bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of optimized single-cell RNA flow cytometry protocol identifies monocytes as main producers of type I interferon in mouse syngeneic tumors
Authors: Lam Khiem C. , Chen Quanyi , Goldszmid Romina S. 
Published: July 2024

AbstractThe tumor microenvironment (TME) consists of complex interactions between cellular and extracellular components, among which the immune system is known to play an integral role in disease progression and response to therapy. Cytokines and chemokines are cell signaling proteins used by immune cells to communicate with each other as well as with other cell types in the body. These proteins control systemic and local immune responses and levels of cytokines/chemokines in the TME have been associated with tumor outcomes. However, cytokines and chemokines have varied expression across cell types, tumors, and host conditions. Therefore, approaches to effectively study the production of these proteins at the single-cell level in the TME are needed to fully elucidate the mechanisms governing the anti-cancer immune response. Here, we detail a protocol to assess the production of cytokines/chemokines across leukocyte populations in mouse tumors using RNA flow cytometry. Importantly, this method can be adapted with minimal changes to study various mouse and human tumors, other RNA analytes, and non-tumor tissues. With this approach, we characterize single-cell production ofIfnb1, Xcl1andCcl5in mouse tumors and identify monocytes and monocyte-derived macrophages as the main producers of type I interferon transcriptIfnb1consistent across 4 different syngeneic tumor models.
Concurrent assessment of neurometabolism and brain hemodynamics to comprehensively characterize the functional brain response to psychotropic drugs: an S-ketamine study
Authors: Boucherie Daphne E , Reneman Liesbeth , Booij Jan , Immink Rogier , Hollmann Markus W , Schrantee Anouk 
Published: July 2024

AbstractNeuroimaging techniques are crucial for understanding pharmacological treatment effects in neuropsychiatric disorders. Here, we present a novel approach that simultaneously assesses hemodynamic and neurometabolic brain responses to psychotropic drugs using interleaved pharmacological magnetic resonance imaging (phMRI) and magnetic resonance spectroscopy (phMRS). This method was tested using a double-dose, placebo-controlled, randomized, crossover design using S-ketamine, and acquiring 7 Tesla phMRI and phMRS data to evaluate time- and dose-dependent effects in 32 healthy controls. S-ketamine elicited robust phMRI responses in the dorsal-frontal, cingulate, and insular cortices, which correlated with glutamate and opioid receptor maps and subjective dissociation scores. These hemodynamic changes were paralleled by increases in glutamate and lactate, especially at higher doses. Furthermore, accuracy in predicting received S-ketamine dose increased when combining both techniques. Here, we show for the first time that concurrent phMRI and phMRS assessments provide important complementary insights into the functional brain response to pharmacological interventions.
Molecular Dynamics of Phosphatidylcholine Model Membranes of Splenic Lymphoma Cells
Authors: Kio Michael , Lucker Joshua , Klauda Jeffery B. 
Published: July 2024

AbstractIn eukaryotic cell membranes, phosphatidylcholine (PC) is one of the most prevalent phospholipids. Using the CHARMM36 lipid force field, we conducted molecular dynamics (MD) simulations on phosphatidylcholine (PC) only headgroup with varied fatty acid chains. Specifically, we investigated five PC components: 1,2-diauroyl-sn-glycero-3-phospocholine (DLPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3- phospcholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1- stearoyl-2-oleoylphosphatidylcholine (SOPC) in both pure and cancer model of PCs. We analyzed various characteristics such as lipid area, lateral compressibility, deuterium order parameter, bilayer thickness, radial distribution functions, and electron density. Our research revealed that PCs in the cancer model membrane are larger in surface area per lipid compared with pure PC membranes. This suggests that our PC model for cancer PCs may be more permeable and porous compared to pure PC membraness. In general, chain order parameter values were lower in cancer PCs compared to pure PCs. The electron density studies of cancer PCs revealed a decrease in bilayer thickness as temperature increases, indicating that cancer PCs experience thinning at higher temperatures. Overall, our results give insight into significant differences between the cellular makeup and functioning of pure PCs and cancer PCs at the molecular level.
Contrastive Learning for Graph-Based Biological Interaction Discovery: Insights from Oncologic Pathways
Authors: Nguyen Phuong-Nam 
Published: July 2024

ABSTRACTBackgroundContrastive learning has emerged as a pivotal technique in representation learning, particularly for self-supervised and unsupervised tasks. Link prediction, crucial for network analysis, forecasts the formation of connections between nodes. Machine learning enhances link prediction by learning patterns from data, leading to improved performance and scalability.MethodIn this study, we propose a contrastive learning approach tailored for isomorphic graphs to uncover intrinsic interactions within biological networks. By creating data augmentations through vertex permutations, we train models to learn permutation-invariant representations.ResultsIn this study, we propose a contrastive learning approach tailored for isomorphic graphs to uncover intrinsic interactions within biological networks. By creating data augmentations through vertex permutations, we train models to learn permutation-invariant representations. Our approach was validated using five cancer-targeting biomarkers:ADGRF5, TP53, BRAF, KRAS, andGNAS.ConclusionWe discovered new connections between G-coupled receptors (GPR137B, GPR161, andGPR27) and key path-ways, interactions between cyclin-dependent kinase inhibitors (CDKN1AandCDK8) and specific biomarkers, and identifiedNFK-BIAas a central node linking all targeting biomarkers. This study highlights the potential of contrastive learning to reveal novel insights into cancer research and therapeutic targets. The implementation of this project is made available at:https://github.com/namnguyen0510/Contrastive-Learning-for-Graph-Based-Biological-Interaction-Discovery.
Induction of cytoplasmic dsDNA and cGAS-STING immune signaling after exposure of breast cancer cells to X-rays or high energetic carbon ions
Authors: Totis C. , Averbeck N. B. , Jakob B. , Schork M. , Volpi G. , Hintze D.F. , Durante M. , Fournier C. , Helm A. 
Published: July 2024

AbstractRadiotherapy can trigger activation of the cGAS-STING axis via cytoplasmic dsDNA fragment induction. The activation of cGAS–STING initiates innate immune signaling mediated by interferon type-I that can contribute to eradicate the malignancy. The effect was shown to depend on the fractionation scheme employed. We hypothesized that the innate immune response can also depend on radiation quality because densely ionizing radiation, such as carbon ions, have different effects on DNA lesion quality. We show here that carbon ions induced a significantly higher yield of cytosolic dsDNA fragments per unit dose as compared to photons in anin vitro4T1 breast cancer model. The higher efficiency also translated in expression and release of interferon-β by the tumor cells. Cytoplasmic dsDNA fragments as well as interferon-β release increased with doses up to 24 Gy and no differences for a fractionation scheme (3x8 Gy) were found as compared to the single high doses of photons. In conclusion, we found that the release of interferon-β after radiation is increasing with the radiation dose up to 20 Gy and that carbon ions have the potential to elicit a strong innate immune signaling.
Effector-Specific Neural Representations of Perceptual Decisions Independent of Motor Actions and Sensory Modalities
Authors: Esmeyer Marlon F. , Schmidt Timo T. , Blankenburg Felix 
Published: July 2024

AbstractNeuroscientific research has shown that perceptual decision-making occurs in effector-specific brain regions that are associated with the required motor response. Recent functional magnetic resonance imaging (fMRI) studies that dissociated decisions from coinciding processes, such as motor actions partly challenge this, indicating abstract representations that might vary across stimulus modalities. However, cross-modal comparisons have been difficult since most task designs differ not only in modality but also in effectors, motor response, and level of abstraction. Here, we describe an fMRI experiment where participants compared frequencies of two sequentially presented visual flicker stimuli in a delayed match-to-comparison task, which controlled for motor actions and stimulus sequence. Using Bayesian modelling, we estimated subjective frequency differences based on the time order effect. These values were applied in support vector regression analysis of a multi-voxel pattern whole-brain searchlight approach to identify brain regions containing information on subjective decision values. Furthermore, a conjunction analysis with data from a re-analyzed analogue vibrotactile study was conducted for a cross-modal comparison. Both analyses revealed significant activation patterns in the left dorsal (PMd) and ventral (PMv) premotor cortex as well as in the bilateral intraparietal sulcus (IPS). While previous primate and human imaging research have implicated these regions in transforming sensory information into action, our findings indicate that the IPS processes abstract decision signals while PMd and PMv represent an effector-specific, but motor response independent encoding of perceptual decisions that persists across sensory domains.
EMG1 methyltransferase activity regulates ribosome occupancy at viral uORFs
Authors: Harrington Elena M. , Murphy James C. , Aspden Julie L. , Whitehouse Adrian 
Published: July 2024

SummaryViruses do not encode their own translational machinery and rely exclusively on the translational machinery of the host cell for the synthesis of viral proteins. Viruses have evolved diverse mechanisms to redirect the cellular translation apparatus to favour viral transcripts. A unique mechanism employed by Kaposi’s sarcoma-associated herpesvirus (KSHV) involves manipulation of cellular ribosome composition, producing virus-induced specialised ribosomes. These ribosomes scan through KSHV uORFs in late lytic genes, allowing efficient translation of downstream main KSHV ORFs. Herein, we highlight the enhanced association of the ribosomal biogenesis factor EMG1 with precursor-40S ribosome complexes during KSHV lytic replication. Depletion of EMG1 results in significantly reduced expression of viral proteins and progression through the lytic cascade, culminating in a dramatic reduction of infectious virus production. We further demonstrate that the methyltransferase activity of EMG1 is required for effective regulation of translation of KSHV uORFs in late lytic genes.
Quantifying defective and wild-type viruses from high-throughput RNA sequencing
Authors: Muñoz-Sánchez Juan C. , Olmo-Uceda María J. , Oteo José-Ángel , Elena Santiago F. 
Published: July 2024

AbstractDefective viral genomes (DVGs) are variants of the wild-type (wt) virus that lack the ability to complete an infectious cycle independently. However, in the presence of their parental (helper) wt virus, DVGs can interfere with the replication, encapsidation, and spread of functional genomes, acting as a significant selective force in viral evolution. DVGs also affect the host’s immune responses and are linked to chronic infections and milder symptoms. Thus, identifying and characterizing DVGs is crucial for understanding infection prognosis. Quantifying DVGs is challenging due to their inability to sustain themselves, which makes it difficult to distinguish them from the helper virus, especially using high-throughput RNA sequencing (RNA-seq). Accurate quantification is essential for understanding their interactions with their helper virus. We present a method to simultaneously estimate the abundances of DVGs and wt genomes within a sample by identifying genomic regions with significant deviations from the expected sequencing depth. Our approach involves reconstructing the depth profile through a linear system of equations, which provides an estimate of the number of wt and DVG genomes of each type. Until now,in silicomethods have only estimated the DVG-to-wt ratio for localized genomic regions. This is the first method that simultaneously estimates the proportions of wt and DVGs across RNA sequencing of the whole genome.Availability and implementationThe Matlabcode and the synthetic datasets are freely available athttps://github.com/jmusan/wtDVGquantific.
Beyond Symptom Management: FAAH Inhibition as a Path to Mitigate Alzheimer’s Disease Progression in Mouse Models of Amyloidosis
Authors: Oddi Sergio , Scipioni Lucia , Totaro Antonio , Giacovazzo Giacomo , Ciaramellano Francesca , Tortolani Daniel , Leuti Alessandro , Businaro Rita , Armeli Federica , Bilkei-Gorzo Andras , Coccurello Roberto , Zimmer Andreas , Maccarrone Mauro 
Published: July 2024

AbstractThe endocannabinoidN-arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimer’s disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis APP/PS1 and Tg2576. Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inactivation robustly suppressed β-amyloid production and accumulation, associated with decreased expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1-dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis, and provide proof-of-concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD.
Chromosome Numbers and Reproductive Life Cycles in Green Plants: A phylo-transcriptomic perspective
Authors: Dhakal Rijan R. , Harkess Alex , Wolf Paul G. 
Published: July 2024

AbstractThe strong correlation between reproductive life cycle type and chromosome numbers in green plants has been a long-standing mystery in evolutionary biology. Within green plants, the derived condition of heterosporous reproduction has emerged from the ancestral condition of homospory in disparate locations on the phylogenetic tree at least 11 times, of which 3 lineages are extant. In all green plant lineages where heterospory has emerged, there has been a significant downsizing in chromosome numbers (refer to figure 1). This dynamic has been investigated without clear answers for many decades. In this study, we combine known ideas from existing literature with novel methods, tools, and data to generate fresh insights into an old question.Using gene family evolution models and selection analyses, we identified gene families that have undergone significant expansion, contraction, or selection in heterosporous lineages. Our results reveal both shared and lineage-specific genomic changes associated with the evolution of heterospory. We found expansions in gene families related to developmental regulation, signaling pathways, and stress responses across heterosporous groups. Notably, the MATE efflux family showed consistent expansion and evidence of selection in heterosporous lineages, suggesting a potentially conserved role in heterospory evolution. These findings highlight novel insights that may underpin the association between heterospory and reduced chromosome numbers.The general importance of chromosome numbers, structure, and sizes in cellular biology notwithstanding, the association between the emergence of heterosporous reproduction and chromosome number reduction/genome downsizing is not fully understood. It remains unclear why there exists an association between aspects of biology at such disparate levels as reproductive life-cycles and chromosome numbers/genome size. Exploring and answering this conundrum of evolutionary biology can add to our broader understanding of life sciences and of biology at different levels. Applying the novel tools and methods emerging from ongoing progress in biotechnology and computational sciences presents an opportunity to make new inroads into this long-standing question.
Mechanism-guided engineering of a minimal biological particle for genome editing
Authors: Ngo Wayne , Peukes Julia T. , Baldwin Alisha , Xue Zhiwei Wayne , Hwang Sidney , Stickels Robert R. , Lin Zhi , Satpathy Ansuman T. , Wells James A. , Schekman Randy , Nogales Eva , Doudna Jennifer A. 
Published: July 2024

ABSTRACTThe widespread application of genome editing to treat or even cure disease requires the delivery of genome editors into the nucleus of target cells. Enveloped Delivery Vehicles (EDVs) are engineered virally-derived particles capable of packaging and delivering CRISPR-Cas9 ribonucleoproteins (RNPs). However, the presence of lentiviral genome encapsulation and replication components in EDVs has obscured the underlying delivery mechanism and precluded particle optimization. Here we show that Cas9 RNP nuclear delivery is independent of the native lentiviral capsid structure. Instead, EDV-mediated genome editing activity corresponds directly to the number of nuclear localization sequences on the Cas9 enzyme. EDV structural analysis using cryo-electron tomography and small molecule inhibitors guided the removal of ∼80% of viral residues, creating a minimal EDV (miniEDV) that retains full RNP delivery capability. MiniEDVs are 25% smaller yet package equivalent amounts of Cas9 RNPs relative to the original EDVs, and demonstrated increased editing in cell lines and therapeutically-relevant primary human T cells. These results show that virally-derived particles can be streamlined to create efficacious genome editing delivery vehicles that could simplify production and manufacturing.SIGNIFICANCE STATEMENTOur results highlight the importance of understanding how virally-derived particles function to eliminate unnecessary viral proteins and create more efficacious and easier-to-produce delivery vehicles for therapeutic genome editing.
Proprioception impacts body perception in healthy aging – insights from a Psychophysical and Computational Approach
Authors: Risso G. , Bieri M. , Bertoni T. , Mastria G. , Allet L. , Serino A. , Bassolino M. 
Published: July 2024

AbstractThe experience of owning a body (body ownership, BO) and the perception of our body dimensions (metric body representation, mBR) depend on the integration of multisensory cues. As the human sensory system is subjected to a decline along the lifespan, encompassing all sensory modalities, we hypothesize that body perception may be different in older, as compared to young adults. Here, we investigate this hypothesis by comparing the multisensory processing underlying BO and mBR in healthy older (> 65 years) and young individuals. First, we applied rigorous computational and psychophysical methods to assess alterations in mBR and BO quantitatively. We then modeled the manifold relationship between the observed body misperceptions and the potential underlying sensory, motor, and cognitive factors. The results highlight significant differences between the two groups, with higher distortions in perceived arm dimensions and an increased tendency to experience BO towards a virtual hand in the aged group. These differences in both mBR and BO are explained by the reduced proprioceptive abilities of older adults, suggesting a crucial role of proprioception in driving age-dependent plasticity in body representations. Overall, our modeling and experimental approach provide new perspectives on altered body perception during aging, suggesting that they stem from the physiological proprioceptive decline occurring in older adults, and laying the groundwork to generate prevention and stimulation strategies to restore accurate body perception in aging.
Differentiation of Acute Disseminated Encephalomyelitis from Multiple Sclerosis Using a Novel Brain Lesion Segmentation and Classification Pipeline
Authors: Radi Osama , Huang Aiden , Murakami Kira 
Published: July 2024

AbstractMultiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system, while Acute Disseminated Encephalomyelitis (ADEM) is a sudden, often monophasic inflammatory condition of the brain and spinal cord. Only 17% of ADEM cases are correctly diagnosed on the first visit due to overlapping clinical and radiological presentations with Multiple Sclerosis (MS) [1]. Both ADEM and MS are demyelinating diseases, meaning they cause brain lesions by damaging the myelin sheath, leading to scar tissue that disrupts nerve signals [2]. Previous machine learning pipelines have differentiated Neuromyelitis Optica Spectrum Disorder (NMOSD) (a different demyelinating disease) from MS and ADEM from NMOSD based on MRI imagery with varying accuracies [3, 4]. Our novel Classifier for Demyelinating Disease (CDD) pipeline is the first to differentiate ADEM from MS using MRI imagery. It does this in two stages: a segmentation stage which creates segmentation masks of the lesions and a classification stage to classify them as either ADEM or MS. Additionally, we introduce a novel ADEM dataset from open-access medical case reports. The CDD pipeline achieves an accuracy of 90.0% on our validation dataset, making it a potentially viable diagnostic tool in the future. All data and code is available here.2
Sequencing 1206 genomes reveals origin and movement ofAedes aegyptidriving increased dengue risk
Authors: Crawford Jacob E. , Balcazar Dario , Redmond Seth , Rose Noah H. , Youd Henry A. , Lucas Eric R. , Sudirman Made Ali Rusdiyah , Alnazawi Ashwaq , Badolo Athanase , Chen Chun-Hong , Cosme Luciano V. , Henke Jennifer A. , Hung Kim Y. , Kluh Susanne , Liu Wei-Liang , Maringer Kevin , Micieli María Victoria , Pless Evlyn , Sombié Aboubacar , Surendran Sinnathamby N. , Wahid Isra , Armbruster Peter A. , Weetman David , McBride Carolyn S. , Gloria-Soria Andrea , Powell Jeffrey R. , White Bradley J. 
Published: July 2024

AbstractThe number of dengue cases worldwide has increased ten-fold over the past decade asAedes aegypti, the primary vector of this disease, thrives and expands its distribution, revealing limitations to current control methods. To better understand howAe. aegyptievolved from a forest dwelling, generalist species to a highly anthropophilic urban species and the impact of contemporary gene flow on the future of dengue control, we sequenced 1,206 genomes from mosquitoes collected at 74 locations around the globe. Here we show that after evolving a preference for humans in the Sahel region of West Africa, the origin of the fully domesticated, anthropophilic subspeciesAe. aegypti aegypti(Aaa) occurred in the Americas during the Atlantic Slave Trade era and was followed by its explosive expansion around the globe. In recent decades,Aaahas invaded coastal Africa, the ancestral home range, introducing insecticide resistance mutations and an affinity for human hosts. Evidence of back-to-Africa migration is found in regions with recent dengue outbreaks, raising concern that global movement ofAaacould increase transmission risk of arboviruses including dengue in urban Africa. These data provide a platform to further study this important mosquito vector species and underscore developing complexity in the fight to limit the spread of dengue, Zika, and chikungunya diseases.