to demonstrate that at steady-state, the majority of misfolded GPI-APs reside in the ER in association with calnexin and TMED9. During RESET, they dissociate from calnexin and increase their association with TMED9. Inhibition of TMED9’s function through siRNA-induced depletion or chemical inhibitor, BRD4780, blocked ER-export of misfolded GPI-APs. By contrast, TMED9-inhibition did not prevent ER-export of wild type GPI-APs, indicating a specific role for TMED9 in GPI-AP PQC. Intriguingly, we discovered that acute treatment with BRD4780 induced a shift in TMED9 localization away from the ER to the downstream Golgi cisternae and blocked the RESET pathway. Upon removal of BRD4780 following acute treatment, TMED9 regained access to the ER where TMED9 was able to associate with the RESET substrate and restore the RESET pathway. These results suggest that TMED9 plays a requisite role in RESET by capturing misfolded GPI-APs that are released by calnexin within the ER and conveying them to the Golgi.
Mapping the landscape of social behavior
Authors: Klibaite Ugne , Li Tianqing , Aldarondo Diego , Akoad Jumana F. , Ölveczky Bence P. , Dunn Timothy W. 
Published: September 2024

AbstractSocial interaction is integral to animal behavior. However, we lack tools to describe it with quantitative rigor, limiting our understanding of its principles and neuropsychiatric disorders, like autism, that perturb it. Here, we present a technique for high-resolution 3D tracking of postural dynamics and social touch in freely interacting animals, solving the challenging subject occlusion and part assignment problems using 3D geometric reasoning, graph neural networks, and semi-supervised learning. We collected over 140 million 3D postures in interacting rodents, featuring new monogenic autism rat lines lacking reports of social behavioral phenotypes. Using a novel multi-scale embedding approach, we identified a rich landscape of stereotyped actions, interactions, synchrony, and body contact. This enhanced phenotyping revealed a spectrum of changes in autism models and in response to amphetamine that were inaccessible to conventional measurements. Our framework and large library of interactions will greatly facilitate studies of social behaviors and their neurobiological underpinnings.