bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA-mediated Allosteric Activation in CRISPR-Cas13a
Authors: Sinha Souvik , Molina Vargas Adrian M. , Arantes Pablo R. , Patel Amun , O’Connell Mitchell R. , Palermo Giulia 
Published: July 2023

ABSTRACTCas13a is a recent addition to the CRISPR-Cas toolkit that exclusively targets RNA, which makes it a promising tool for RNA detection. The protein uses a CRISPR RNA (crRNA) to target RNA sequences, which are cleaved by a composite active site formed by two ‘Higher Eukaryotes and Prokaryotes Nucleotide’ (HEPN) catalytic domains. In this system, an intriguing form of allosteric communication controls RNA cleavage activity, yet its molecular details are unknown. Here, multiple-microsecond molecular dynamics simulations are combined with graph theory and RNA cleavage assays to decipher this activation mechanism. We show that the binding of a target RNA acts as an allosteric effector of the spatially distant HEPN catalytic cleft, by amplifying the allosteric signals over the dynamical noise, that passes through the buried HEPN interface. Critical residues in this region – N378, R973, and R377 – rearrange their interactions upon target RNA binding, and alter allosteric signalling. Alanine mutation of these residues is experimentally shown to select target RNA over an extended complementary sequence beyond guide-target duplex, for RNA cleavage. Altogether, our findings offer a fundamental understanding of the Cas13a mechanism of action and pave new avenues for the development of more selective RNA-based cleavage and detection tools.
PROTECTIVE EFFECTS OF TRITERPENOID BETULIN ON TYPE 2 DIABETES MELLITUS IN RATS
Authors: Shlyahtun A. H. , Maksimchik Yu. Z. , Zakrzeska A. , Sutsko I. P. , Raduta A. F. , Buksha E. V. , Bogdevich E. V. , Kitlas P. , Tomulewicz M. 
Published: July 2023

AbstractType 2 diabetes mellitus (T2DM) is a complex chronic metabolic disease characterized by long-term hyperglycemia, which is, in turn, resulted from the impaired insulin signaling caused by a combination of insulin resistance or inadequate insulin production. Prevalence and incidence of T2DM are increasing dramatically across the world, and it is accompanied with severe complications and premature mortality of patients with diabetes. Given the fact that synthetic drugs have disadvantages in view of the side effects, the implementation of naturally occurring compounds for diabetes treatment may be a promising alternative. Betulin is a naturally occurring triterpenoid which has been shown to possess the ability of altering body lipids and exert hypoglycemic and hepatoprotective effects. It is suggested that the application of betulin in T2DM may have a favorable effect to ease the severity of diabetic complications. Thus, the aim of the present study was to assess biological effects of betulin in T2DM conditions.Diabetes-induced rats were administered with two different doses of betulin for 28 consecutive days. It was shown that long-term administration of betulin at the doses of 50 and 100 mg/kg/day to the rats prevented diabetes-associated changes in a body weight of the animals, significantly reversed insulin resistance and abolished the impairment of glucose metabolism. It was accompanied with the dose-dependent normalization of serum lipid contents. Histopathological changes and structural abnormalities in the liver of diabetics were restored by the administration of betulin. Also, betulin was able to restrain systemic inflammation detected in diabetic animals according to the altered levels of serum TNFα. Thus, the results obtained in the current study were found to be in agreement with earlier findings on beneficial effects of betulin in conditions pathogenetically close to T2DM. We hypothesized that the ability of betulin to restrain systemic inflammation and to normalize the lipid metabolism can explain improved insulin resistance and glycemic control and it can provide a possible mechanism for the beneficial antidiabetic effects of betulin.
Pupil-size sensitivity to listening demand depends on motivational state
Authors: Kraus Frauke , Obleser Jonas , Herrmann Björn 
Published: July 2023

AbstractMotivation plays a role when a listener needs to understand speech under acoustically demanding conditions. Previous work has demonstrated pupil-linked arousal being sensitive to both listening demands and motivational state during listening. It is less clear how motivational state affects the temporal evolution of the pupil size and its relation to subsequent behavior. We used an auditory gap-detection task (N=33) to study the joint impact of listening demand and motivational state on the pupil-size response and examine its temporal evolution. Task difficulty and a listener’s motivational state were orthogonally manipulated through changes in gap duration and monetary-reward prospect. We show that participants’ performance decreased with task difficulty, but that reward prospect enhanced performance under hard listening conditions. Pupil size increased with both increased task difficulty and higher reward prospect, and this reward-prospect effect was largest under difficult listening conditions. Moreover, pupil-size time courses differed between detected and missed gaps, suggesting that the pupil response indicates upcoming behavior. Larger pre-gap pupil size was further associated with faster response times on a trial-by-trial within-participant level. Our results reiterate the utility of pupil size as an objective and temporally sensitive measure in audiology. However, such assessments of cognitive-resource recruitment need to consider the individual’s motivational state.Significance statementThe literature is inconclusive to what degree pupil size may be representing the interaction of listening task demand and an individual’s motivational state. Using an auditory gap-detection task, we manipulated both the degree of listening demand and a person’s motivational state, and investigated the temporal evolution of the pupil-size response and its relation to behavior. We find that the pupil size represents the interaction of demand and motivational state. These results highlight the importance of considering a person’s motivational state when using pupil size as a clinical measure. Pupil size appears as a key tool when assessing the impact of motivational state on the recruiting of cognitive resources.
Functional and Structural Characterization of an IclR Family Transcription Factor for the Development of Dicarboxylic Acid Biosensors
Authors: Pham Chester , Nasr Mohamed , Skarina Tatiana , Leo Rosa Di , Kwan David H. , Martin Vincent J.J. , Stogios Peter J. , Mahadevan Radhakrishnan , Savchenko Alexei 
Published: July 2023

AbstractProkaryotic transcription factors (TFs) regulate gene expression in response to small molecules, thus representing promising candidates as versatile small molecule-detecting biosensors valuable for synthetic biology applications. The engineering of such biosensors requires thoroughin vitroandin vivocharacterization of TF ligand response as well as detailed molecular structure information. In this work we characterize the PcaR TF belonging to the IclR family. We presentin vitrofunctional analysis of PcaR’s ligand profile and construction of genetic circuits for the characterization of PcaR as anin vivobiosensor in the model eukaryoteSaccharomyces cerevisiae. We report the crystal structures of PcaR in theapostate and in complex with one of its ligands, succinate, which suggests the mechanism of dicarboxylic acid recognition by this TF. This work provides key structural and functional insights enabling the engineering of PcaR for dicarboxylic acid biosensors.Graphical AbstractHighlightsPcaR is an IclR family transcription regulator responsive to dicarboxylic acidsPcaR was established as anin vivobiosensor in yeastCrystal structure of PcaR in theapoform was solvedCrystal structure with PcaR in complex with succinate was solvedSequence alignments unveil ligand-binding positions in the IclR family
Mechano-induced homotypic patterned domain formation by monocytes
Authors: Du Wenxuan , Zhu Jingyi , Wu Yufei , Kiemen Ashley L. , Sun Sean X. , Wirtz Denis 
Published: July 2023

AbstractMatrix stiffness and corresponding mechano-signaling play indispensable roles in cellular phenotypes and functions. How tissue stiffness influences the behavior of monocytes, a major circulating leukocyte of the innate system, and how it may promote the emergence of collective cell behavior is less understood. Here, using tunable collagen-coated hydrogels of physiological stiffness, we show that human primary monocytes undergo a dynamic local phase separation to form highly patterned multicellular multi-layered domains on soft matrix. Local activation of the β2 integrin initiates inter-cellular adhesion, while global soluble inhibitory factors maintain the steady-state domain pattern over days. Patterned domain formation generated by monocytes is unique among other key immune cells, including macrophages, B cells, T cells, and NK cells. While inhibiting their phagocytic capability, domain formation promotes monocytes’ survival. We develop a computational model based on the Cahn-Hilliard equation, which includes combined local activation and global inhibition mechanisms of intercellular adhesion suggested by our experiments, and provides experimentally validated predictions of the role of seeding density and both chemotactic and random cell migration on pattern formation.
Kremen1 regulates the regenerative capacity of support cells and mechanosensory hair cells in the zebrafish lateral line
Authors: Megerson Ellen , Kuehn Michael , Leifer Ben , Bell Jon , McGraw Hillary F. 
Published: July 2023

SummaryMechanosensory hair cells in the inner ear mediate the sensations of hearing and balance, and in a specialize lateral line sensory system of aquatic vertebrates, the sensation of water movement. In mammals, hair cells lack the ability of regenerate following damage, resulting in sensory deficits. In contrast, non-mammalian vertebrates, such zebrafish, can renew hair cells throughout the life of the animal. Wnt signaling is required for development of inner ear and lateral line hair cells and regulates regeneration. Kremen1 inhibits Wnt signaling and hair cell formation, though its role in regeneration has not been established. We use a zebrafishkremen1mutant line, to show that when Wnt signaling is overactivated in the lateral line, excessive regeneration occurs in the absence of increased proliferation, due to an increase in support cells. This contrasts with the previously described role of Wnt signaling during hair cell regeneration. This work will allow us to understand the biology of mechanosensory hair cells, and how regeneration might be promoted following damage.
Inducing a meditative state by artificial perturbations: A causal mechanistic understanding of brain dynamics underlying meditation
Authors: Dagnino Paulina Clara , Galadí Javier A. , Càmara Estela , Deco Gustavo , Escrichs Anira 
Published: July 2023

AbstractContemplative neuroscience has increasingly explored meditation using neuroimaging. However, the brain mechanisms underlying meditation remain elusive. Here, we implemented a causal mechanistic framework to explore the spatiotemporal dynamics of expert meditators during meditation and rest. We first applied a model-free approach by defining a probabilistic metastable substate (PMS) space for each state, consisting of different probabilities of occurrence from a repertoire of dynamic patterns. Different brain signatures were mainly found in the triple-network model (i.e., the executive control, salience, and default-mode networks). Moreover, we implemented a model-based approach by adjusting the PMS of the resting state to a whole-brain model, which enabled us to explorein silicoperturbations to transition to the meditation state. Consequently, we assessed the sensitivity of different brain areas regarding their perturbability and their mechanistic local-global effects. Using a synchronous protocol, we successfully transitioned from the resting state to the meditative state by shifting areas mainly from the somatomotor and dorsal attention networks. Overall, our work reveals distinct whole-brain dynamics in meditation compared to rest, and how the meditation state can be induced with localized artificial perturbations. It motivates future work regarding meditation as a practice in health and as a potential therapy for brain disorders.
A single-cell transcriptomic atlas reveals resident dendritic-like cells in the zebrafish brain parenchyma
Authors: Rovira Mireia , Ferrero Giuliano , Miserocchi Magali , Montanari Alice , Wittamer Valérie 
Published: July 2023

ABSTRACTRecent studies have highlighted the heterogeneity of the immune cell compartment within the steady-state murine and human CNS. However it is not known whether this diversity is conserved among non mammalian vertebrates, especially in the zebrafish, a model system with increasing translational value. Here, we reveal the complexity of the immune landscape of the adult zebrafish brain. Using single-cell transcriptomics, we characterized these different immune cell subpopulations, including cell types that have not been -or have been poorly-characterized in zebrafish so far. By histology, we found that, despite microglia being the main immune cell type in the parenchyma, the zebrafish brain is also populated by a distinct myeloid population that shares a gene signature with mammalian dendritic cells (DC). Notably, zebrafish DC-like cells rely onbatf3, a gene essential for the development of conventional DC1 in the mouse. Using specific fluorescent reporter lines that allowed us to reliably discriminate DC-like cells from microglia, we quantified brain myeloid cell defects in commonly usedirf8-/-,csf1ra-/-andcsf1rb-/-mutant fish, revealing previously unappreciated distinct microglia and DC-like phenotypes. Overall, our results suggest a conserved heterogeneity of brain immune cells across vertebrate evolution and also highlights zebrafish-specific brain immunity characteristics.
ChromaFold predicts the 3D contact map from single-cell chromatin accessibility
Authors: Gao Vianne R. , Yang Rui , Das Arnav , Luo Renhe , Luo Hanzhi , McNally Dylan R. , Karagiannidis Ioannis , Rivas Martin A. , Wang Zhong-Min , Barisic Darko , Karbalayghareh Alireza , Wong Wilfred , Zhan Yingqian A. , Chin Christopher R. , Noble William , Bilmes Jeff A. , Apostolou Effie , Kharas Michael G. , Béguelin Wendy , Viny Aaron D. , Huangfu Danwei , Rudensky Alexander Y. , Melnick Ari M. , Leslie Christina S. 
Published: July 2023

AbstractThe identification of cell-type-specific 3D chromatin interactions between regulatory elements can help to decipher gene regulation and to interpret the function of disease-associated non-coding variants. However, current chromosome conformation capture (3C) technologies are unable to resolve interactions at this resolution when only small numbers of cells are available as input. We therefore present ChromaFold, a deep learning model that predicts 3D contact maps and regulatory interactions from single-cell ATAC sequencing (scATAC-seq) data alone. ChromaFold uses pseudobulk chromatin accessibility, co-accessibility profiles across metacells, and predicted CTCF motif tracks as input features and employs a lightweight architecture to enable training on standard GPUs. Once trained on paired scATAC-seq and Hi-C data in human cell lines and tissues, ChromaFold can accurately predict both the 3D contact map and peak-level interactions across diverse human and mouse test cell types. In benchmarking against a recent deep learning method that uses bulk ATAC-seq, DNA sequence, and CTCF ChIP-seq to make cell-type-specific predictions, ChromaFold yields superior prediction performance when including CTCF ChIP-seq data as an input and comparable performance without. Finally, fine-tuning ChromaFold on paired scATAC-seq and Hi-C in a complex tissue enables deconvolution of chromatin interactions across cell subpopulations. ChromaFold thus achieves state-of-the-art prediction of 3D contact maps and regulatory interactions using scATAC-seq alone as input data, enabling accurate inference of cell-type-specific interactions in settings where 3C-based assays are infeasible.
Motor learning- and consolidation-related resting state fast and slow brain dynamics across wake and sleep
Authors: Roshchupkina Liliia , Wens Vincent , Coquelet Nicolas , Urbain Charline , de Tiege Xavier , Peigneux Philippe 
Published: July 2023

AbstractLearning and consolidation of motor skills dynamically evolve both online during practice and offline after training. We investigated, using magnetoencephalography, the neural dynamics underpinning motor learning and its consolidation in relation to sleep during resting-state periods shortly after the end of learning (short-term boost window, within 30 min) and at more delayed time scales (silent 4h and next day 24h windows) with an intermediate nap or wakefulness after the boost window. Resting-state neural dynamics in brain networks were investigated at fast (sub-second) and slower (supra-second) timescales using Hidden Markov modelling (HMM) and resting-state functional connectivity (rsFC), respectively, as well as their relationship with the evolution of motor performance. HMM results show that fast dynamic activities in a Temporal/Sensorimotor state network predict individual motor performance achievements, suggesting a trait-like association between rapidly recurrent neural patterns and motor behaviour. Short, post-training re-exposure to the task modulated fast and slow network characteristics during the boost but not in the silent window. These short practice-related induction effects were observed again on the next day, to a reduced extent as compared to the boost window. Daytime naps did not significantly modulate memory consolidation both at behavioural and neural levels. These results emphasise the critical role of the transient boost window in motor learning and subsequent memory consolidation processes and provide further insights into the relationship between the multiscale neural dynamics of brain networks, motor learning, and consolidation.
Genetic context drives age-related disparities in synaptic maintenance and structure across cortical and hippocampal neuronal circuits
Authors: Heuer Sarah E. , Nickerson Emily W. , Howell Gareth R. , Bloss Erik B. 
Published: July 2023

ABSTRACTThe disconnection of neuronal circuits through synaptic loss is presumed to be a major driver of age-related cognitive decline. Age-related cognitive decline is heterogeneous, yet whether genetic mechanisms differentiate successful from unsuccessful cognitive decline through synaptic structural mechanisms remains unknown. Previous work using rodent and primate models leveraged various techniques to suggest that age-related synaptic loss is widespread on pyramidal cells in prefrontal cortex (PFC) circuits but absent on those in area CA1 of the hippocampus. Here, we examined the effect of aging on synapses on projection neurons forming a hippocampal-cortico-thalamic circuit important for spatial working memory tasks from two genetically distinct mouse strains that exhibit susceptibility (C57BL/6J) or resistance (PWK/PhJ) to cognitive decline during aging. Across both strains, synapses on the CA1-to-PFC projection neurons appeared completely intact with age. In contrast, we found synapse loss on PFC-to-nucleus reuniens (RE) projection neurons from aged C57BL/6J but not PWK/PhJ mice. Moreover, synapses from aged PWK/PhJ mice but not from C57BL/6J exhibited morphological changes that suggest increased synaptic efficiency to depolarize the parent dendrite. Our findings suggest resistance to age-related cognitive decline results in part by age-related synaptic adaptations, and identification of these mechanisms in PWK/PhJ mice could uncover new therapeutic targets for promoting successful cognitive aging and extending human health span.
Metabolic Nutrient Preferences ofVibrio mimicus: Leveraging Nucleotides and Oligopeptides from Yellow Catfish for Enhanced Infectivity
Authors: Feng Yang , Wang Jiao , Fan Wei , Geng Yi , Huang Xiaoli , Ouyang Ping , Chen Defang , Guo Hongrui , Deng Huidan , Lai Weimin , Zuo Zhicai , Zhong Zhijun 
Published: July 2023

AbstractIn the context of host-microbe interactions, the microenvironment plays a critical role in facilitating microbial survival, and variations in these microenvironments may influence the pathogenicity of microorganisms.Vibrio mimicus, a major pathogen responsible for infections in aquatic animals, poses a substantial threat to yellow catfish (Pelteobagrus fulvidraco) and grass carp (Ctenopharyngodon idella), two naturally occurring hosts displaying markedly different susceptibility levels. This study aims to unravel the underlying mechanisms behind this susceptibility discrepancy in the two teleost species. Employing metabolomic analysis, we identified a distinctive microenvironment in yellow catfish, characterized by abundant purine nucleotides and oligopeptides. Furthermore, a total of 67 specific metabolites were identified from both yellow catfish and grass carp, with 33 displaying heightened expression on the body surface of yellow catfish, including nucleotides, amino acids, and gangliosides, while 34 were predominantly expressed on the body surface of grass carp, primarily comprising lipids. Subsequent investigations revealed that certain compounds related to nucleotides and oligopeptides exhibited significant growth-promoting effects and were utilized byV. mimicusas nutrients, with deoxyguanosine proving to be notably more than twice as effective as glucose. Moreover, duringV. mimicusinfection, numerous metabolites such as oligopeptides, purine nucleotides, and specific metabolites experienced considerable depletion in the skin of yellow catfish. Concurrently, several genes associated with nucleosidase and peptidase were upregulated in the skin and muscles of infected fish. These findings suggest that the microenvironment provided by different hosts plays a pivotal role in determining the infectivity of the pathogen. Additionally, our results indicate that the microenvironment on the surface of yellow catfish, characterized by an abundance of purine nucleotides and oligopeptides, indirectly enhancesV. mimicusgrowth, ultimately augmenting its infectivity.
Mechanosensitive ion channel MSL8 is required for pulsatile growth and cell wall dynamics inArabidopsispollen tubes
Authors: Coomey Joshua H. , Haswell Elizabeth S. 
Published: July 2023

ABSTRACTHIGHLIGHTPollen tube growth requires tight control of apical wall expansion. We present evidence for a mechanosensitive ion channel, MSL8, as a braking signal in growth dynamics through cell wall regulation.The male gametophyte in flowering plants, pollen, both performs the critical role of fertilization and represents a unique and accessible system for interrogating plant cell mechanics. Pollen endures multiple mechanical hurdles during its lifecycle: desiccation in the anther, rapid rehydration on the stigma, and germination to produce a rapidly growing pollen tube that will eventually reach the ovule. A key component in this robust mechanical system is MscS-Like 8 (MSL8), a mechanosensitive ion channel. We previously proposed that that MSL8 serves as an “osmotic safety valve”, regulating pressure in the germinating pollen tube by releasing anions in response to plasma membrane tension, thereby preventing pollen tube rupture. However, we subsequently identified defects in the cell walls ofmsl8mutant pollen, suggesting that it plays a role independent of osmoregulation, a conclusion also supported by mathematical modeling. Here, we show that pollen tubes lacking MSL8 channel function by genetic knockout or channel-blocking point mutation lose major growth pauses, have altered pectin esterification patterns, and are sensitive to pectin crosslinking. Together, these data suggest a mechanism whereby tension-gated ion release through mechanosensitive channels regulates apoplastic function and cell wall dynamics.