bluuebunny/crossref_metadata_2025_split huggingface dataset:
Region-specific Nucleus Accumbens Dopamine Signals Encode Distinct Aspects of Avoidance Learning
Authors: Lopez Gabriela C. , Van Camp Louis D. , Kovaleski Ryan F. , Schaid Michael D. , Andrés Moreno-Ramos Oscar , Awatramani Rajeshwar , Cox Julia M. , Lerner Talia N. 
Published: August 2024

AbstractAvoidance learning – learning to avoid bad outcomes – is an essential survival behavior. Dopamine signals are widely observed in response to aversive stimuli, indicating they could play a role in learning about how to avoid these stimuli. However, it is unclear what computations dopamine signals perform to support avoidance learning. Furthermore, substantial heterogeneity in dopamine responses to aversive stimuli has been observed across nucleus accumbens (NAc) subregions. To understand how heterogeneous dopamine responses to aversive stimuli contribute to avoidance learning, we recorded NAc core (Core) and NAc ventromedial shell (vmShell) dopamine during a task in which mice could avoid a footshock punishment by moving to the opposite side of a 2-chamber apparatus during a five-second warning cue. We found that NAc Core and vmShell dopamine signals responded oppositely during shocks and warning cues. Both signals evolved substantially – but differently – with learning. NAc vmShell dopamine responses to cues and shocks were present during early learning but not sustained during expert performance. NAc Core dopamine responses strengthen with learning and are especially evident during expert performance. Our data support a model in which NAc vmShell dopamine guides initial cue-shock associations by signaling salience, while NAc Core dopamine encodes prediction errors that guide the consolidation of avoidance learning.
Integrative Analysis of Gene Expression, Protein Abundance, and Metabolomic Profiling Elucidates Complex Relationships in Chronic Hyperglycemia-Induced Changes in Human Aortic Smooth Muscle Cells
Authors: Bohara Smriti , Bagheri Atefeh , Ertugral Elif G. , Radzikh Igor , Sandlers Yana , Jiang Peng , Kothapalli Chandrasekhar R. 
Published: August 2024

AbstractType 2 diabetes mellitus (T2DM) is a major public health concern with significant cardiovascular complications (CVD). Despite extensive epidemiological data, the molecular mechanisms relating hyperglycemia to CVD remain incompletely understood. We here investigated the impact of chronic hyperglycemia on human aortic smooth muscle cells (HASMCs) cultured under varying glucose conditionsin vitro, mimicking normal (5 mmol/L), pre-diabetic (10 mmol/L), and diabetic (20 mmol/L) conditions, respectively. Patient-derived T2DM-SMCs served as disease phenotype controls. Results showed significant increases in cellular proliferation, area, perimeter, and F-actin expression with increasing glucose concentration (p< 0.01), albeit not exceeding the levels in T2DM cells. Atomic force microscopy analysis revealed significant decreases in Young’s moduli, membrane tether forces, membrane tension, and surface adhesion in SMCs at higher glucose levels (p< 0.001), with T2DM-SMCs being the lowest among all the cases (p< 0.001). T2DM-SMCs exhibited elevated levels of pro-inflammatory markers such as IL-6, IL-8, and MCP-1 compared to glucose-treated SMCs (p< 0.01). Conversely, growth factors such as FGF-2 and TGF-β were higher in SMCs exposed to 10 mmol/L glucose but lower in T2DM-SMCs (p< 0.01). Pathway enrichment analysis showed significant increases in the expression of inflammatory cytokine-associated pathways, especially involving IL-10, IL-4 and IL-13 signaling in genes that are up-regulated by elevated glucose levels. Differentially regulated gene (DGE) analysis showed that compared to normal glucose receiving SMCs, 513 genes were upregulated and 590 genes were downregulated in T2DM-SMCs; fewer genes were differentially expressed in SMCs receiving higher glucose levels. Finally, the altered levels in genes involved in ECM organization, elastic fiber synthesis and formation, laminin interactions, and ECM proteoglycans were identified, which highlight the role of hyperglycemia in vascular remodeling and CVD progression. Our results collectively suggest that chronic hyperglycemia in vascular SMCs leads to morphological, biomechanical, and functional alterations, potentially contributing to the pathogenesis of T2DM-associated CVD. The observed differences in gene expression patterns betweenin vitrohyperglycemic models and patient-derived T2DM-SMCs highlight the complexity of T2DM pathophysiology and underline the need for further studies.
FREQ-NESS Reveals the Dynamic Reconfiguration of Frequency-Resolved Brain Networks During Auditory Stimulation
Authors: Rosso M. , Fernández-Rubio G. , Keller P. , Brattico E. , Vuust P. , Kringelbach M. L. , Bonetti L. 
Published: August 2024

AbstractThe brain is a dynamic system whose network organization is often studied by focusing on specific frequency bands or anatomical regions, leading to fragmented insights, or by employing complex and elaborate methods that hinder straightforward interpretations. To address this issue, a new analytical pipeline namedFREQuency-resolved Network Estimation via Source Separation(FREQ-NESS) is introduced. This is designed to estimate the activation and spatial configuration of simultaneous brain networks across frequencies by analyzing the frequency-resolved multivariate covariance between whole-brain voxel time series. FREQ-NESS is applied to source-reconstructed magnetoencephalography (MEG) data during resting state and isochronous auditory stimulation. Results reveal simultaneous, frequency-specific brain networks during resting state, such as the default mode, alpha-band, and motor-beta networks. During auditory stimulation, FREQ-NESS detects: (1) emergence of networks attuned to the stimulation frequency, (2) spatial reorganization of existing networks, such as alpha-band networks shifting from occipital to sensorimotor areas, (3) stability of networks unaffected by auditory stimuli. Furthermore, auditory stimulation significantly enhances cross-frequency coupling, with the phase of attuned auditory networks modulating the gamma band amplitude of medial temporal lobe networks. In conclusion, FREQ-NESS effectively maps the brain’s spatiotemporal dynamics, providing a comprehensive view of brain function by revealing simultaneous, frequency-resolved networks and their interaction.
Transformations in prefrontal ensemble activity underlying rapid threat avoidance learning
Authors: Gabriel Christopher J. , Gupta Tanya , Sanchez-Fuentes Asai , Zeidler Zachary , Wilke Scott A. , DeNardo Laura A. 
Published: August 2024

SUMMARYThe capacity to learn cues that predict aversive outcomes, and understand how to avoid those outcomes, is critical for adaptive behavior. Naturalistic avoidance often means accessing a safe location, but whether a location is safe depends on the nature of the impending threat. These relationships must be rapidly learned if animals are to survive. The prelimbic subregion (PL) of the medial prefrontal cortex (mPFC) integrates learned associations to influence these threat avoidance strategies. Prior work has focused on the role of PL activity in avoidance behaviors that are fully established, leaving the prefrontal mechanisms that drive rapid avoidance learning poorly understood. To determine when and how these learning-related changes emerge, we recorded PL neural activity using miniscope calcium imaging as mice rapidly learned to avoid a threatening cue by accessing a safe location. Over the course of learning, we observed enhanced modulation of PL activity representing intersections of a threatening cue with safe or risky locations and movements between them. We observed rapid changes in PL population dynamics that preceded changes observable in the encoding of individual neurons. Successful avoidance could be predicted from cue-related population dynamics during early learning. Population dynamics during specific epochs of the conditioned tone period correlated with the modeled learning rates of individual animals. In contrast, changes in single-neuron encoding occurred later, once an avoidance strategy had stabilized. Together, our findings reveal the sequence of PL changes that characterize rapid threat avoidance learning.
Label-free acoustic and optical microscopy of live tumor spheroids in hydrogel for high-throughput 3D In-vitro drug screening
Authors: Ghosh Biswajoy , Agarwal Komal , Habib Anowarul , Agarwal Krishna , Melandsø Frank 
Published: August 2024

ABSTRACT3D cell cultures, including spheroids, have become essential tools in cancer research and drug discovery due to their ability to more accurately mimic in-vivo tissue environments compared to traditional 2D cultures. However, imaging these thick, complex structures remains a challenge, as conventional optical microscopy techniques are limited by shallow depth penetration. This study explores the complementary use of gradient light interference microscopy (GLIM) and scanning acoustic microscopy (SAM) for label-free imaging of 3D spheroid clusters embedded in hydrogels. GLIM offers high-resolution optical imaging but struggles with depth in dense samples, while SAM provides greater depth penetration and a larger field of view, albeit with lower resolution. By correlating SAM and GLIM imaging, this study demonstrates how the two techniques can be synergistically used to enhance the visualization of spheroids, capturing both large-scale structural features and fine cellular details. The benefits make such a platform suitable for screening high-number multi-well plates and evaluating necrotic and angiogenic features from the core of the thick sample. Such platforms have the potential of combining acoustic and optical imaging modalities for high-throughput screening and physical characterization in 3D cell culture research, advancing our understanding of drug efficacy in complex biological systems.
The SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity
Authors: Witt Kristen C. , Dziulko Adam , An Joohyun , Pekovic Filip , Cheng Arthur Xiuyuan , Liu Grace Y. , Lee Ophelia Vosshall , Turner David J. , Lari Azra , Gaidt Moritz M. , Chavez Roberto , Fattinger Stefan A. , Abraham Preethy , Dhaliwal Harmandeep , Lee Angus Y. , Kotov Dmitri I. , Coscoy Laurent , Glaunsinger Britt A. , Valkov Eugene , Chuong Edward B. , Vance Russell E. 
Published: August 2024

AbstractType I interferons (IFN-Is) are essential for antiviral immunity but must be tightly regulated1–3. The conserved transcriptional repressor SP140 inhibits interferon beta (Ifnb1) expression via an unknown mechanism4,5. Here we report that SP140 does not directly repressIfnb1transcription. Instead, SP140 negatively regulatesIfnb1mRNA stability by directly repressing the expression of a previously uncharacterized regulator we call RESIST (REgulated Stimulator of Interferon via Stabilization of Transcript, previously annotated as Annexin-2 Receptor). RESIST promotesIfnb1mRNA stability by counteractingIfnb1mRNA destabilization mediated by the Tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. SP140 localizes within nuclear bodies, punctate structures that play important roles in silencing DNA virus gene expression in the nucleus4. Consistent with this observation, we found that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 was independent of its ability to regulateIfnb1. Our results establish dual antiviral and interferon regulatory functions for SP140. We propose that SP140 and RESIST participate in antiviral effector-triggered immunity6,7.
Design of diverse, functional mitochondrial targeting sequences across eukaryotic organisms using variational autoencoder
Authors: Boob Aashutosh Girish , Tan Shih-I , Zaidi Airah , Singh Nilmani , Xue Xueyi , Zhou Shuaizhen , Martin Teresa A. , Chen Li-Qing , Zhao Huimin 
Published: August 2024

AbstractMitochondria play a key role in energy production and cellular metabolism, making them a promising target for metabolic engineering and disease treatment. However, despite the known influence of passenger proteins on localization efficiency, only a few protein-localization tags have been characterized for mitochondrial targeting. To address this limitation, we exploited Variational Autoencoder (VAE), an unsupervised deep learning framework, to design novel mitochondrial targeting sequences (MTSs).In silicoanalysis revealed that a high fraction of generated peptides are functional and possess features important for mitochondrial targeting. Additionally, we devised a sampling scheme to indirectly address biases arising from the differences in mitochondrial protein import machinery and characterized artificial MTSs in four eukaryotic organisms. These sequences displayed significant diversity, sharing less than 60% sequence identity with MTSs in the UniProt database. Moreover, we trained a separate VAE and employed latent space interpolation to design dual targeting sequences capable of targeting both mitochondria and chloroplasts, shedding light on their evolutionary origins. As a proof-of-concept, we demonstrate the application of these artificial MTSs in increasing titers of 3-hydroxypropionic acid through pathway compartmentalization and improving 5-aminolevulinate synthase delivery by 1.62-fold and 4.76-fold, respectively. Overall, our work not only demonstrates the potential of generative artificial intelligence in designing novel, functional mitochondrial targeting sequences but also highlights their utility in engineering mitochondria for both fundamental research and practical applications in biology.
Multi-scale reactor designs extend the physical limits of CO2fixation
Authors: Akbari Amir , Palsson Bernhard O. 
Published: August 2024

AbstractCO2valorization is a promising strategy for climate adaptation and transitioning towards a circular carbon economy. Here, we present a multi-scale, integrated systems approach for designing biomanufacturing systems that can utilize CO2as a feedstock, focusing on the Wood–Ljungdahl and reductive glycine pathways. This approach relies on first principles, coupling the optimization of pathway and process variables. We examine the CO2-fixation capacity of both pathways in single- and multi-compartment reactor systems, demonstrating that the reductive glycine pathway has the potential to fix CO2at significantly higher rates than photosynthetic organisms. We show that small differences in the energy-dissipative and stoichiometric structures of carbon-fixation pathways could significantly impact optimal designs and feasible design spaces. Our first-principle, systems-level approach quantifies these differences and uncovers strategies to expand the design space and extend the physical limits of carbon fixation, offering insights into pathway selection and process configurations for efficient biomanufacturing.
Inflammatory reprogramming of the tumor microenvironment by infiltrating clonal hematopoiesis is associated with adverse outcomes in solid cancer
Authors: Buttigieg Marco M. , Vlasschaert Caitlyn , Bick Alexander G. , Vanner Robert J. , Rauh Michael J. 
Published: August 2024

AbstractClonal hematopoiesis (CH) – the expansion of somatically-mutated hematopoietic cells in blood – is common in solid cancers. CH is associated with systemic inflammation that may lead to cancer, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naïve patient samples from the CPTAC cohort. CH was present in 18.3% of patients, with one-third of CH mutations also detectable in tumor-derived DNA from the same individual (CH-Tum), reflecting CH-mutant leukocyte infiltration. The presence of CH-Tum was associated with worse survival across cancers, particularly for glioblastoma.Transcriptomics and proteomics revealed that CH drives inflammation in the TME in a cancer- and CH driver-specific manner, and may improve immunotherapy responses. In glioblastoma, CH associated with pronounced macrophage infiltration, inflammation, and an aggressive, mesenchymal phenotype. Our findings demonstrate that CH shapes the TME, with potential applications as a biomarker in precision oncology.
A-Islands: A plant dataset for biodiversity research and species monitoring on Australian islands
Authors: Schrader Julian , Coleman David , Abbott Ian , Bryant Sally , Buckley Ralf , Crayn Darren , Gallagher Rachael V. , Harris Stephen , Heatwole Harold , Jackes Betsy , Kreft Holger , Mills Kevin , Kirkpatrick Jamie , Latz Peter K. , Neldner John , Sattler Cornelia , Visoiu Micah , Wenk Elizabeth H. , Woinarski John C. Z. , Worboys Stuart , Wright Ian J. , Zorn Isabel , Westoby Mark 
Published: August 2024

AbstractAustralia’s coastline is fringed by more than 8,000 continental islands. These islands feature a diverse array of landforms, rock and soil types and geological origins. Some of these islands are among the least invaded, most pristine habitats in Australia and support high plant diversity. Here, we present a new Australia-wide curated dataset for plant species occurrences on islands. Combining information from 1,349 species lists and floras, A-Islands includes data on >6,500 plant species from 844 islands ranging in size from 18 m2to 4,400 km2, exhibiting different degrees of isolation from the mainland, and spanning all major Australian climate zones. Of these, 251 islands have been repeatedly sampled up to 11 times making it possible to investigate temporal compositional change. A-Islands is open access and will be continuously updated. Its simple data structure consisting of three comma separated files allows easy integration with other Australian and global plant-occurrence databases and can serve as a repository for island research in Australia. Knowing which species occur on Australia′s islands will provide opportunities for future research, including studying changes in biodiversity and species-turnover within and among archipelagos, tests of classical island biogeography theory and as a baseline for ecological monitoring and conservation.
The pro-apoptotic effect of chronic contractile activity-induced extracellular vesicles on Lewis Lung Carcinoma cells
Authors: Obi Patience O. , Souza Tamiris F.G. , McManus Kirk J. , West Adrian R. , Gordon Joseph W. , Saleem Ayesha 
Published: August 2024

AbstractRegular exercise reduces tumor growthin vivoandin vitro, but the exact mechanisms have yet to be fully elucidated. We have previously shown that chronic contractile activity (CCA) increases the concentration of skeletal muscle-derived EVs, and these in turn increased mitochondrial biogenesis in myoblasts. Here, we hypothesized that skeletal muscle-EVs derived post-CCA will mediate the anti-tumorigenic effects associated with chronic exercise. C2C12 myoblasts were differentiated into myotubes, electrically paced, and EVs isolated from conditioned media from control and CCA myotubes using differential ultracentrifugation. Lewis lung carcinoma (LLC) cells were treated with the total number of control-EVs or CCA-EVs isolated after each day of contractile activity for 4 days. Permeabilized CCA-EVs with or without proteinase K before co-culture with LLC cells were used as controls. Effect of EV treatment on cell count, viability, apoptosis, senescence, migration, and mitochondrial content was measured. CCA-EV treatment reduced cell count by 18% and cell viability by 6%vs.control-EVs. CCA-EVs increased the incidence of apoptotic hallmarks: DNA fragmentation by 13%, Annexin V+/PI+ cells by 21%, and the expression of pro-apoptotic Bax (by 25%) and Bax/Bcl-2 ratio (by 60%)vs.control-EVs. CCA-EVs increased number of senescent cells by 29%, and senescence markers, HMGB1 (by 49%) and p16 (by 92%)vs.control-EVs. When CCA-EVs were pretreated with Triton X-100 with or without proteinase-K, the increase in apoptosis and senescence was abrogated, confirming the effect is due to intact EVs and likely through EV membrane-proteins. CCA-EVs did not have any effect on cell migration and mitochondrial contentvs.control-EVs. This study illustrates for the first time the potential of CCA-induced skeletal muscle-EVs in mediating anti-tumorigenic effects traditionally linked with chronic exercise.
Modulating Bacterial Nanocellulose Crystallinity through Post-Transcriptional Repression inKomagataeibacter xylinus
Authors: Mangayil Rahul , Sarlin Essi , Ellis Tom , Santala Ville 
Published: August 2024

AbstractBacterial nanocellulose (BC), a versatile and biodegradable polymer, has been extensively studied as an alternative biomaterial for various applications. For biomedical and packaging uses, where precise control over nanocellulose structure is essential, existing literature describes BC structural modification processes that involve additives or additional steps. With the aim to develop a programmable method to control the bulk microstructure, we developed sRNA-based post-transcriptional repression cassettes that allows precise regulation of the crystalline phase of BC. Before investigating the effects of post-transcriptional repression ofbcsD, bcsZ, andccpAgenes, known to influence BC crystallinity, we validated the specificity of the sRNA repression cassette by targeting a genome-integrated red fluorescent protein, mRFP1. The observed growth inhibition (>80%) caused by overexpressed Hfq RNA chaperone inKomagataeibacter xylinuswas alleviated (≤ 23%) by its removal, resulting in a 43% reduction in relative mRFP1 expression. By varying the design of the repression cassette and the inducer concentrations, we successfully modulated the repression of the target genes [with relative expression reductions of 6%-34% for bcsD, 8%-24% for bcsZ, and 2%-20% for ccpA, as confirmed by qRT-PCR]. These gene repression levels led to statistically significant changes in the amorphous content of the BC microstructure, as demonstrated by X-ray diffraction and wide-angle X-ray scattering analysis.
PKA prevents resection of DNA double strand breaks and favor non-homologous end-joining
Authors: Khater-Sellou Houaria , Magdalou Indiana , Ogryzko Vasily , Lopez Bernard S. 
Published: August 2024

AbstractGenome rearrangement is a hallmark of cancer and ageing. DNA double-strand breaks (DSBs) are highly toxic lesions that can generate genome rearrangements. Several pathways compete for DSB repair, and selection of the appropriate repair process is decisive for genetic stability. DSB repair act according to two steps: 1-the choice between nonhomologous end-joining (NHEJ)versusresection of DNA ends, generating single-stranded DNA (ssDNA); 2-on ssDNA, homologous recombination (HR) and sub-processes. Here we show that 53BP1, which plays a prime role at the first step by protecting against resection and fostering NHEJ, physically interacts with the catalytic subunits of the cAMP dependant protein kinase A (PKAcs). PKA favors the recruitment of 53BP1 at DNA damages sites, and consistently, prevents resection, favoring NHEJ. Inhibition of PKA stimulated resection and coherently reduces NHEJ. Reversely, activation of PKA with 8-Bromo-cAMP stimulate NHEJ and reduces HR. These data open new avenues for potential anticancer strategies. More generally, they underline the high complexity of the regulation of DSB repair, identifying PKA as a novel actor of the DNA damage response, acting at the choice of the DSB repair process, which might be essential for genome integrity maintenance.