bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissecting the cell cycle regulation, DNA damage sensitivity and lifespan effects of caffeine in fission yeast
Authors: Alao John-Patrick , Kumar Juhi , Stamataki Despina , Rallis Charalampos 
Published: November 2022

AbstractCaffeine is a widely consumed neuroactive substance. It can modulate cell cycle progression, override DNA damage checkpoint signalling and increase chronological lifespan (CLS) in various model systems. Early studies suggested that caffeine inhibits the phosphatidylinositol 3-kinase-related kinase (PIKK) Rad3 to override DNA damage-induced cell cycle arrest in fission yeast. We have previously suggested that caffeine modulates cell cycle progression and lifespan by inhibiting the Target of Rapamycin Complex 1 (TORC1). Nevertheless, whether this inhibition is direct or not, has remained elusive. TORC1 controls metabolism and mitosis timing by integrating nutrients and environmental stress response (ESR) signalling. Nutritional or other stresses activate the Sty1-Ssp1-Ssp2 (AMP-activated protein kinase complex, AMPK) pathway, which inhibits TORC1 and accelerates mitosis through Sck2 inhibition. Additionally, activation of the ESR pathway can extend lifespan in fission yeast. Here, we demonstrate that caffeine activates Ssp1, Ssp2 and the AMPKβ regulatory subunit Amk2 to advance mitosis. Ssp2 is phosphorylated in an Ssp1-dependent manner following exposure to caffeine. Furthermore, Ssp1 and Amk2, are required for resistance to caffeine under conditions of prolonged genotoxic stress. The effects of caffeine on DNA damage sensitivity are uncoupled from mitosis in AMPK pathway mutants. We propose that caffeine interacts synergistically with other genotoxic agents to increase DNA damage sensitivity. Our findings suggest that caffeine accelerates mitotic division and is beneficial for CLS through AMPK. Direct pharmacological targeting of AMPK may serve towards health span and lifespan benefits beyond yeasts, given the highly conserved nature of this key regulatory cellular energy sensor.
Automated model discovery for human brain using Constitutive Artificial Neural Networks
Authors: Linka Kevin , Pierre Sarah St. , Kuhl Ellen 
Published: November 2022

AbstractThe brain is our softest and most vulnerable organ, and understanding its physics is a challenging but significant task. Massive efforts have been dedicated at testing the human brain, and various competing models have emerged to characterize its response to mechanical loading. However, selecting the best constitutive model remains a heuristic process that strongly depends on user experience and personal preference. Here we challenge the conventional wisdom to first select a constitutive model and then fit its parameters to experimental data. Instead, we propose a new strategy that simultaneously discovers both model and parameters that best describe the data. Towards this goal, we integrate more than a century of knowledge in thermodynamics and state-of-the-art machine learning to build a family of Constitutive Artificial Neural Networks that enable automated model discovery for human brain tissue. Our overall design paradigm is to reverse engineer a Constitutive Artificial Neural Network from a set of functional building blocks that are, by design, a generalization of widely used and commonly accepted constitutive models, including the neo Hooke, Blatz Ko, Mooney Rivlin, Demiray, Gent, and Holzapfel models. By constraining the input, output, activation functions, and architecture, our network a priori satisfies thermodynamic consistency, material objectivity, material symmetry, physical constrains, and polyconvexity. We demonstrate that our network autonomously discovers both model and parameters that best characterize the behavior of human gray and white matter under tension, compression, and shear. Importantly, our network weights translate naturally into physically meaningful material parameters, e.g., shear moduli of 1.82kPa, 0.88kPa, 0.94kPa, and 0.54kPa for the cortex, basal ganglia, corona radiata, and corpus callosum. Our results suggest that Constitutive Artificial Neural Networks have the potential to induce a paradigm shift in soft tissue modeling, from user-defined model selection to automated model discovery. Our source code, data, and examples are available athttps://github.com/LivingMatterLab/CANN.
The photosystem I supercomplex from a primordial green algaOstreococcus tauriharbors three light-harvesting complex trimers
Authors: Ishii Asako , Shan Jianyu , Sheng Xin , Kim Eunchul , Watanabe Akimasa , Yokono Makio , Noda Chiyo , Song Chihong , Murata Kazuyoshi , Liu Zhenfeng , Minagawa Jun 
Published: November 2022

AbstractAs a ubiquitous picophytoplankton in the ocean and an early-branching green alga,Ostreococcus tauriis a model prasinophyte species for studying the functional evolution of the light-harvesting systems in photosynthesis. Here, we report the structure and function of theO. tauriphotosystem I (PSI) supercomplex in the low light, where it expands its photon-absorbing capacity by assembling with the light-harvesting complexes I (LHCI) and a prasinophyte-specific light-harvesting complex (Lhcp). Its architecture exhibits hybrid features of the plant-type and the green algal-type PSI supercomplexes, consisting of a PSI core, a Lhca1-Lhca4-Lhca2-Lhca3 belt attached on one side and a Lhca5-Lhca6 heterodimer associated on the other side between PsaG and PsaH. Interestingly, nine Lhcp subunits, including one Lhcp1 monomer with a phosphorylated amino-terminal threonine and eight Lhcp2 monomers, oligomerize into three trimers and associate with PSI on the third side between Lhca6 and PsaK. The Lhcp1 phosphorylation and the light-harvesting capacity of PSI were subjected to reversible photoacclimation, suggesting that the formation ofOtPSI–LHCI–Lhcp supercomplex is likely due to a state transition-like mechanism induced by light intensity change. Notably, this supercomplex did not exhibit far-red peaks in the 77 K fluorescence spectra, which is possibly due to weak coupling of the chlorophylla603-a609 pair inOtLhca1-4.
Subsensory stochastic electrical stimulation targeting muscle afferents alters gait control during locomotor adaptations to haptic perturbations
Authors: Severini Giacomo , Koenig Alexander , Cajigas Iahn , Lesniewski-Laas Nicholas , Niemi Jim , Bonato Paolo 
Published: November 2022

AbstractSubsensory noise stimulation targeting sensory receptors has been shown to improve balance control in healthy and impaired individuals. However, the potential for application of this technique in other contexts is still unknown. Gait control and adaptation rely heavily on the input from proprioceptive organs in the muscles and joints. Here we investigated the use of subsensory noise stimulation as a means to influence motor control by “boosting” proprioception during locomotor adaptations to forces delivered by a robot. The forces increase step length unilaterally and trigger an adaptive response that restores the original symmetry. Healthy participants performed two adaptation experiments, one with stimulation applied to the hamstring muscles and one without. We found that participants adapted faster but to a lesser extent when undergoing subsensory stimulation. We argue that this behaviour is due to the dual effect that the stimulation has on the afferents encoding position and velocity that are present in the muscle spindles.
Prediction of Transport, Deposition, and Resultant Immune Response of Nasal Spray Vaccine Droplets using a CFPD-HCD Model in a 6-Year-Old Upper Airway Geometry to Potentially Prevent COVID-19
Authors: Hayati Hamideh , Feng Yu , Chen Xiaole , Kolewe Emily , Fromen Catherine 
Published: November 2022

AbstractThis study focuses on the transport, deposition, and triggered immune response of intranasal vaccine droplets to the Angiotensin-converting enzyme 2-rich region (i.e., the olfactory region (OR)) in the nasal cavity of a 6-year-old female to possibly prevent COVID-19. To investigate how administration strategy can influence nasal vaccine efficiency, a validated multiscale model (i.e., computational fluid-particle dynamics (CFPD) and host-cell dynamics (HCD) model) was employed. Droplet deposition fraction, size change, residence time, and the area percentage of OR covered by the vaccine droplets and triggered immune system response were predicted with different spray cone angles, initial droplet velocities, and compositions. Numerical results indicate that droplet initial velocity and composition have negligible influences on the vaccine delivery efficiency to OR. In contrast, the spray cone angle can significantly impact the vaccine delivery efficiency. The triggered immunity was not significantly influenced by the administration investigated in this study, due to the low percentage of OR area covered by the droplets. To enhance the effectiveness of the intranasal vaccine to prevent COVID-19 infection, it is necessary to optimize the vaccine formulation and administration strategy so that the vaccine droplets can cover more epithelial cells in OR to minimize the available receptors for SARS-CoV-2.
Endometrial decidualization status modulates endometrial perivascular complexity and trophoblast outgrowth in gelatin hydrogels
Authors: Zambuto Samantha G. , Theriault Hannah , Jain Ishita , Crosby Cody O. , Pintescu Ioana , Chiou Noah , Zoldan Janet , Underhill Gregory H. , Clancy Kathryn B.H. , Harley Brendan A.C. 
Published: November 2022

AbstractThe endometrium undergoes rapid cycles of vascular growth, remodeling, and breakdown during the menstrual cycle and pregnancy. Decidualization is an endometrial differentiation process driven by steroidal sex hormones that is critical for blastocyst-uterine interfacing and blastocyst implantation. Certain pregnancy disorders may be linked to decidualization processes. However, much remains unknown regarding the role of decidualization and reciprocal trophoblast-endometrial interactions on endometrial angiogenesis and trophoblast invasion. Here, we report an artificial endometrial perivascular niche embedded in gelatin methacrylol hydrogels that displays morphological and functional patterns of decidualization. We show vessel complexity and soluble factor secretion are sensitive to decidualization and affect trophoblast motility. Importantly, we demonstrate the engineered perivascular niche can be combined with epithelial cultures to form a stratified endometrial model. This artificial perivascular niche provides a well-characterized platform to investigate dynamic changes in angiogenesis in response to pathological and physiological endometrial states.TeaserWe describe an endometrial vessel model to understand endometrial vasculature in the menstrual cycle and pregnancy.
Knockdown of mitochondrialatp1mRNA by a custom-designed pentatricopeptide repeat protein alters F1FoATP synthase
Authors: Yang Fei , Vincis Pereira Sanglard Lilian , Lee Chun-Pong , Ströher Elke , Singh Swati , Oh Glenda Guec Khim , Millar A. Harvey , Small Ian , Colas des Francs-Small Catherine 
Published: November 2022

ABSTRACTWe show that a custom-designed RNA-binding protein binds and specifically induces cleavage ofatp1RNA in mitochondria, significantly decreasing the abundance of the Atp1 protein and the assembled F1FoATP synthase inArabidopsis thaliana. The transformed plants are characterized by delayed vegetative growth and reduced fertility. Five-fold depletion of Atp1 level was accompanied by a decrease in abundance of other ATP synthase subunits, lowered ATP synthesis rate of isolated mitochondria, but no change to mitochondrial electron transport chain complexes, adenylates or energy chargein planta. Transcripts for amino acid transport and a variety of stress response processes were differentially expressed in lines containing the PPR protein, indicating changes to achieve cellular homeostasis when ATP synthase was highly depleted. Leaves of ATP-synthase-depleted lines showed higher respiratory rates and elevated levels of most amino acids at night, most notably serine family amino acids. The results show the value of using custom-designed PPR proteins to influence expression of specific mitochondrial transcripts to carry out reverse genetics studies on mitochondrial gene functions and the consequences of ATP synthase depletion on cellular functions inArabidopsis.One sentence SummaryKnockdown of mitochondrialatp1mRNA by a custom-designed pentatricopeptide repeat protein alters F1Fo ATP synthase, plant growth and amino acid metabolism and ATP synthesis inArabidopsis thaliana
Individual differences in volitional social motivation in male and female mice following social stress
Authors: Navarrete Jovana , Schneider Kevin N. , Smith Briana M. , Goodwin Nastacia L. , Zhang Yizhe Y. , Gross Ethan , Tsai Valerie S. , Heshmati Mitra , Golden Sam A. 
Published: November 2022

AbstractBackgroundA key challenge in developing new treatments for neuropsychiatric illness is the disconnect between preclinical models and the complexity of human social behavior. We aimed to integrate voluntary social self-administration into a preclinical rodent stress model, as a platform for the identification of basic brain and behavior mechanisms underlying stress-induced individual differences in social motivation. Here, we introduce an operant social stress (OSS) procedure with male and female mice, where lever presses are reinforced by freely moving social interaction with a familiar social partner across social stress exposure.MethodsOSS is composed of three phases: (i) social self-administration training, (ii) social stress concurrent with daily reinforced social self-administration testing, and (iii) post-stress operant social reward testing under both non-reinforced and reinforced conditions. We resolve social stress-induced changes to social motivation behaviors using hierarchical clustering and aggregated z-scores, capturing the spectrum of individual differences that we describe with a social index score.ResultsOSS captures a range of stress-related dynamic social motivation behaviors inclusive of sex as a biological variable. Both male and female mice lever press for access to a social partner, independent of social partner coat color or familiarity. Social stress attenuates social self-administration in males and promotes social reward seeking behavior in females. Hierarchical clustering does not adequately describe the relative distributions of social motivation following stress, which we find is better described as a non-binary behavioral distribution that we define by introducing the social index score. This index is stable across individual mice.ConclusionWe demonstrate that OSS can be used to detect stable individual differences in stress-induced changes to social motivation in male and female mice. These differences may reflect unique neurobiological, cellular and circuit mechanisms not captured by preclinical models that omit voluntary social behaviors. The inclusion of volitional social procedures may enhance the understanding of behavioral adaptations promoting stress resiliency and their mechanisms under more naturalistic conditions.
GABAergic neuron-to-glioma synapses in diffuse midline gliomas
Authors: Barron Tara , Yalçın Belgin , Mochizuki Aaron , Cantor Evan , Shamardani Kiarash , Tlais Dana , Franson Andrea , Lyons Samantha , Mehta Vilina , Jahan Samin Maleki , Taylor Kathryn R. , Keough Michael B. , Xu Haojun , Su Minhui , Quezada Michael A. , Woo Pamelyn J , Fisher Paul G. , Campen Cynthia J. , Partap Sonia , Koschmann Carl , Monje Michelle 
Published: November 2022

AbstractPediatric high-grade gliomas are the leading cause of brain cancer-related death in children. High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling1,2and direct neuron-to-glioma synapses3–5. Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric3and adult high-grade gliomas4, but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology,in vivooptogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAAreceptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation3, we find that the activity of GABAergic interneurons promotes DMG proliferationin vivo. Increasing GABA signaling with the benzodiazepine lorazepam – a positive allosteric modulator of GABAAreceptors commonly administered to children with DMG for nausea or anxiety - increases GABAAreceptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAAreceptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and diffuse midline glioma cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context.
Flap-enabled next-generation capture (FENGC): precision targeted single-molecule profiling of epigenetic heterogeneity, chromatin dynamics, and genetic variation
Authors: Zhou Mingqi , Nabilsi Nancy H. , Wang Anqi , Gauthier Marie-Pierre L. , Murray Kevin O. , Azari Hassan , Owens William S. , Newman Jeremy R. B. , Pardo-Palacios Francisco J. , Conesa Ana , Riva Alberto , Clanton Thomas L. , Reynolds Brent A. , Concannon Patrick , Brant Jason O. , Bacher Rhonda , Kladde Michael P. 
Published: November 2022

AbstractTargeted sequencing is an increasingly sought technology. Available methods, however, are often costly and yield high proportions of off-target reads. Here, we present FENGC, a scalable, multiplexed method in which target sequences are assembled into 5′ flaps for precise excision by flap endonuclease. Recovery of length-matched sequences, amplification with universal primers, and exonucleolytic removal of non-targeted genomic regions mitigate amplification biases and consistently yield ≥ 80% on-target sequencing. Furthermore, optimized sequential reagent addition and purifications minimize sample loss and facilitate rapid processing of sub-microgram quantities of DNA for detection of genetic variants and DNA methylation. Treatment of cultured human glioblastoma cells and primary murine monocytes with GC methyltransferase followed by FENGC and high-coverage enzymatic methyl sequencing provides single-molecule, long-read detection of differential endogenous CG methylation, dynamic nucleosome repositioning, and transcription factor binding. FENGC provides a versatile and cost-effective platform for targeted sequence enrichment for analysis of genetic and/or epigenetic heterogeneity.
Reliable and accurate gene expression quantification with subpopulation structure-aware constraints for single-cell RNA sequencing
Authors: Tu Ching-Chih , Hung Jui-Hung 
Published: November 2022

AbstractBackgroundSingle-cell RNA sequencing (scRNA-seq) analysis analyzes the type and state of individual cells by estimating the gene expression of each cell and enables researchers to study the biological phenomena that cannot be observed in bulk RNA sequencing.MotivationHowever, the current scRNA-seq quantification tools estimate the gene expression profile of each cell independently, ignoring the fact that there are multiple cell types in the scRNA-seq data and the expression level should be highly correlated with the cell type. Since scRNA-seq suffers from a low sequencing depth, the conventional strategy leads to a high proportion of missing values in the gene expression profile, obscuring the biological characteristics of cell subpopulations and further impacting the correctness of the subsequent downstream analysis.ResultsIn this study, we proposed Quasic, a novel scRNA-seq quantification pipeline which examines the potential cell subpopulation information during quantification, and uses the information to calculate the gene expression level. Using the human peripheral blood mononuclear cells and the simulated doublet dataset, we verified that Quasic not only correctly reinforced the cell signatures, but also identified the corresponding cell subpopulations and biological pathways more accurately. In addition, we also applied Quasic to the breast cancer cell line dataset (MCF-7), and successfully identified more potentially therapeutic resistant cells of which characteristics are consistent with that from previous studies.ConclusionsThe proposed pipeline can let the gene expression profile of each cell be more consistent with the corresponding subpopulation, making the biological features unique to the subpopulation more apparent and convenient for analysis. By using Quasic, researchers can effectively extract the desired cell subpopulation information from their sampled cells, enable them to perform cell subpopulation-related studies more accurately.